Familial Adenomatous Polyposis—Risk of Cancer, Cancer Prevention, and Long‐Term Consequences: Learnings from Five Decades with the Danish Polyposis Register

ABSTRACT

Familial adenomatous polyposis (FAP) is a hereditary condition marked by the growth of hundreds to thousands of adenomatous polyps in the colon and rectum, significantly elevating the risk of colorectal cancer (CRC) if left untreated. Caused by pathogenic variants in the APC gene, FAP is typically identified in adolescence, often leading to the recommendation of prophylactic colectomy to reduce the risk of CRC. However, even with colectomy, FAP patients face higher risks for other cancers, notably in the duodenum and pancreas. Our studies emphasize the importance of lifelong endoscopic surveillance and tailored treatment strategies to detect and manage precancerous lesions in the gastrointestinal tract. Advances in genetic screening have also significantly improved early detection and family risk management, especially for at‐risk relatives. The Danish Polyposis Register, for example, is a comprehensive, nationwide database enabling tracking and preventative care for FAP families, effectively prolonging life expectancy by facilitating early intervention and surveillance of cancer risks. Endoscopic evaluation may differentiate between classical FAP and attenuated FAP (AFAP), a milder form with fewer polyps and a delayed onset, although both types require consistent monitoring due to elevated cancer risks. Innovations in genetic research, including the use of whole‐genome sequencing, continue to refine risk assessments, helping to prevent unnecessary surgical interventions while providing personalized management plans for each patient. The disease's impact extends beyond physical health; the hereditary nature of FAP leads to psychological stress, often resulting in higher anxiety, depression, and educational challenges among patients. Adolescents and young adults, in particular, might benefit from targeted psychological support and educational interventions to help manage the mental and social implications of living with a chronic, cancer‐prone condition. Studies underscore the need for interdisciplinary care to support these aspects of patients' lives, as they face unique challenges not experienced by other populations. Overall, research suggests that FAP treatment must integrate comprehensive cancer surveillance, proactive genetic screening, mental health support, and tailored medical interventions. The success of multidisciplinary, national registers like Denmark's emphasizes the importance of such models worldwide and should encourage the development of similar programs to improve patient outcomes and support those at high risk for hereditary cancers.

1. Preface

When I began my surgical fellowship, my knowledge of familial adenomatous polyposis (FAP) was limited. However, I was aware that the Danish Polyposis Register was based at Hvidovre and led by Steffen Bülow, a distinguished researcher whose work was frequently published in the leading journals. To be honest, I found him quite intimidating. After completing my PhD in 2016, I delved into his research and asked Niels Jespersen about who might be continuing Bülow's work. Niels then introduced me to Steffen, which was the beginning of our collaborative research journey. From the start, it was clear that we shared the same uncompromising approach to scientific writing. Over time, a strong friendship developed, with us often meeting in Gentofte for lunch, a beer, or simply a cup of coffee. I have rarely felt such a deep connection form with someone in such a short period. I miss Steffen dearly and hope that this thesis and my ongoing clinical and scientific work will honor his legacy by improving the lives of FAP patients.

I am deeply grateful to HC Pommergaard and Johan Burisch, two of the most talented gastroenterological researchers in Europe, for their invaluable support with the papers comprising this thesis. Their feedback has significantly enhanced the impact of my work, and I cherish the friendships we have built. I would also like to thank Helle Højen, my dedicated secretary, who keeps everything organized in the Polyposis Register and in my professional life. Niels Jespersen and Palle Nordblad Schmidt have taught me numerous clinical and endoscopic techniques for treating FAP patients, and I look forward to passing this knowledge on to the next generation of FAP endoscopists.

My sincere thanks go to my department heads, Inge Marie Poulsen and Inge Nordgaard Lassen, for providing the space and encouragement needed for my research. I am also grateful to Professor Flemming Bendtsen, who has been an academic mentor, offering invaluable advice during challenging moments over the past decade. Anne Marie Jelsig has worked with the genetic aspects of FAP and other polyposis syndromes for 15 years, and together we have published numerous papers, including two in Gastroenterology in the past 5 years. I admire your dedication, Anne Marie, and sincerely hope that our collaboration will continue for many more years to come.

I also extend my gratitude to Professor Thomas van Overeem Hansen, Senior Researcher Tine Plato Kuhlmann, Associate Professor Srdan Novovic, and internationally recognized experts Professors Evelien Dekker, Monique van Leerdam, Francesc Belaguer, Maria Pelisse, and Andy Latchford for their collaborations. Finally, I want to thank Laus Wullum and Klaus Kaae Andersen from Omicron for their statistical support.

To my wife, Helena, thank you for your unwavering support despite the frequent travel and late nights that my work demands. I love you, and I am grateful for your patience and understanding. Lastly, to my three sons, thank you for reminding me of what truly matters in life—and it isn't the Premier League. I dedicate this thesis entirely to Karl, JB, and Johan.

John Gásdal Karstensen, November 2024.

2. List of Papers

The dissertation is based on the following scientific publications:

1. Karstensen JG, Burisch J, Pommergaard HC, Aalling L, Højen H, Jespersen N, Schmidt PN, Bülow S. Colorectal Cancer in Individuals with Familial Adenomatous Polyposis, Based on Analysis of the Danish Polyposis Registry. Clin Gastroenterol Hepatol. 2019 Oct;17 (11):2294–2300.e1 [1].

2. Karstensen JG, Bülow S, Burisch J, Ellebæk MB, Ostapiuk MA, Pommergaard HC, Schmidt PN. Validation of the endoscopic part of the Spigelman classification for evaluating duodenal adenomatosis in familial adenomatous polyposis—a prospective study of inter‐ and intra‐rater reliability. Am J Gastroenterol. 2022 Feb 1;117:343–345 [2].

3. Karstensen JG, Bülow S, Højen H, Jelsig AM, Jespersen N, Andersen KK, Wewer, Burisch J, Pommergaard HC. Cancer in patients with familial adenomatous polyposis—a nationwide Danish cohort study with matched controls. Gastroenterology. 2023 Sep;165:573–581 [3].

4. Karstensen JG, Wullum L, Andersen KK, Beck SH, Bülow S, Højen H, Jelsig AM, Jespersen N, Wewer MD, Pommergaard HC, Burisch J. Psychiatric and educational aspects of familial adenomatous polyposis—a nationwide Danish cohort study with matched controls. Am J Gastroenterol. 2024 May 1;119 (5):957–964 [4].

5. Karstensen JG, Hansen TVO, Burisch J, Djursby M, Højen H, Madsen MB, Jespersen N, Jelsig AM. Re‐evaluating genotypes of patients with adenomatous polyposis of unknown etiology: a nationwide study. Eur J Hum Genet. 2024 May;32 (5):588–592 [5].

6. Karstensen JG, Wewer MD, Bülow S, Hansen TVO, Højen H, Jelsig AM, Kuhlmann TP, Burisch J, Pommergaard HC. Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections—a nationwide Danish cohort study with long‐term follow‐up. Fam Cancer. 2024 Nov;23 (4):607–615 [6].

7. Beck SH*, Karstensen JG*, Bülow S, Andersen KK, Hansen TVO, Højen H, Jespersen N, Kuhlmann TP, Pommergaard HC, Wewer MD, Wullum L, Jelsig AM, Burisch J. Cancer risks in attenuated and classical familial adenomatous polyposis: a nationwide cohort study with matched, non‐exposed individuals. Am J Gastroenterol 2024 Oct 30 (online ahead of print) [7].

*Contributed equally and share first authorship.

3. Abbreviations

AFAP: attenuated familial adenomatous polyposis

APC: adenomatous polyposis coli.

ASGE: American Society of Gastrointestinal Endoscopy.

CFAP: classical familial adenomatous polyposis

CI: confidence interval

CMMR‐D: constitutional mismatch repair deficiency

CRC: colorectal cancer

DFMO: difluoromethylornithine

EMR: endoscopic mucosal resection

EPA: eicosapentaenoic acid

ETBF: enterotoxigenic Bacteroides fragilis

FAP: familial adenomatous polyposis

GAPPS: gastric adenocarcinoma and proximal polyposis of the stomach

HNPCC: hereditary nonpolyposis colorectal cancer

HR: hazard ratio.

IAP: ileoanal J‐pouch

IRA: ileorectal anastomosis

IRR: incidence rate ratio

MAP: MUTYH‐associated polyposis

SD: standard deviation

UC: ulcerative colitis

4. Compressed Account of the Dissertation

4.1. Introduction

Familial adenomatous polyposis (FAP) is a hereditary condition that has been known for over 50 years, and there have been significant advances in both our genetic and clinical understanding of it during this time. The disorder was first described in detail in the early twentieth century by the initial recognition of a unique pattern of familial occurrence of colorectal polyps and cancers [8, 9].

Central to the pathology of FAP is the adenomatous polyposis coli (APC) gene, located on chromosome 5q21‐q22 [10]. Germline pathogenic variants in this gene trigger the formation of numerous adenomatous polyps in the colon and rectum [11]. These polyps, if unaddressed, can turn malignant, resulting in colorectal cancer (CRC), often by the time an individual reaches their early 40s [1]. Given the precancerous nature of these polyps, FAP has been the focus of extensive clinical investigation, especially since CRC ranks globally among the leading causes of cancer‐related deaths [12].

Historically, the primary clinical intervention for FAP was proctocolectomy—the removal of the entire colon and rectum. This invasive procedure aimed to reduce the imminent threat of CRC. However, the evolution of surgical techniques, supported by a deeper understanding of the disease, has led to more refined surgical options like colectomy with ileoanal anastomosis (IRA). This procedure preserves the rectum, thereby offering a better postsurgical quality of life for patients [13, 14]. Yet, surgical intervention is only one component of the comprehensive care plan. Regular postoperative endoscopic surveillance is imperative to ensure the early detection of any new or recurring polyps [15, 16, 17]. In addition to the colorectal implications of FAP, studies have indicated an increased risk of other malignancies, such as duodenal, thyroid, and pancreatic cancers [3, 18, 19, 20]. This broader oncological risk profile necessitates a multifaceted surveillance approach.

The extensive genetic knowledge of FAP has made predictive genetic testing possible. Identifying at‐risk family members before the onset of symptoms, through targeted genetic tests, offers a proactive approach that allows for early interventions and management strategies. Such advances underscore the convergence of genetics and clinical care, redefining the trajectory for those predisposed to FAP [21]. Additionally, genetic testing of at‐risk family members means that FAP can reliably be ruled out of half of at‐risk individuals, sparing them an endoscopic examination.

For evaluating the progress of clinical and genetic insights into FAP, the Danish Polyposis Register has emerged as an invaluable asset. For half a century, this register has meticulously registered and followed cases of FAP, providing a wealth of data that ranges from genetic variations to histopathologic outcomes and therapeutic results. These data facilitate research that is unbiased and comprehensive. For clinicians on the ground, it offers important insights that directly influence patient care. The genetic origins and profound clinical implications of FAP represent both a challenge and an opportunity for advancing our understanding of CRC. The condition requires continuous research, persistent clinical vigilance, and a commitment to multifaceted patient care.

4.2. Familial Adenomatous Polyposis

4.2.1. Definitions

At its core, FAP is an autosomal dominant inherited disorder characterized by early and prolific development of adenomatous polyps within the colon and rectum (Table 1) [1].

TABLE 1.

Definitions.

FAP	Patients have a pathogenic variant in the APC gene Patients with more than 100 colorectal adenomas and no known pathogenic variants in other polyposis genes or Young patients with fewer than 100 adenomas and a family history of FAP
Classical FAP	Patients with more than 100 adenomas before the age of 25 years and no known pathogenic variants in other polyposis genes
Attenuated FAP	Patients with fewer than 100 adenomas and a pathogenic variant in the APC gene
Verified FAP	FAP confirmed by histology or genetic analysis
Assumed FAP	A family history of FAP, as well as clinical implications of FAP, but without histologic or genetic confirmation
Probands	Patients diagnosed because of bowel symptoms or colorectal screening and without any knowledge of hereditary bowel disease
Call‐ups	Screen‐detected patients diagnosed at prophylactic examination because of FAP diagnosis in first‐degree relatives

Abbreviations: APC, adenomatous polyposis coli; FAP, familial adenomatous polyposis.

The genetic foundation of FAP is in pathogenic variants within the APC gene located on chromosome 5q21. However, while FAP is the most common cause of colorectal adenomatous polyposis, it is not the only cause [22]. Several other hereditary disorders may clinically imitate FAP by developing colorectal adenomatosis, including polymerase proofreading‐associated polyposis (POLE and POLD1) and oligodontia‐colorectal syndrome (AXIN2), which are dominantly inherited, and constitutional mismatch repair deficiency (CMMR‐D), MUTYH‐associated polyposis (MAP), and NTHL1‐associated polyposis, which are inherited in a recessive pattern (Table 2) [23, 24, 25, 26, 27, 28].

TABLE 2.

Adenomatous polyposis syndromes.

Syndrome	Gene	Inheritance	Increased cancer risks
Familial adenomatous polyposis	APC	Autosomal dominant	Colorectal, duodenal, gastric, pancreatic, thyroid, hepatoblastoma
Oligodontia‐colorectal cancer syndrome	AXIN2	Autosomal dominant	Colorectal
Polymerase proofreading‐associated polyposis	POLD1	Autosomal dominant	Colorectal, uterus, breast, bladder, brain
Polymerase proofreading‐associated polyposis	POLE	Autosomal dominant	Colorectal, uterine, duodenal, ovary
Hereditary mixed polyposis syndrome	GREM1	Autosomal dominant	Colorectal
MBD4‐associated neoplasia syndrome	MBD4	Autosomal recessive	Colorectal, myelodysplastic syndrome, acute myeloid leukemia
MLH3‐related polyposis	MLH3	Autosomal recessive	Uncertain: potentially colorectal, gastric, brain, breast
MSH3‐related polyposis	MSH3	Autosomal recessive	Uncertain: potentially colorectal, gastric, brain, breast
MUTYH‐associated polyposis	MUTYH	Autosomal recessive	Colorectal, ovary, bladder, breast, uterine, gastric, pancreatic, skin
NTHL1 tumor syndrome	NTHL1	Autosomal recessive	Colorectal, breast, duodenal, uterus

Additionally, new and still poorly described syndromes, such as MBD4‐associated neoplasia syndrome, MSH3‐associated CRC, and MLH3‐associated CRC, have recently been described [29, 30, 31]. Common to all these polyposis syndromes is the known genetic etiology. It is important to emphasize that in a proportion of patients with colorectal polyposis who have undergone adequate genetic workup, the genetic cause of their polyposis syndrome remains unknown [5]. All present guidelines consequently recognize both a clinical and genetic definition of FAP, where the clinical criterion is the presence of more than 100 cumulative colorectal adenomas [15, 32, 33, 34, 35, 36, 37]. Furthermore, young patients with colorectal adenomatosis, but fewer than 100 adenomas and a family history of FAP, may also be diagnosed in the absence of a known pathogenic variant in APC [35]. Finally, patients with another known genetic etiology are not considered to have FAP and should instead receive dedicated treatment protocols [38].

4.2.2. Phenotypes

FAP is often divided into two phenotypes. Classical familial adenomatous polyposis (CFAP) is the more aggressive phenotype of the genetic disorder (Table 1) and in this form individuals develop over 100, often thousands, of adenomatous polyps throughout their colon and rectum. The onset of these polyps is typically early, appearing in childhood to early adolescence, and 95% have developed colorectal polyposis by the age of 35 [39]. Given the sheer number and density of these polyps, individuals with CFAP face an almost certain risk of developing colorectal cancer by their fourth or fifth decade if there is no surgical intervention [1]. Beyond the colon, patients with CFAP may also face extracolonic manifestations, such as polyps in the stomach and duodenum, desmoid tumors, and other benign growths [40].

In contrast, attenuated familial adenomatous polyposis (AFAP) presents as a milder variant of the disorder [41]. Those with AFAP tend to have fewer polyps, typically ranging between 10 and 100 across the colon and rectum. The appearance of these polyps usually comes later in life than with CFAP. This delay also impacts the age at which surgery is needed and patients' risk of colorectal cancer which, while elevated, tends to manifest a decade or more later than in CFAP [7, 42]. Genetically, AFAP can also be traced back to pathogenic variants in the APC gene, but these mutations are often located in specific regions of the gene that result in a milder presentation [43]. Additionally, the extracolonic features common in CFAP are less frequent in AFAP, though some patients may still exhibit them [7]. Both forms of FAP require early detection and endoscopic surveillance to minimize the associated risks, and understanding their distinct presentations is vital for tailored medical care, for planning future studies, and for any indications useful for chemoprevention. FAP is also associated with various extraintestinal manifestations, which include desmoid tumors, osteomas, congenital hypertrophy of the retinal pigment epithelium, thyroid cancer, hepatoblastoma, dental abnormalities, and epidermoid cysts [40, 44, 45, 46]. However, some historic nomenclatures, such as Gardner syndrome, which is characterized by extraintestinal manifestations, and Turcot syndrome, in which FAP patients develop brain tumors (especially medulloblastomas), are poorly defined phenotypically and genetically and should be avoided [47, 48].

4.2.3. Genotypes

FAP is caused by pathogenic loss‐of‐function variants in the APC gene on chromosome 5q21 [10]. CFAP, typified by the onset of hundreds to thousands of polyps during adolescence, is commonly attributed to pathogenic variants situated between codons 1250 and 1464 of the APC gene [40, 49, 50]. Additionally, whole genome deletions have been associated with a classical phenotype [51]. In contrast, pathogenic variants found either at the very start (5′ end) or concluding segment (3′ end) of the APC seem to be associated with AFAP [52, 53]. Despite its milder presentation, AFAP still carries a substantial risk of cancer [7]. The linking of specific pathogenic variants with extracolonic manifestations further complicates the genotype–phenotype correlations of FAP. For example, pathogenic variants between codons 1395 and 1495 have been associated with the development of desmoid tumors, which are benign but can be problematic due to their invasive nature [54]. Additionally, variants between codon 976 and 1067 have been implicated in a heightened risk of polyps and tumors in the upper gastrointestinal tract [55]. However, our recent study of all Danish patients with duodenal cancer and/or severe duodenal adenomatosis requiring surgical resection failed to identify any robust correlation between genotypes and phenotypes [6]. Recognizing the pathogenic variants in the APC gene facilitates a broader understanding of how genetics intertwines with clinical presentations. Yet, proven genotype–phenotype correlations that might guide patient care have yet to be established.

A study conducted by our group examined the rate of pathogenic variants in families with colorectal polyposis where the causative mutation remained unidentified, despite clinical presentations suggestive of FAP. Applying advanced, next‐generation sequencing and whole‐genome sequencing, we aimed to identify pathogenic variants in 31 Danish families exhibiting over 100 cumulative colorectal adenomas. The results revealed pathogenic variants in APC and MUTYH in a significant subset, alongside other implicated genes like NTHL1 and POLE (Figure 1). Such comprehensive genetic profiling is vital for enhancing diagnostic precision, which in turn supports targeted surveillance protocols. By identifying pathogenic variants in 60% of the cases previously classified as being of “unknown genetic etiology,” this study contributes to an evolving framework where FAP‐like syndromes can be reclassified for optimal management and genetic counseling. Of note, after a nationwide genetic work‐up of FAP patients without a known genetic etiology, over 90% of families enrolled in the surveillance program now have a known genetic etiology.

FIGURE 1.

Results of genetic testing in patients with colorectal polyposis. From Karstensen JG, Hansen TVO, Burisch J, et al. Re‐evaluating genotypes of patients with adenomatous polyposis of unknown etiology: A nationwide study. Eur J Hum Genet. 2024 May;32 (5):588–592. DOI: https://doi.org/10.1038/s41431‐024‐01585‐z. Copyright via https://creativecommons.org/licenses/by/4.0/.

One final genotype is gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), which is a rare hereditary cancer syndrome characterized by numerous polyps in the proximal stomach, but sparing the duodenum and colon [56]. It increases the risk of gastric adenocarcinoma and is associated with mutations in the promoter 1B region of the APC gene [57].

4.2.4. Incidence and Prevalence of FAP

The reported global incidence of FAP varies, but results from national Finnish and Swedish registers during the 1990s estimated an annual mean incidence rate ranging from 0.86 to 2.38 per 1000,000 [58, 59]. In 2019, our group analyzed the results of the Danish Polyposis Register and found that the mean annual incidence rate of FAP in the period 1990–1999 was 1.9/1000,000/year, while the mean annual incidence rate in the period 2000–2017 was 3.2/1000,000/year—a statistically insignificant increase (Figure 2) [1]. This is not surprising, but in future studies the incidence might be reduced due to the implementation of prenatal diagnostic methods like pre‐implantation genetic testing, which may reduce the incidence of call‐ups [60, 61]. Conversely, widespread genetic testing can identify patients who do not present with a classical phenotype, and these individuals might have gone undiagnosed in earlier decades. This hypothesis is supported by data from the Danish Polyposis Register, which show that over the past 5 years the incidence of AFAP has surpassed that of CFAP (Figure 3) [7]. Many of these patients would never have been identified without a comprehensive genetic work‐up.

FIGURE 2.

Relationship between the annual incidence and prevalence rates of familial adenomatous polyposis. Karstensen JG, Burisch J, Pommergaard HC, et al. Colorectal Cancer in Individuals With Familial Adenomatous Polyposis, Based on Analysis of the Danish Polyposis Registry. Clin Gastroenterol Hepatol 2019;17:2294–2300 e1. DOI: https://doi.org/10.1016/j.cgh.2019.02.008. Copyright according to https://www.elsevier.com/about/policies‐and‐standards/copyright/permissions.

FIGURE 3.

Number of newly diagnosed familial adenomatous polyposis patients and their phenotypes. Beck SH, Karstensen JG, Bülow S, et al. A Cancer risks in attenuated and classical familial adenomatous polyposis: A nationwide cohort study with matched, non‐exposed individuals. Am J Gastroenterol 2024 Oct 30 (online ahead of print). DOI: https://doi.org/10.14309/ajg.0000000000003167. Copyright via CC RightsLink license number 5981551008549.

In recent years, the reported prevalence of FAP has risen, suggesting a shift not only in diagnostics but also in treatment efficacy [58, 59]. We recently estimated the prevalence of FAP in the Danish population and demonstrated a significant increase from 48.6/1,00,000 by the end of 1999 to 61.1/1000,000 by the end of 2017 (Figure 2) [1]. Several factors might have contributed to the increase in prevalence despite a stable incidence. Historically, FAP was diagnosed based on the presence of numerous adenomatous polyps in the colon and rectum. However, advances in genetic testing and increased awareness among healthcare professionals have led to the recognition of milder phenotypes, notably AFAP [41]. AFAP, characterized by fewer polyps and a later onset, previously fell under the diagnostic radar due to its subtler presentation. This more nuanced understanding means that individuals with a disease that would once have been deemed “too mild” to constitute FAP are now being appropriately diagnosed and managed. A second reason is the improved treatment of FAP, where prophylactic colectomy plays a crucial role in avoiding CRC. Likewise, endoscopic surveillance and resection of precursor lesions have limited the risk of duodenal cancer and, in particular, unresectable duodenal cancer [62]. The impact of these interventions becomes clear when we compare the projected life expectancy of probands with that of call‐ups. Call‐ups have seen their life expectancy extended by 14 years compared to probands, which we believe underscores how genuinely effective the tracing and follow‐up regimen for FAP patients has been (Figure 4) [1]. The compounding FAP prevalence reflects advances in their care and monitoring, as well as improved disease recognition. The challenge now lies in maintaining this momentum, refining our diagnostic tools, and ensuring comprehensive care for all FAP patients, regardless of phenotype severity.

FIGURE 4.

Kaplan–Meier plot presenting the cumulative crude survival rates after receiving the familial adenomatous polyposis diagnosis for probands and call‐up patients. Karstensen JG, Burisch J, Pommergaard HC, et al. Colorectal Cancer in Individuals With Familial Adenomatous Polyposis, Based on Analysis of the Danish Polyposis Registry. Clin Gastroenterol Hepatol 2019;17:2294–2300 e1. DOI: http://doi.org/10.1016/j.cgh.2019.02.008. Copyright according to https://www.elsevier.com/about/policies‐and‐standards/copyright/permissions.

4.3. Risk of Cancer

4.3.1. General Risk

Characterized by a profusion of colorectal adenomatous polyps due to pathogenic variants in the APC gene, FAP is fundamentally linked with a nearly inevitable risk of CRC. Yet, the oncological implications of FAP extend beyond the colon. The upper gastrointestinal tract, particularly the duodenum and periampullary regions, are not spared from the risk of malignant transformation by FAP. The oncogenic potential is further evident in the association between FAP and thyroid cancers, especially the papillary subtype and in pediatric oncology, and the association with hepatoblastoma, particularly in children under five. The universal risk of cancer in the natural course of the disease is nearly 100%, but with the introduction of prophylactic colectomy, this risk can be ameliorated. However, a recent study from the Danish Polyposis Register found that the overall risk of cancer in the post‐colectomy era has still increased four‐fold (Figure 5). The point estimates for the risk of cancer after 30 years of follow‐up were 60.7% in FAP versus 81.1% in non‐exposed patients who were alive without cancer; cancer developed in 11.4% versus 5.6% of FAP versus non‐exposed patients, respectively, and 27.9% versus 13.4% of FAP versus non‐exposed patients had died, respectively [3]. Of note, the probands who were diagnosed due to symptoms and subsequently had not been enrolled in surveillance at the time of their FAP diagnosis had a hazard ratio (HR) for developing cancer of 5.4, while the HR was 2.9 for call‐ups who were at‐risk individuals and usually diagnosed in their teens [3]. A Dutch study evaluating the cancer burden of FAP patients found that 52% of FAP patients suffered a cancer‐related death [20]. Finally, AFAP patients, who supposedly experience a milder course of disease, also experience a three‐fold increase in the general risk of cancer compared to non‐exposed individuals (Figure 6) [7]. In other words, the overall risk of cancer for FAP patients is reduced by surveillance and colectomy, but is certainly not comparable to the risk faced by non‐exposed individuals.

FIGURE 5.

Absolute risk of cancer and death (illness‐death model) for familial adenomatous polyposis versus non‐exposed individuals. Karstensen JG, Bülow S, Hojen H, et al. Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls. Gastroenterology 2023;165:573–581 e3. DOI: http://doi.org/10.1053/j.gastro.2023.05.010. Copyright via https://creativecommons.org/licenses/by/4.0/.

FIGURE 6.

Absolute risk of cancer and death (illness‐death model) for classical and attenuated familial adenomatous polyposis versus non‐exposed individuals. Beck SH, Karstensen JG, Bülow S, et al. A Cancer risks in attenuated and classical familial adenomatous polyposis: A nationwide cohort study with matched, non‐exposed individuals. Am J Gastroenterol 2024 Oct 30 (online ahead of print). DOI: http://doi.org/10.14309/ajg.0000000000003167. Copyright via CC RightsLink license number 5981551008549.

The cancer risk in FAP is multifaceted, encompassing a broad spectrum of malignancies that shape the life trajectory of affected individuals. While the epidemiology and risks associated with FAP changed significantly after the introduction of colectomy, the overall risk remains high. While much current research focuses on enhancing the benefits of surveillance and surgery, the underlying risk tied to the pathophysiological origins of the pathogenic variant in the APC gene requires further exploration.

4.3.2. Colorectal Cancer

The cornerstone of FAP's clinical significance lies in its near‐inevitable progression to CRC. Without intervention, virtually all individuals with FAP will develop CRC, often by the age of 40, and even in the post‐colectomy era the risk of CRC is four times greater among FAP patients than non‐exposed individuals [1, 3]. Given this high risk, endoscopic surveillance is vital.

Endoscopy, primarily colonoscopy, allows for direct visualization of the polyps and assessment of their number, size, and location. Polyps larger than 1 cm have a higher malignant potential, and as the polyp number increases, so does the risk of developing cancer [63]. When evaluating FAP patients, it is important to distinguish a classical phenotype from an attenuated one. Additionally, any endoscopic indications of malignant transformation should be meticulously noted. While the presence of malignancy does not inherently alter the surgical choice between proctocolectomy and colectomy, it does necessitate a conventional staging of metastasis. This can also influence the surgical technique used during colectomy. In 2016, a colorectal adenomatosis staging system was introduced that accounts for both the number and size of polyps [64]. Notably, if high‐grade dysplasia is found, it is recommended the patient be elevated to the highest stage within the system. Surveillance is also stratified according to this staging. This system, named IPSS, performed well in an inter‐rater study; however, it is important to emphasize that it has not undergone external validation. Moreover, beyond chemoprevention studies, its application in everyday clinical practice remains limited.

Historically, a prophylactic proctocolectomy has been the mainstay treatment for FAP. This intervention drastically reduces the risk of CRC, and we have demonstrated that the risk for call‐ups is greatly reduced during preoperative surveillance; call‐ups who developed CRC with colon in situ were diagnosed during their initial endoscopic evaluation [1]. Likewise, the benefits of these interventions can be estimated by comparing the anticipated life expectancy of probands and call‐ups, which are often estimated to be a median of 55.0 years (95% CI, 51.2–58.8) and 72.0 years (95% CI, 63.3–80.7), respectively [1]. Likewise, our recent study comparing CRC rates between FAP patients and a matched cohort of non‐exposed individuals revealed that probands face a considerably higher risk of CRC (HR 6.83; 95% CI, 3.80–12.27, p < 0.001). In contrast, this elevated risk was not statistically significant among the call‐up patients (HR 1.31; 95% CI, 0.48–3.59; p = 0.606) [3]. The CRC incidence for FAP patients fell significantly, by 3.28% per year from 1986 to 2021 (p = 0.008). Upon stratification by phenotype, the adjusted risk for colon cancer was higher in CFAP and AFAP patients than in the non‐exposed group, with a HR of 2.16 (95% CI, 0.99–4.72; p = 0.0522) and 2.72 (95% CI, 1.19–6.22; p = 0.0177), respectively [7]. Both CFAP and AFAP patients also exhibited an elevated risk for rectal cancer when compared to non‐exposed individuals, with HRs of 12.66 (95% CI, 7.04–22.76; p < 0.001) and 9.12 (95% CI, 4.35–19.12; p < 0.001), respectively. To summarize, the risk of CRC among FAP patients is greater for all phenotypes but can be markedly reduced with colectomy.

It is estimated that about 30% of patients with FAP who retain their rectum after colectomy with an IRA will develop rectal cancer by age 60 [13, 65]. Moreover, a risk of CRC localized at the cuff persists after establishing an IAP. Consequently, endoscopic postoperative surveillance is crucial. In Denmark, after surgery, patients routinely receive an annual flexible sigmoidoscopy. Should endoscopic monitoring prove inadequate, a subsequent surgical resection is recommended. In our study examining CRC incidence, we demonstrated that FAP patients face a heightened risk of developing CRC as a secondary primary cancer when compared to non‐exposed individuals, with a HR of 5.26 (95% CI, 1.09–25.3; p = 0.038) [3]. Interestingly, when CRC manifested, 69.2% of these patients still had an intact colon, while the rest had undergone colectomy. This suggests that the CRC cases might have emerged later in life, potentially associated with a milder polyposis phenotype.

The inherent nature of FAP and its potent risk of CRC has traditionally made surgery an inevitable intervention. However, with advances in endoscopic techniques and tools there is growing interest in whether rigorous endoscopic surveillance and polypectomy could postpone or, in some cases, even negate the need for surgery. Several, mostly Japanese, studies have demonstrated that in selected patients retaining the colon may be feasible and safe if patients undergo regular endoscopic procedures with numerous polypectomies. A retrospective study of 12 patients found that after a median of 5 years and 11 colonoscopies per patient, and a combined 424 polypectomies, none of the patients developed CRC or received a colectomy [66]. Nevertheless, 10 patients had lesions removed with high‐grade dysplasia. In another study from Japan, 90 FAP patients who declined prophylactic colectomy were monitored [67]. Over a median observation period of 5 years, a staggering 55,701 polyps were removed endoscopically, along with five non‐invasive cancers. Impressively, despite the high polyp count, invasive cancer was successfully averted in all 90 patients. These methods, combined with frequent surveillance, might provide a window of opportunity to manage FAP non‐surgically in select cases. However, it is crucial to acknowledge the challenges of this approach: missing a surveillance interval or failing to remove polyps adequately could have catastrophic consequences.

In conclusion, while colectomy remains a cornerstone in managing FAP, evolving endoscopic techniques offer hope for less invasive strategies in the future. However, this paradigm shift requires careful patient selection, rigorous surveillance, and preferably comparative interventional studies to ensure patient safety and optimal outcomes.

4.3.3. Duodenal Cancer Risk

Duodenal adenomas can, if left untreated, develop into duodenal cancer, which has a devastating prognosis. Historical data have estimated the lifetime risk of developing adenomatous polyps in the duodenum is 50%–90% in individuals diagnosed with FAP [19, 68, 69]. Using recent data from our nationwide register, we found that between 1990 and 2021, 70.6% of patients underwent EGD at least once (Figure 7) [6]. Of these, 59.2% presented with duodenal adenomas proven by histopathology. In another recent study by our group comparing FAP patients stratified by phenotype, we demonstrated that the risk was higher for CFAP than for AFAP (HR 4.02; 95% CI, 2.48–6.52; p < 0.001) [7]. The occurrence of advanced lesions with high‐grade dysplasia was extremely rare in AFAP, while 14.5% of CFAP patients developed high‐grade dysplasia in the duodenum. This resulted in a greater risk of duodenal/small bowel cancer for FAP patients than for non‐exposed individuals, with a HR of 14.49 (95% CI, 1.76–119.47; p = 013) [3]. We found that duodenal cancer was restricted to FAP patients with a classical phenotype [6].

FIGURE 7.

Flowchart for a Danish nationwide cohort of patients with familial adenomatous polyposis. Karstensen JG, Wewer MD, Bülow S, et al. Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections—a nationwide Danish cohort study with long‐term follow‐up. Fam Cancer. 2024 Nov;23 (4):607–615. DOI: https://doi.org/10.1007/s10689‐024‐00415‐x. Copyright via https://creativecommons.org/licenses/by/4.0/.

The Spigelman classification is recommended for risk stratification of duodenal adenomatosis in FAP patients [34, 36]. Introduced in 1989, this classification combines polyp size and count with adenoma morphology and the severity of dysplasia (Table 3) [70]. Its simplicity makes it valuable for determining appropriate surveillance intervals and surgical referrals. However, it has some drawbacks: it may underemphasize the significance of ampullary lesions, and no firm correlation has been established between its classifications and the risk of duodenal cancer [71, 72, 73]. It also necessitates biopsies from duodenal lesions that many endoscopists might either leave in situ or opt to remove entirely with simple polypectomy or endoscopic mucosal resection (EMR). Between 2018 and 2021, our group conducted a prospective, inter‐observer study of consecutive FAP cases scheduled for upper GI monitoring [2]. The primary endpoint was the inter‐rater reliability of the Spigelman classification. We also evaluated the endoscopic subscores, the efficacy in identifying adenomas at the major papilla and, in cases of their presence, ascertained their size using a 10 mm threshold. Every examination was meticulously recorded and subsequently analyzed by five experienced endoscopists familiar with FAP. Our findings revealed an impressive inter‐rater reliability of 0.95 and an intra‐rater reliability of 0.91, emphasizing the Spigelman score's high reproducibility. However, consistency in endoscopically evaluating the major papilla was somewhat less impressive, highlighting the challenge of assessing FAP patients. This study is not without limitations. Primarily, only a small fraction of its patients had severe duodenal adenomatosis with high‐grade dysplasia or villous morphology; but the core of the study was the reproducibility of its endoscopic factors. A second limitation was that our video recordings were unedited. This meant that the biopsy specimen details were visible, which could have introduced some minor bias into the endoscopists' evaluations. In summary, our assessment of the Spigelman classification demonstrates its outstanding reliability. Currently, it remains a cornerstone of routine endoscopies for FAP patients.

TABLE 3.

Spigelman score for duodenal polyposis in familial adenomatous polyposis.

Criterion	1 point	2 points	3 points
Polyp number	1–4	5–20	> 20
Polyp size (mm)	1–4	5–10	> 20
Histology	Tubular	Tubulovillous	Villous
Dysplasia	Low‐grade a		High‐grade a

Note: Stage 0: 0 points; stage I: 1–4 points; stage II: 5–6 points; stage III: 7–8 points; stage IV: 9–12 points.

^a Originally, three grades of dysplasia were incorporated.

The Spigelman classification was developed at a time when endoscopies were mostly diagnostic [70]. During this period, the development of duodenal adenomatosis and subsequent cancer could only be halted by surgical resection. Today, endoscopic polypectomy in the duodenum can be conducted with a minimal risk of adverse events [74, 75, 76]. Even EMR and endoscopic papillectomies have become routine at centers with a high volume of FAP patients [77, 78, 79]. In a recent nationwide cohort study of all known Danish FAP patients, we assessed the risk of requiring duodenal resection due to extensive polyposis or cancer. Over a 30‐year span, the incidence of duodenal surgery was estimated at 1.31 per 1000 person‐years, with a median age at surgery of 53 years. The number of duodenal resections did not decline during this period. Remarkably, 71.0% of FAP patients who underwent these highly invasive resections did so for benign indications, as confirmed by final histopathology. Yet, among these patients, two‐thirds had never previously had a duodenal polypectomy, and a mere 16% underwent a duodenal EMR. This suggests that the full benefit of endoscopic interventions was not fully realized [6]. But proof of the benefits of these invasive endoscopic procedures are lacking. Currently, a European polyposis consortium prospectively enrolls FAP patients in a protocol where all adenomas exceeding 10 mm are removed by endoscopic techniques and where surveillance intervals are tailored according to the number, size, and histopathological severity of the adenomas [80]. The results of this study are eagerly awaited, but it is important to point out that there is still an urgent need for additional interventional comparative studies.

4.3.4. Pancreatic Cancer

The genetic basis of FAP is pathogenic variants in the APC gene. While these variants primarily increase the risk for duodenal and colorectal cancer, they may also be associated with several extraintestinal malignancies. While pancreatic cancer has not traditionally been considered a part of this spectrum, our evolving epidemiological understanding, partly driven by the introduction of colectomy and the consequent decrease in colorectal cancer risk and prolonged life expectancy, has intensified the focus on a potential correlation between pancreatic cancer and FAP. In 1994, a comprehensive study involving nearly 200 FAP families demonstrated a marked elevation in the relative risk for pancreatic cancer, where there was an augmented risk of 4.5 compared to the background population. Furthermore, the cumulative risk of pancreatic cancer in FAP patients by the age of 80 was estimated to be 1.7% [18]. At first glance, this figure might appear modest, but when seen in the context of the aggressive nature and dismal survival rates associated with pancreatic cancer, even a marginal increase in risk is clinically important. Following this study, a case series reported four pancreatic cancers in a FAP cohort comprising 127 patients; none of the cancers were classical exocrine pancreatic adenocarcinomas, but instead consisted of two neuroendocrine tumors, one acinar cell carcinoma, and one pancreaticoblastoma [81].

In 2023, we presented a nationwide cohort study evaluating the risk of cancer for FAP patients compared to matched, non‐exposed individuals. After adjusting for age and sex, the risk of developing pancreatic cancer was estimated to have a HR of 6.45 (95% CI, 2.02–20.64; p = 0.002). The study indicated an elevated risk for both probands and call‐ups, underscoring the possibility that pancreatic cancer tends to manifest later in life compared to CRC. While there was no exploration of associations with specific genotypes, it was noted that none of the FAP patients were related. One of the key strengths of this study was its long‐term follow‐up, coupled with the use of national registers, which reduced the potential for bias. However, a drawback of relying solely on national registers for this disease is that the data are dependent on accurate entries by clinicians and pathologists. Differentiating between duodenal and pancreatic cancers, especially those with an ampullary or periampullary location, can prove challenging. However, an audit of the Danish Polyposis Register confirmed the accurate registration of the pancreatic cancers. Additionally, a subsequent analysis of Danish FAP patients that stratified the data according to phenotype found that the risk of pancreatic cancer was only significantly increased for FAP patients with a classical phenotype (HR 7.66; 95% CI, 1.67–35.26; p = 0.009) and not AFAP patients (HR 3.19; 95% CI, 0.61–16.42; p = 0.168), when compared to non‐exposed individuals [7].

In the initial years following the identification of FAP, numerous countries set up national registries to monitor both surveillance and treatment. Although there were recommendations to maintain this practice, there appears to have been a decline in the number of national FAP registries since then [82]. This is unfortunate, as when trying to prove associations between FAP and pancreatic cancer (among other types), it is greatly reassuring when correlations have been reproduced in other national studies.

The heightened risk of pancreatic cancer in FAP patients necessitates enhanced surveillance. However, the current surveillance approach, which typically involves alternating annual MRI and endoscopic ultrasound, is imperfect. This approach can yield false positive results, leading to unnecessary surgical resections, while missing some cancers that develop between tests (interval cancers) [83]. While FAP patients do have an increased risk of pancreatic cancer, it is a comparatively modest one when placed against patients with pathogenic variants in STK11 (Peutz‐Jeghers Syndrome), CDK2NA, and PRSS1, who face a 20%–40% lifetime risk of pancreatic cancer [84, 85, 86, 87]. Recent findings from the Cancer of Pancreas Screening‐5 study showed that screening high‐risk individuals resulted in earlier detection of pancreatic cancers. This early detection significantly improved survival rates compared to cancers identified without such screening [88]. While this study did not include FAP patients, given the serious nature of pancreatic cancer we suggest that FAP patients with a classical phenotype undergo protocolized monitoring at specialized centers.

4.3.5. Gastric Cancer

The risk of gastric cancer among FAP patients in Western populations has generally been considered low and comparable to the background population [89, 90, 91]. However, recent data from Western high‐volume centers have demonstrated an increase in gastric cancer incidence in these populations [92, 93]. Furthermore, it has been proposed that the risk is on the rise [92]. Studies from Asia have generally reported a higher risk of gastric cancer in FAP patients and a higher risk compared to patients of Western origin [94, 95]. Additionally, it is estimated that gastric cancer accounts for 2.8% of deaths in Japanese FAP patients [96]. While these data may be suggestive of an increased risk of gastric cancer, a more recent nationwide Danish study failed to confirm this assumption. It calculated a HR of 3.29, but the 95% confidence interval was notably wide, at 0.53–20.23, which might reflect the sample size, as well as the limited number of instances of gastric cancer [3]. However, another epidemiological Dutch study of 567 proven APC mutation carriers only identified one patient with gastric cancer, thereby confirming a low risk of cancer among FAP patients [20]. These conflicting data might be explained by the referral pattern to those single centers, which reported an increased risk of gastric cancer. On the other hand, the numbers from these centers are considerable and the epidemiology of FAP patients might be changing at the same time as their risk of CRC decreases and their life expectancy increases. Future case series, as well as epidemiological studies, will have to closely monitor the incidence of gastric cancer in FAP patients and endeavor to identify risk factors.

Endoscopically, FAP patients may present with fundic gland polyps (FGP), which are identified in up to 90% of FAP patients [97]. These polyps have traditionally not been related to the development of cancer and are not considered to represent a precursor lesion. However, the nature of these FGPs in FAP patients is distinctive, as there have been reports describing dysplastic transformation of FGP [98, 99]. Furthermore, adenomatous polyps, including pyloric gland adenomas and tubular adenomas, have been identified with greater frequency in FAP patients [100, 101]. Each of these polyp types carries its specific risk profile for malignant transformation, necessitating a thorough understanding of their epidemiology within the FAP cohort. Several risk factors for malignant transformation, including gastric carpeting with FGP, polypoid mounding, as well as the development of a white mucosal patch, have been proposed [92, 93, 101, 102]. Atrophic gastritis due to H. pylori infection has been strongly associated with an increased risk of malignant transformation [99, 103]. When carrying out an endoscopy, these findings should obviously be borne in mind; however, possible risk factors such as these often originate at single‐center studies from tertiary referral units, which might preclude their generalization. Additionally, conflicting evidence continues to accumulate that suggests the risk of malignant transformation from adenomas might not be correlated to the severity of dysplasia in gastric adenomas [104]. There is still a lack of standardized endoscopic reporting of gastric findings in FAP, but it is urgently needed as gastric examinations of FAP patients can prove extremely challenging due to the presence of FGP.

In conclusion, the association between FAP and gastric cancer should remain a subject for future studies, and robust epidemiological evidence needs to be gathered to identify the specific subgroups of FAP patients most at risk, and to clarify the optimal surveillance protocols. Understanding these nuances is essential for informed clinical decision‐making, risk stratification, and the formulation of surveillance guidelines tailored to FAP patients.

4.3.6. Thyroid Cancer

The rate of occurrence of thyroid cancer in individuals with FAP has varied considerably between studies. While retrospective studies have observed its prevalence to be between 0.4% and 2.6%, prospective research indicates a somewhat higher prevalence ranging from 2.6% to 11.8% [105, 106, 107]. There is an overwhelming female predominance, with an 80:1 female‐to‐male ratio, and most diagnoses occur in young adults, particularly between the ages of 18 and 35 [106]. We analyzed the risk of cancer among Danish FAP patients and failed to identify a significantly higher risk compared to non‐exposed individuals (HR 1.43; 95% CI, 0.32–6.49; p = 0.641) [3]. However, during the follow‐up period, from 1986 to 2019, we did not conduct any thyroid cancer screening and thus our results only included symptomatic cases. The most common histological type found in these patients was papillary thyroid cancer, which often presents with a distinctive cribriform pattern [105]. Moreover, FAP is commonly associated with a specific and rare subtype of papillary thyroid carcinoma known as the cribriform‐morular variant [108]. The variants of thyroid cancer associated with FAP are seldom the cause of death among affected individuals. In a cohort study conducted in the Netherlands of 567 confirmed APC carriers, only one death was attributed to thyroid cancer [20]. This underscores the relative rarity of fatal outcomes due to thyroid cancer in individuals with FAP, despite its association with the condition.

4.3.7. Hepatoblastoma

Children from FAP families face a risk of hepatoblastoma that is 750 to 7500 times greater than in the general population, with an absolute risk of about 2% in FAP‐affected children [21, 109]. Most cases of HPB are diagnosed between the ages of 1 and 4 years [110]. The prognosis of hepatoblastoma varies, partially correlating with the tumor size. Current treatments, including partial hepatectomy and chemotherapy, offer excellent outcomes, with survival rates exceeding 90% for stage I and II diseases [111]. The sample size of the data in the Danish Polyposis Register is insufficient to conduct adequate epidemiological studies of hepatoblastoma. Hence, a multinational collaboration, preferably including nationwide registers, is needed to further elucidate the prevalence and possible genotype–phenotype correlations for hepatoblastoma.

4.3.8. Other Cancers

Medulloblastoma, a type of brain tumor, has been associated with a variant of FAP known as Turcot syndrome and is identified in approximately 1% of FAP patients [112]. Additionally, FAP has been proposed as a risk factor for developing adrenal masses, where it has been observed in 16%–26% of patients [113, 114]. Of note, only a minority of these are considered malignant. The incidence of jejunal or ileal cancers in patients with FAP is reported in the literature to be very low [20, 115]. Current prospective studies monitoring jejunal polyps, even when severe duodenal polyposis is present, have not demonstrated an increased risk of developing jejunal carcinoma [116].

4.3.9. Desmoid Tumors

Desmoid tumors occur in about 10%–30% of individuals with FAP, representing a risk over 800 times higher than in the general population [54, 117]. These benign, yet locally invasive, tumors predominantly develop in the second and third decades of life, with 80% appearing by age 40 [54]. Desmoids can cause significant morbidity and even mortality, particularly when they are intra‐abdominal. Factors contributing to the development of desmoid tumors in FAP individuals include an APC pathogenic variant 3′ of codon 1399 or 5′ of codon region 543–713, a family history of desmoid tumors, being female, and prior abdominal surgery, especially proctocolectomy with IAP [54, 118]. As desmoids are not registered in the Danish Cancer Register, they are not included in our epidemiological studies, which is a major limitation. Consequently, epidemiological studies will have to rely on pathological data. When estimating causes of death among FAP patients, we found that 1.4% of deaths were attributed to desmoid disease, while a Dutch study estimated it to be 10.4% [1, 20]. This considerable and unexplainable difference calls for further studies of desmoid disease in FAP.

4.4. Current Recommendations

Optimal management of FAP necessitates a cohesive multidisciplinary strategy. Centralization of patient care is imperative to build adequate expertise and to inform research efforts. Several international guidelines, with diverse recommendations, are available and a selected number of these are subject to comparison in this section [15, 34, 36, 119]. However, it is essential to underline the paucity of robust empirical evidence supporting these recommendations, especially the absence of prospective and interventional comparative studies.

In general, presymptomatic genetic testing is recommended for at‐risk children aged 12 to 14 years, which is almost in line with the initial colonoscopic evaluation that is recommended between the ages of 10 and 14, depending on the specific guidelines (Table 4) [15, 21, 34, 36, 119]. The initial endoscopic evaluation secures a safe and elective planning of colectomy, including its modality (IRA vs. IAP). In some guidelines, including the Danish ones, an index coloscopy in AFAP families can be planned somewhat later, between the ages of 14–20 years, which might be reasonable if patients have an attenuated phenotype; however, it is important to emphasize that there can be considerable intrafamilial variation in the phenotype [15, 34, 119, 120].

TABLE 4.

Surveillance of patients with familial adenomatous polyposis.

	ASGE		DKS/DSMG		ESGE		ACG
Organ	Age of onset/years	Interval/years	Age of onset/years	Interval/years	Age of onset/years	Interval/years	Age of onset/years	Interval/years
Colon	10–12	1–2	10–12	1–3	12–14	1–2	10–15	1–2
Upper Gastrointestinal	20–25 or before colectomy	According to Spigelman	25	According to Spigelman score, adjusted for appearance of the ampulla	25	According to Spigelman score, adjusted for appearance of the ampulla	25–30	1–5

Abbreviations: ACG, American College of Gastroenterology; ASGE, American Society of Gastrointestinal Endoscopy; DKS, Danish Surgical Society; DSMG, Danish Society of Medical Genetics; EGD, esophagogastroduodenoscopy; ESGE, European Society of Gastrointestinal Endoscopy.

Upper GI endoscopy is recommended beginning at age 25, or between 20 and 25 by the American Society of Gastrointestinal Endoscopy (ASGE). In AFAP patients it can be initiated about a decade later [15, 34, 36, 119]. Traditionally, the first upper GI endoscopy corresponds with the age at which duodenal adenomas typically appear. Likewise, there is a consensus in the standard guidelines to stratify surveillance intervals according to the Spigelman classification [15, 34, 36, 70, 119]. However, the traditional approach should be reconsidered in favor of a more proactive strategy involving recurrent duodenal polypectomies [74, 80]. This approach aims to disrupt the natural progression of duodenal adenomatosis more effectively, and it is preferable to remove lesions at a stage where only simply polypectomy is required, before advanced techniques, such as EMR, are needed.

As there are several organs in which an increased risk of cancer is either manifest or likely for FAP patients compared to the background population, a more intensive surveillance protocol might be tempting [40]. However, the evidence for surveillance for hepatoblastoma is limited and the number of surveillance procedures per event would be enormous [121]. It is also questionable whether a screen‐detected hepatoblastoma has a better prognosis than one diagnosed due to symptoms. For thyroid cancer, it should be emphasized that the lesions related to FAP are papillary thyroid carcinoma, which has a slow progression and a favorable prognosis [122, 123]. Consequently, the benefit of thyroid cancer screening in FAP patients might be limited in terms of survival rates. In some organs without an increased risk of cancer, it may not be advisable to look for precursor lesions if these hardly ever develop into cancer. This might be the case in the small bowel, where routine surveillance, usually with video capsule enteroscopy, is not recommended for FAP patients. In individuals with advanced duodenal adenomatosis, video capsule enteroscopy may be considered as a surveillance tool for high‐risk lesions.

No comparative studies evaluating different surveillance protocols have been conducted and future multicenter collaboration will be crucial for gathering evidence to substantiate the existing guidelines.

4.5. Psychological Impact

4.5.1. Psychiatric Comorbidity in FAP

The psychological consequences associated with FAP often remain overshadowed by the risk of cancer and surgery. Delving deeper into the psychiatric aspects of the disease, several nuances emerge that underscore the importance of an integrated approach to patient care. While the risk of CRC has been limited by prophylactic colectomy, endoscopic surveillance, and genetic testing, there is still an increased risk of developing CRC, especially among probands. Furthermore, the risk of duodenal, pancreatic, and several other cancers remains higher, which results in a significantly increased risk of cancer for both probands and call‐up patients [3]. These factors must be taken into consideration when assessing the mental impact of FAP.

Genetic testing is advised around ages 12–14 years for at‐risk individuals. A positive result will necessitate lifelong monitoring and a high likelihood of facing major gastrointestinal surgery. The anticipation of future surgery and increased cancer risk may generate anxiety and depression in FAP patients, and feelings of guilt in the parents who have passed the disorder on to their offspring [124, 125, 126]. However, a recent systematic review could not confirm any psychological harm post‐genetic testing [127]. In addition to the mental impact of receiving a diagnosis of FAP, it has been hypothesized that the impact of pathogenic variants in the APC gene extends beyond a predisposition to cancer. Alterations in APC protein might be associated with neurological conditions such as memory deficits, anxiety‐related behaviors, and autism‐like disabilities [128, 129]. Nonetheless, our understanding of the psychological and mental health dimensions of FAP remains limited.

In 2023, we conducted a cohort study of all known FAP patients alive between 1996 and 2021 [4]. Each patient was paired with four non‐exposed individuals matched by birth year, postal code at birth, and sex. We wanted to estimate if there was an increased risk of incident psychiatric disorders among FAP patients compared to the non‐exposed individuals and found that after adjusting for sex and age, the risk of a psychiatric diagnosis (HR 1.72, 95% CI, 1.25–2.35, p < 0.001), psychiatric contacts (HR 1.76, 95% CI, 1.31–2.38, p < 0.001), and the need for any psychiatric prescription (HR 1.52, 95% CI, 1.28–1.81, p < 0.001) were all higher (Figure 8). In addition, when compared to non‐exposed individuals, FAP patients were at significantly higher risk of experiencing any psychiatric event (HR 1.55, 95% CI, 1.32–1.83, p < 0.001). Interestingly, after adjusting for the event of cancer, we found the risk of any psychiatric event remained significantly higher among FAP patients (HR 1.42, 95% CI, 1.20–1.68, p < 0.001) (Figure 8). In an epidemiological study, pinpointing exact causes is speculative. However, surgical interventions, particularly colectomy, could contribute significantly to increased mental illness. However, our analysis failed to identify a significant correlation between colectomy and the risk of any psychiatric event (HR 0.88, 95% CI, 0.62–1.26, p = 0.491). Likewise, when comparing post‐colectomy FAP patients to an internal cohort of post‐colectomy ulcerative colitis (UC) patients, we found that the risk of any psychiatric event was increased for post‐colectomy FAP patients compared to post‐colectomy UC patients (incidence rate ratio (IRR) 2.41, 95% CI, 1.58–3.89, p < 0.001). Additionally, the risk of psychiatric contacts (IRR 4.40, 95% CI, 1.54–18.6, p = 0.016) and the need for any psychiatric prescription (IRR 2.32, 95% CI, 1.50–3.83, p < 0.001) were also higher in FAP and UC patients. Due to regulatory constraints, the cohorts of patients with UC and FAP were analyzed separately. Consequently, the incidence of psychiatric events was calculated individually for UC patients and then compared with the incidence in FAP patients, using the IRR for a comprehensive analysis.

FIGURE 8.

Estimated hazard ratios grouped by both event and inclusion of cancer as a time‐varying covariate. Karstensen JG, Wullum L, Andersen KK, et al. Psychiatric and educational aspects of familial adenomatous polyposis—a nationwide Danish cohort study with matched controls. Am J Gastroenterol. 2024 May 1;119 (5):957–964. DOI: https://doi.org/10.14309/ajg.0000000000002612. Copyright via CC RightsLink license number 5981550411359.

To summarize, our analysis found a severely increased risk of psychiatric disorders and needs among FAP patients, which calls for attention and further investigations. It has been demonstrated that FAP offspring, both with and without FAP themselves, do not differ when it comes to the risk of receiving a psychiatric diagnosis [125]. Similarly, in a study of 22 positive and 26 negative patients tested for a FAP, children who tested positive and who had a similarly affected sibling experienced more depression, albeit not reaching a clinical level. Additionally, some children who tested negative but had a positive sibling displayed significant anxiety during subsequent evaluations [124]. This could suggest that experiencing parental illness is the main driver of mental illness among FAP adolescents [125]. Further studies of FAP children and teenagers should include analyses of siblings without FAP and factors such as cancer and early death in their parents. Finally, it is crucial that the risk estimates are corrected for phenotype.

4.5.2. Educational Impact of FAP

The influence of FAP on the education of children and teenagers is critical. FAP is a genetic condition that is in general diagnosed either between 10 and 14 years in call‐ups or during adult life due to symptoms. For call‐up FAP patients, this means that from an early age they must undergo a number of endoscopic examinations and prepare for a colectomy, which is usually performed in their late teens. During these years, the educational system plays a pivotal role in ensuring that these students do not fall behind academically while coping with their medical circumstances.

In our recent epidemiological cohort study of all known Danish FAP patients, where each was matched with four non‐exposed individuals, we found that FAP patients are at increased risk of developing psychiatric disorders, with a need for subsequent consultation and medication [4]. In this study, we also analyzed the highest attained educational level for both FAP and non‐exposed patients. Interestingly, we found that the FAP patients reached a significantly lower educational level than non‐exposed patients (Figure 9). In our analysis, we found that any psychiatric event and the risk of a psychiatric diagnosis interacted significantly with educational level. Remarkably, when analyzing subgroups of FAP patients, we found the lower educational level was mainly driven by call‐ups and that educational level was significantly lower (p = 0.008) for FAP patients who had undergone a colectomy than for patients who had not.

FIGURE 9.

Distribution of education attained across non‐exposed individuals and patients with familial adenomatous polyposis. Patients with familial adenomatous polyposis are split into call‐ups and probands. Karstensen JG, Wullum L, Andersen KK, et al. Psychiatric and educational aspects of familial adenomatous polyposis—a nationwide Danish cohort study with matched controls. Am J Gastroenterol. 2024 May 1;119 (5):957–964. DOI: https://doi.org/10.14309/ajg.0000000000002612. Copyright via CC RightsLink license number 5981550411359.

A recent study examining the reintegration of adolescent and young adult cancer survivors into school settings highlights the significant social and systemic hurdles they encounter after prolonged absences due to their illness [130]. It has also been demonstrated that adolescents and young adults who survive cancer experience financial hardships late into life [131]. In cases of FAP, although cancer during adolescence is uncommon and typically presents in probands, the psychological and physical burdens can be substantial [1]. The consequences of surgical interventions, such as colectomy, may be as impactful as those of a malignant condition. Despite this, the healthcare system's primary focus remains on cancer prevention, with a notable lack of studies and interventions addressing the social implications of such diseases. Likewise, our knowledge about risk factors for these children and adolescents is scarce. Consequently, there is an urgent unmet need for initiatives aimed at supporting these individuals' educational trajectories.

4.6. Discussion and Perspectives

4.6.1. Chemoprevention in FAP

Chemoprevention is increasingly being recognized as a pivotal strategy for individuals diagnosed with FAP (Table 5) [132, 133]. The aim is to decelerate the development of polyps, which may delay or reduce the need for bowel resection. Both duodenal and colorectal adenomatosis have been the target of these studies, and several different agents have been tested in comparative studies; however, common among these agents is that they have not originally been designed for the purpose of treating FAP or preventing the development of adenomas. The following section offers a review of the most promising studies.

TABLE 5.

Randomized controlled trials of chemoprevention in familial adenomatous polyposis.

Agent	Authors	Primary endpoint(s)	Sample size	effect	Side effects
Aspirin	Burn et al.	Polyp number in the rectum and sigmoid colon	206	No intervention significantly reduced polyp count in the rectum or sigmoid colon	No serious side effects. Some had bloating, and one persistent nosebleed
	Ishikawa et al.	Incidence of colorectal polyps of at least 5.0 mm at 8 months	104	The crude OR adjusted for age and sex was 0.32 (0.12–0.86)	Nausea, vomiting, and stomach pain (8%)
Celecoxib	Steinbach et al.	The changes in number of colorectal polyps	77	14.5% reduction in involved areas compared with 1.4% for placebo (p = 0.436)	Mild, but up to 10% in each study group
	Phillips et al.	Improvement of duodenal adenomatosis	83	Improved duodenal disease compared to previous examination	Few
	Burke et al.	Earliest occurrence of ≥ 20 polyps (> 2 mm in size)	106	No significant difference	Comparable in both groups, but three severe events in celecoxib group
Sulindac	Giardiello et al. (1993)	Number and sizes of colorectal polyps	22	Significant decrease in number and size of polyps	No adverse events
	Giardiello et al. (2002)	Occurrence and sizes of colorectal polyps	41	No difference in occurrence and size	Few, but one possible drug‐induced persistent neutropenia
	Debinski el al.	Development of duodenal polyps	24	Fewer polyps in sulindac group	Not reported
Curcumin	Cruz‐Correa	Number of rectal polyps	44	No difference in number of polyps in the intervention and placebo group	Mild
Eicosapentaenoic acid (EPA)	West et al.	Number and size of rectal polyps	55	Reduction in polyp number and size	Mild, and the same in both groups
Ascorbic acid	Bussey et al.	Number and size of rectal polyps	47	No differences in number or location of polyps	Mild, and the same in both groups
Erlotinib	Samadder et al. (2023)	Change in the sum of the diameters of duodenal polyps at 6 months	46	Significantly decreased duodenal polyp burden	Common, but less severe than combination studies with sulindac
DFMO/celecoxib	Lynch et al.	Colorectal adenoma count in a defined field	112	No significant difference in adenoma count	Mild, but fatigue observed more in celecoxib arm
DFMO/sulindac	Burke et al.	Composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high‐grade dysplasia in the rectum or pouch, or progression of duodenal disease	171	No differences between combination treatment and the agents alone	Mild, but the combination group had more rashes, upper abdominal pain, and erosive gastritis
Erlotinib/sulindac	Samadder et al. (2016)	Change in the sum of the diameters of duodenal polyps at 6 months	92	Significant decrease in duodenal polyp burden	Acne‐like rash observed in 87%

Aspirin has been demonstrated to decrease the risk of developing advanced adenomas, as well as CRC, in the general non‐FAP population, as well in Lynch patients [134, 135]. In light of these results, the CAPP1 trial enrolled 227 FAP patients randomized to various treatments, including aspirin [136]. In the primary analysis of 133 patients, no significant benefit was found for a daily regimen of 600 mg of aspirin, 30 g of resistant starch, or both, compared to placebo in reducing polyp burden. The only notable outcome was the decreased size of the largest polyp in patients who took aspirin for over a year. The study was limited by a median follow‐up period of only 17 months. The J‐FAPP IV study, a recent randomized controlled trial, recruited 104 FAP patients to evaluate the efficacy of aspirin/mesalazine, aspirin/placebo, mesalazine/placebo, or placebo/placebo [137]. Its findings were that low‐dose aspirin notably decreased the recurrence of polyps larger than 5 mm. As the mean age of its study participants was over 30 years, and as it only included FAP patients with an intact colon, it has been criticized for relying on an AFAP population, which may hamper extrapolation of its results to CFAP patients [138]. These findings, together with other studies, appear to agree that there is no well‐established rationale for endorsing aspirin as a chemopreventive agent for FAP.

Celecoxib is an extensively researched COX‐2 inhibitor for FAP, which is based on the COX‐2 enzyme's important link to APC and wnt/β‐catenin signaling, which is overexpressed in the colonic cells of polyposis syndrome patients [139, 140]. The European Medicines Agency first recommended the use of celecoxib for FAP in 2000 after a study showed a marked decrease in polyps in a specific section of the colon in 77 patients [141]. The same group also demonstrated that duodenal manifestations improved for patients taking celecoxib compared to placebo [142]. However, celecoxib's effectiveness could not be confirmed in a study of children with FAP [143]. Sulindac is a non‐selective COX inhibitor with additional non‐COX pathway actions. It was tested in 1993 for the treatment of colorectal polyposis in FAP patients [144]. Initial results indicated a significant decrease in both polyp number and size, yet subsequent research in pediatric populations did not yield statistically significant results [145]. Sulindac has also been studied in a randomized controlled trial focusing on duodenal polyps. The study reported fewer polyps in the interventional group, but the study only enrolled 22 patients [146].

One therapeutic combination that has shown promising results is sulindac and erlotinib, which has the potential to reduce duodenal polyposis by targeting EGFR and COX‐2. In the FAPEST trial, 91 FAP patients were randomized to receive either sulindac with low‐dose erlotinib or a placebo to compare duodenal polyp load after 6 months; the treatment group experienced a significant decline in duodenal adenomas compared to the placebo group, and a subgroup analysis demonstrated the same results for colorectal and pouch polyp burdens [147, 148]. However, the frequency of adverse events (cardiotoxicity, interstitial lung disease, and dermatological symptoms) means this treatment protocol should be used with caution. Addressing these concerns, a 2022 phase II trial tested weekly doses of erlotinib, aiming to balance efficacy in polyp reduction with a more favorable adverse event profile. In this 6 month study of 46 individuals, a weekly regimen of erlotinib resulted in a 30% reduction in duodenal adenoma burden (p < 0.0001) and a median 30% decrease in lower GI polyp load (p = 0.03) [149]. Although adverse events were reported, they were less severe and generally manageable.

Fish oil's eicosapentaenoic acid (EPA), an omega‐3 fatty acid, inhibits the COX‐2 enzyme, leading to the creation of molecules that promote cell death and reduce inflammation, while also curtailing the production of arachidonic acid, known for its cancer‐promoting and inflammatory properties. In a 6 month trial with FAP patients who had undergone colectomy ileorectal anastomosis, EPA significantly decreased the rectal polyp count and overall polyp load compared to a placebo. Vitamin C, with its noted anti‐cancer antioxidant effects, was subject to a randomized controlled trial of 49 FAP patients who received either daily ascorbic acid or placebo over 18 months, with regular endoscopic surveillance every 3 months. There was no difference seen in the number of polyps between study groups after 12 months [150]. Cruz‐Correa et al. were encouraged by preliminary studies to undertake a randomized study comparing curcumin monotherapy against a placebo over 6 months with 44 FAP patients for lower GI polyposis [151]. The trial did not demonstrate any effectiveness in reducing the number of colorectal adenomas, polyp size, or the total burden.

Difluoromethylornithine (DFMO), initially combined with sulindac in a study of 375 patients with sporadic colorectal polyps, appeared to reduce adenoma recurrence [152]. This combination was recently evaluated in FAP through a randomized, double‐blinded trial, which found no notable difference in slowing upper or lower GI tract conditions (including major surgery, removal of advanced adenomas, high‐grade dysplasia in the rectum or pouch, or duodenal disease progression) across groups treated with both sulindac and DFMO, sulindac alone, or DFMO alone. However, a subsequent post hoc analysis suggested that the sulindac‐DFMO combination could reduce the risk of lower GI tract disease progression by 80% compared to either drug alone [153]. Lynch et al. carried out a double‐blind, multicenter, randomized study from 2001 to 2008 comparing DFMO/celecoxib to celecoxib alone in treating adult FAP patients. The results, including the primary endpoint of polyp burden, were not statistically significant in the intention‐to‐treat analysis for the combination therapy. Yet, the video‐assessed global polyp burden suggests that the combination therapy may improve overall polyposis compared to celecoxib monotherapy. The potential clinical benefits of this finding remain uncertain [154].

In summary, while chemoprevention is a promising avenue for modulating FAP's inherent natural history, balancing the benefits of a diminished polyp burden against potential systemic adverse effects and inherent agent limitations is paramount. It is crucial to bear in mind that adenomas are still a surrogate marker, and that from a patient's perspective it is the risk of cancer and major surgery that are the most pressing concerns.

4.6.2. Psychological Interventions

Our study clearly demonstrates that among FAP patients there is an increased risk of psychiatric needs and a reduced level of education [4]. To effectively intervene, we need to further elucidate the risk factors within the FAP cohort. It is remarkable that both the risk of a psychiatric diagnosis, as well as the lower educational level, are mainly found in call‐ups who receive the FAP diagnosis during childhood or adolescence. However, the mean age at which mood disorders were reported was 35, which was the same age as in the matched, non‐exposed individuals, as well as the background population [3]. It is around the age of 35 that parents with FAP who have passed the condition on to their offspring might experience profound feelings of guilt. It also seems likely that individuals who undergo colectomy in their late teens face challenges that hinder their academic performance. These hypotheses are speculative, and future studies seeking to identify risk factors are essential if we are to better understand the pathophysiology of FAP. Such risk factors might include postoperative outcomes in terms of bowel and sexual function, as well as external factors such as growing up with a parent at risk of cancer, or indeed, suffering with cancer. The clinical phenotype of FAP is also likely to influence the specific psychological impact of the disease.

When treating adolescents and young adults with cancer, a recent joint position statement from the European Society for Medical Oncology and European Society for Pediatric Oncology points out several challenges that require assistance from healthcare systems (Table 6) [155]. Although the typical FAP patient does not develop cancer at a young age, the challenges they face are similar to patients who do develop cancer. However, the multidisciplinary support to face these challenges is often missing for FAP patients without cancer. It should be a priority in the years ahead to strengthen the help made available to FAP patients without cancer; if carried out in a scientific, multinational way, it would gather important knowledge in the process, which might be of value in treating other hereditary syndromes as well.

TABLE 6.

Psychosocial care.

Complex (and often unmet) psychological needs

Physical changes

Development of self‐image, identity, relationships, sexuality and independence

Age‐appropriate information and communication challenges, shared decision‐making, compliance and treatment adherence

Privacy and peer support

Peculiar behaviors at this age and risk‐taking (including alcohol/substance abuse)

Need for age‐specific psychological support

4.6.3. Deeper Understanding of the Pathophysiology of FAP

Despite the clear identification of the genetic an etiology of FAP, the progression from possessing the genetic predisposition to the formation of adenomas remains poorly understood. This gap in our knowledge is highlighted by the reality that none of the pharmaceuticals used in chemopreventive trials have been designed to treat FAP. This lack of specificity could account for the restricted application of such therapeutic agents. Within families bearing the same pathogenic APC variants, the time of onset and the frequency of polyp formation can vary significantly, suggesting that factors other than the specific APC variant contribute to the disease progression [156]. Recent studies indicate that gut microbiota play an important role in the development of colorectal adenomas and the consequent progression to cancer through a number of mechanisms, including production of bioactive tumorigenic metabolites and DNA damage, where it has been demonstrated that bacterial drivers are involved in the development of precancerous lesions and the subsequent accumulation of gene mutations [157, 158]. Many different bacteria have been identified as playing a role in stool‐based studies of CRC, and animal models which resemble FAP have shown that specific changes in the intestinal microbial community could influence a multistep progression toward colorectal carcinogenesis [158]. One specific bacterial strain that has repeatedly been linked to FAP and CRC is colibactin‐producing E. coli [159]. E. coli is a diverse group of highly prevalent Gram‐negative gastrointestinal bacteria of more than 700 serotypes. Some E. coli express polyketide synthase (pks+), which produces the toxin colibactin, a DNA‐damaging metabolite that induces DNA double‐strand breaks and cell cycle arrest [160, 161]. Colibactin‐producing E. coli seems to be positively associated with CRC, as pks+ E. coli strains are found in about 60% of human CRC specimens, compared to only 20% in healthy individuals [162]. Other studies have shown that short‐term in vitro exposure to pks+ E. coli leads to the transformation of normal, healthy epithelial cells into a premalignant state with enhanced proliferation that is characteristic of CRC cells, and small‐molecule inhibitors of colibactin have been shown to prevent colibactin‐producing E. coli tumorigenesis in mice [163, 164, 165].

Bioactive colibactin is highly unstable and colibactin biosynthesis has numerous precursors which have made isolation and characterization of the genotoxin difficult. However, a distinct mutational pks signature identified in epithelial cells exposed to pks+ E. coli strains has been detected in a large selection of human cancer genomes; it was particularly enriched in CRC, and the APC gene contained the highest number of mutations matching the pks signature [166]. Moreover, in a study of colonic mucosa of FAP patients, bacterial mucosal invasion and patchy biofilms with E. coli were observed to be scattered along the entire colon. In cultures of mucosal tissues from these patients, 68% had pks+ E. coli compared with only 22% of healthy controls [159]. Furthermore, colibactin was present in the mucus layer of FAP biofilms in direct contact with the FAP epithelium altogether indicating that colibactin‐producing pks⁺ E. coli promote tumorigenesis [167]. All of these observations suggest that colibactin‐producing pks+ E. coli promote tumorigenesis [159]. In another, more recent study, orally administered colibactin‐producing E. coli , derived from a patient with CRC, induced DNA damage in the epithelial cells of the luminal surface of the mouse rectum, thus suggesting that regulation of pks +  E. coli colonization can be used to prevent colorectal carcinogenesis [168].

According to a study by Dejea et al., 60% of FAP patients harbored enterotoxigenic Bacteroides fragilis (ETBF), compared to 30% of healthy subjects, suggesting a strong association with FAP [159]. The study found that mucosal co‐association of pks+ E. coli and ETBF occurred at a higher rate than would be expected to occur randomly and was found in more than 50% of FAP patients, compared to fewer than 25% of healthy subjects. This increases carcinogenesis through two pathways: one being mucus degradation, which increases pks+ E. coli adherence; the second is IL‐17 induction, promoted by ETBF, and early augmentation by pks+ E. coli co‐colonization [159].

Apart from E. coli , some Klebsiella pneumoniae also harbor the pks island in their genome and this might contribute to tumorigenesis in patients colonized with this bacterium by the same mechanisms at work in pks+ E. coli [169, 170]. Another bacterium associated with CRC is Fusobacterium nucleatum . F. nucleatum can elicit a host proinflammatory response and possesses virulence characteristics that promote adhesiveness to host epithelial cells [171]. F. nucleatum accelerates the onset of colonic tumors in APC ^Min/+ mice without inducing colitis and selectively expands myeloid‐derived immune cells and leads to NF‐κB activation.

The role of the gut microbiome in the development of CRC is an interesting field of study and understanding its bacteria and their mechanisms of action may lead to new pharmaceuticals for the treatment of CRC. Individuals with hereditary colorectal cancer syndromes face a significantly elevated risk of developing colorectal cancer. Data indicate that 95% of patients with FAP [41] manifest adenomas by the age of 35. Similarly, patients with hereditary nonpolyposis colorectal cancer (HNPCC) frequently present with CRC prior to age 50 [120, 172]. Therefore, the understanding of these patients' underlying gut microbiomes may lead to novel and more targeted therapies and perhaps delay the need for prophylactic colectomy.

Funding

This work was supported by The Misse and Valdemar Risom Foundation; The Disirée and Niels Ydes Foundation.

Conflicts of Interest

John Gásdal Karstensen is a consultant for Ambu, Biodexa, Boston Sci, Olympus, and SNIPR BIOME and received speaker fee from Norgine and Olympus.

Karstensen J. G., “Familial Adenomatous Polyposis—Risk of Cancer, Cancer Prevention, and Long‐Term Consequences: Learnings from Five Decades with the Danish Polyposis Register,” APMIS 134, no. 5 (2026): e70191, 10.1111/apm.70191.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.