Inherited Pancreatic Cancer Syndromes

Abstract

Pancreatic cancer remains one of the most challenging of all cancers. Genetic risk factors are believed to play a major role, but other than genes coding for blood group, genetic risks for sporadic cases remain elusive. However, several germline mutations have been identified that lead to hereditary pancreatic cancer, familial pancreatic cancer and increased risk for pancreatic cancer as part of a familial cancer syndrome. The most important genes with variants increasing risk for pancreatic cancer include BRCA1, BRCA2, PALB2, ATM, CDKN2A, APC, MLH1, MSH2, MSH6, PMS2, PRSS1 and STK11. Recognition of members of high-risk families is important for understanding pancreatic cancer biology, for recommending risk reduction strategies and, in some cases, initiating cancer surveillance programs. Because the best methods for surveillance have not been established the recommendation to refer at-risk patients to centers with ongoing research programs in pancreatic cancer surveillance is supported.

Pancreatic cancer is a rapidly progressive and usually fatal disorder that has risen to be the 4^th leading cause of cancer deaths in the U.S.¹. Lifetime risk for developing pancreatic cancer is approximately one in 71 individuals, with the majority of cases diagnosed between ages 60 and 80 years². More than a dozen types of pancreatic neoplasms have been classified by the world health organization, but ductal adenocarcinomas comprise nearly 90% of cases and are clearly the most lethal.

Inherited risk factors contribute to at least 5–10% of all pancreatic adenocarcinoma cases³, but the recognized contribution of genetic risk is likely to rise dramatically as complex risk combinations are recognized. Genetic variants in several genes have been identified as strong dominant risk factors, however, not all cases of inherited pancreatic cancer can be linked to a known gene⁴. Thus, families of pancreatic cancer patients, and other individuals may be at increased risk of pancreatic cancer but no tests are available to determine whether or not these risk factors are present. However, in other cases risk factors have been identified and organs at highest risk of developing malignancies are known.

Here we review clinical and genetic data on the inherited genetic syndromes associated with pancreatic cancer risk and current medical management options for pancreas surveillance in high risk populations. Further, we discussed allelic variants as they relate to specific patient populations.

Hereditary and Familial Pancreatic Cancers

Germline mutations conferring risk of pancreatic cancer are suggested in kindreds with multiple generations of pancreatic or related cancers, cancer diagnoses under the age of 50, individuals with synchronous and/or metachronous tumors, unusual or rare tumors including tumors more frequent in the opposite gender, and/or families with ethnicity known to have an increased mutation carrier frequency⁵. Furthermore, the presence of pancreatic cancer in a family increases pancreatic cancer risk for relatives regardless of the known gene mutation³. Thus, a good family history is critical to the management of pancreatic cancer risk.

Definition of Hereditary and Familial Pancreatic Cancer

Hereditary pancreatic cancer is defined as a genetic syndrome with an identifiable gene mutation associated with an increased risk for pancreatic cancer. Familial Pancreatic Cancer (FPC) is defined as a family with at least one pair of first-degree relatives (parent-child or sibling pair) with pancreatic cancer without an identifiable syndrome in the family³. Relatives meeting the FPC criteria have an increased risk over the general population for developing pancreatic cancer (Table 1). These individuals can be further stratified dependent on relationships to the affected relatives. An individual with three or more first-degree relatives with pancreatic cancer in a family meeting the FPC definition carries up to a 17 relative risk (RR) for pancreatic cancer⁶. Further, smoking history exacerbates pancreatic cancer risk in the FPC setting as well as reduces age of onset by up to a decade⁷.

Table 1.

Pancreatic Cancer Risk in FPC Families

Number First Degree Relatives with Pancreatic Cancer	Risk for Developing Pancreatic Cancer
0	1–2%
1	4–6%
2	4–7%
3+	17–32%

Based on Klein ⁵⁵ and Brune ⁶.

Surveillance for Early Pancreatic Cancer in FPC

Currently the best treatment option for pancreatic cancer is surgical excision. Pancreatic cancer metastasizes early and progresses rapidly. Therefore, the only cases that have a reasonable chance for a cure or prolonged survival are ones that are detected as high-risk lesions or very early (<2 cm) isolated tumors. At risk relatives who meet the FPC criteria, warrant pancreatic surveillance³. The type, frequency and age to begin surveillance are not yet well defined. Some centers utilize endoscopic ultrasound and/or MRI surveillance programs, both of which detect pancreatic lesions better than CT ⁸.

Inherited Cancer Syndromes Associated with Pancreatic Cancer (Table 2)

Table 2.

Gene	Mutation	Reference	Type of population
ATM	c.8266A>AT p.K2756X (only confirmed germline mutation) c.170G>GA p.W57X c.3214G>GT p.E1072X c.6095G>GA p.R2032K IVS41-1G>GT c.3801delG	Roberts 201229	US Caucasian
BRCA1	c.514delC p. Gln172AsnfsX62 c.1687C>T p.Gln563Stop c.3756_3759delGTCT p.Ser253ArgfsX10 c.5030_5033delCTAA p.Thr1677IlefsX2	Ghierzo 201256	Italian
	185delAG 5382insC	Stadler 201257 Ferrone 200958	Ashkenazi Jews
BRCA2	c.514delC p.Gln172AsnfsX62 c.5796_5797delTA p.His1932GlnfsX12 c.6468_6469delTC p.Glu2157IlefsX18	Ghierzo 201256	Italian
	6174delT	Stadler 201257 Ferrone 200958 Murphy 200221 Goggins 199620	Ashkenaji Jews US Caucasian
	6672insT 6819delTG 4075delGT R2034C G3076E 10323delCins11	Hahn 200359	German/European
	IVS 16-2A>G (splice acceptor site of intron 16) IVS 15-1G>A (splice donor site of intron 15) M192T K3326X	Murphy 200221	US Caucasian Ashkenaji Jews
	2458insT	Goggins 199620	N/A
CDKN2A/p16	p.E27X p.L65P c.201 ACTC>CTTT (promoter) p.G67R p.R144C p.G101W p.E27X	Ghierzo 201260	Italian
	−34G>T (initiation codon) c.47T>G p.L16R c.71G>C p.R24P c.192G>C L64L c.238_251del p.R80fs c.283del p.V95fs c.318G>A p.V106V c.457G>T D183spl	McWilliams 201133	US Caucasian
	c.324T>A p.V95E c.482G>A p.A148T c.323_324insG p.E119X	Bartsch 200261	German
MEN1	c.304G>T p.R102S c.723 to 724 del 320 CCC to C 68 CCC to CC 179 GAG to GTG c.249–252 del c.183G>A p.W61X c.196G>T p.V66F c.482delG	Moore 200162	Italian
	c.1213C>T p.Q405X c.969C>A p.Y323X c.973G>C p.A325P 210–211insAGCCC	Park 200363	Korean
	c.712delA p.K201R	Ohye 199964	Japanese
	c.CCT>CCGG, p.55fs64aaX c.GAG>AAG, p.E26K c.AGC>AAAC p. 66fs50aaX c. CGG>CAG p.R171Q c.CTG>CCG p.L168P c.GTG>GTTG p.236 fs12aaX c.TAT>TAG p.T268X c.GCC>CC p.437 fs15aaX c.GCA>G p.510fs19aaX c.CCG>GG p.493fs65aaX	Bartsch 199865	German
MLH1	K618A	Garguilo 200966	Italian
MSH2	Q402X G322D E205Q V367I	Garguilo 200966	Italian
	c.1046C>T p.P349L	Lindor201167	Northern European
	c.1147C>T p.R383X	Banville200668	Ireland
PALB2	c.1240C>T p.R414X c.508-9delAG p.R170I,183X c.3116delA, p.N1039fs	Slater 201069	European including German, UK, Latvian, Italian, Greek, Hungarian and Spanish
	heterozygous 6.7kb deletion of exon 12 & 13	Tischkowitz200970	Canadian
	c. 172-5delTTGT	Jones et al. 2009 25	US Caucasian
PRSS1	p.N29I p.R22H	Gorry 1997 71 Whitcomb 1996 43	US Caucasian -do-

Hereditary Breast-Ovarian Cancer Syndrome (HBOC)

The HBOC Syndrome is an autosomal dominant disorder with increased risks for breast cancer (47–55% by age 70), ovarian cancer (17–39%), and other cancers including prostate, male breast, melanoma and pancreatic cancer. Cancer diagnoses are observed in multiple generations of a family often with diagnoses before age 50⁹. The majority of cases of HBOC are due to mutations in the BRCA1 or BRCA2 genes.

The BRCA1-BRCA2 HBOC is the most common form of inherited breast and ovarian cancer, accounting for 90–95% of inherited breast and ovarian cancers, respectively^10–12. The incidence of HBOC in the general population is approximately 1 in 500 individuals. Carrier frequency is increased among patients with Ashkenazi (Eastern European) Jewish ethnicity, with 1 in 40 individuals at risk. Specifically, there are three founder mutations in this population: 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2¹³.

BRCA1

The BRCA1 gene, located at 17q21.31 (OMIM: 113705) codes for a protein complex regulating DNA repair, cell cycle checkpoint controls and maintaining genomic stability. Mutations in BRCA1 are primarily associated with early onset breast and ovarian cancer risks, though other cancer risks do occur at higher rates than expected in the general population including pancreatic cancer. Brose and coworkers¹⁴ reported a relative risk of 2.8 compared to the general population risk of 1.3% for pancreatic cancer in BRCA1 mutation carriers. In chronic pancreatitis, which is a risk factor for pancreatic cancer, and in pancreatic cancer tumors there is a down-regulation of BRCA1 mRNA and protein¹⁵. This suggests that BRCA1 may play a role in protecting the pancreas from cancer development. However, Moran and coworkers¹⁶ reported a series of 268 BRCA1 families, in which increased pancreatic cancer risk was not recognized. Further, Axilbund and coworkers sequenced the BRCA1 gene in 66 pancreatic cancer patients meeting the FPC definition and did not identify any mutations¹⁷. Taken together these data suggest that the risk of pancreatic cancer for carriers of BRCA1 mutations is relatively small, and does not warrant inclusion of at-risk subjects in a pancreatic cancer surveillance program.

BRCA2

BRCA2, located on 13q13.1 (OMIM #600185), was identified in 1995 as an associated candidate gene in familial breast cancer¹⁸. The BRCA2 protein product functions as a tumor suppressor by way of interactions with rad51-dependent DNA repair¹⁹. BRCA2 mutations increase breast and ovarian cancers risk, and other cancers including male breast, prostate, melanoma and pancreatic cancer¹⁶. BRCA2 mutations are the most common form of inherited pancreatic cancer risk²⁰. Kindreds with at least 3 or more cases of pancreatic cancer have a 15–17% chance for carrying a BRCA2 mutation²¹. Analysis of 222 BRCA2 families identified a statistically significant increased risk for pancreatic cancer (RR 4.1, 95% CI 1.9–7.8)¹⁶. The Breast Cancer Linkage Consortium indicated that BRCA2 mutation carriers have a 3.5 RR compared to non-mutation carriers (5–7% lifetime risk) for developing pancreatic cancer²². In a genomic sequencing study of unselected, apparently sporadic pancreatic cancers, 3/41 (7.3%) were found to harbor germline BRCA2 mutations, none of which had family history of pancreatic cancer, indicating that multiple underlying genetic factors increase the risk for pancreatic cancer.

Animal studies confirm a major role for BRCA2 in a mouse model of FPC. Feldmann and coworkers²³ developed a double conditional BRCA2 knockout mouse with and without the Trp53 (R172H) deregulating variant. Mice with the BRCA2 (−/−) background resulted in widespread DNA damage throughout the exocrine pancreatic cells, with development of pancreatic intraepithelial neoplasia (PanIN lesions) in most mice and invasive pancreatic ductal adenocarcinoma in about 15% of mice. Combining BRCA2 (−/−) and the Trp53 (R172H) variants accelerated carcinogenesis. The authors conclude that loss of BRCA2 function predisposes the exocrine pancreas to profound DNA damage, and the frequency of invasive neoplasia is accentuated by the concomitant deregulation of p53²³. However, in humans, Brose and coworkers¹⁴ did not see the common loss of BRCA2 mRNA expression and protein in sporadic tumors as they had seen with BRCA1. Taken together, these data suggest that patients with BRCA2 mutations are at increased risk for pancreatic cancer, but that this pathway is not essential or common in sporadic pancreatic cancers.

The high risk of pancreatic cancer in BRCA2 warrants consideration for possible surveillance. For reasons that are not yet understood, some large BRCA2 kindreds have multiple cases of pancreatic cancer, while others have none. Therefore, pancreatic surveillance is only recommended for BRCA2 mutation carriers with a family history of pancreatic cancer. Surveillance may include endoscopic ultrasound or MRI evaluations. Currently there are no formal guidelines for pancreatic cancer surveillance or medical management in the HBOC patient population. However, for other cancers associated with HBOC, the National Comprehensive Cancer Network set forth aggressive, early onset management guidelines for breast and ovarian cancers.

Familial Pancreatic Cancers associated with the Fanconi Anemia DNA repair pathway

PALB2

The partner and localizer of BRCA2 (PALB2) gene (OMIM # 610355), was originally identified as a breast cancer susceptibility gene associated within the Fanconi anemia DNA repair pathway (FANCN). Rahman and coworkers²⁴ identified mono-allelic truncating mutations in 10 out of 923 patients with familial breast cancer indicating a 2.3-fold high risk for breast cancer. In 2009, the first paper was published reporting PALB2 as a FPC susceptibility gene²⁵. Jones and coworkers²⁵ estimated that approximately 3–4% of FPC families may harbor a mutation in PALB2²⁵. Analysis of PALB2 in BRCA-negative families identified a 4-fold increased risk for male breast cancer and a 6-fold increased risk for pancreatic cancer in relatives of the mutation carrier ²⁶.

The importance of PALB2 is yet to be established in larger populations. Recommendations for surveillance have not been established, but individuals from FPC kindreds should be counseled according to the FPC risk, with greater risk assumed if PALB2 tracks with cancer in the family.

Ataxia Telangiectasia (AT)

ATM

Ataxia Telangiectasia (AT) is a rare autosomal recessive condition characterized by early onset progressive cerebellar ataxia, telangiectasia of the skin, ionizing radiation sensitivity and immunodeficiency. AT presents during the first decade of life in biallelic mutation carriers and these individuals carry a 38% risk for cancer. The gene affected is the ATM gene. Monoallelic mutation carriers harbor cancer risks including breast and pancreas. Female mutation carriers are reported to have an increased risk for breast cancer equal to that of having one first-degree relative with breast cancer²⁷.

The possible importance of ATM in pancreatic cancer was highlighted in BxPC-3 cells (containing wild type K-ras) which were treatment with curcumin²⁸. Curcumin resulted in phosphorylation of ATM at Ser-1981, G2/M cell cycle arrest and apoptosis of the tumor cells²⁸. This beneficial effect of curcumin was eliminated with SiRNA silencing of ATM.

In a recent analysis of 166 unrelated FPC patients, 2.4% were identified as ATM mutation carriers²⁹. Further, 4.6% of FPC patients carried an ATM mutation if there were more than three cases of pancreatic cancer in their relatives²⁹. Analysis of gene function are necessary to elucidate pancreatic cancer relationship to AT.

Genetic counseling and specific medical management is warranted for families with ATM mutations, and guidance is available³⁰. Pancreatic cancer surveillance is not clearly defined in this population, though patients meeting the FPC definition may consider pancreatic surveillance programs.

Familial Atypical Multiple Mole Melanoma Syndrome

CDKN2A

The Familial Atypical Multiple Mole Melanoma syndrome (FAMMM) is characterized by an increased predisposition toward dysplastic nevus and early onset melanoma in an autosomal dominant inheritance pattern. CDKN2A, a cell cycle regulator gene coding for the p16 protein product, has functional effects in melanoma and pancreatic cancer cell lines, thus implicating it as a potential risk factor for inherited pancreatic cancer risk³¹. Vasen and coworkers³² determined that a germline founder mutation in a Dutch cohort was associated with up to a 17% lifetime risk for pancreatic cancer in this FAMMM family. In other FPC kindreds, mutations throughout CDKN2A have been observed without melanomas³³. In a series of 120 American non-Hispanic pancreatic cancer cases with a family history of pancreatic cancer, 3.3% carried a CDKN2A mutation. Further, the penetrance for developing pancreatic cancer was estimated at 58% by age 80 for mutation carriers.

Medical management is rigorously suggested to begin in childhood due to the rapid and early onset development of atypical nevi. Recommendations include semi-annual dermatology evaluations including baseline photography beginning in childhood as well as pancreatic cancer surveillance consideration. Lifestyle modification includes applying SPF lotions and limiting sun exposure. Pancreatic cancer risk appears to be especially high in smokers³³, and minimizing such exposure is recommended.

Familial Adenomatous Polyposis (FAP)

APC

Familial Adenomatous Polyposis (FAP) syndrome is classically known for the multitude of early onset gastrointestinal adenomas. In this autosomal dominant condition, symptoms present on average at age 16 years³⁴. Inherited mutations in the tumor suppressor gene, APC, account for the majority of cases. Though the primary cancer risk in FAP is colon cancer, extra-colonic risks including duodenal, thyroid, hepatic and pancreatic cancers exist. Small bowel cancers occur in 50–90% of patients with FAP and are usually periampullary³⁵. Hepatoblastoma is observed in early childhood and poses a risk of 1.6%. Thyroid cancers are observed in approximately 2% of patients with FAP. Pancreatic cancer is considered a low risk cancer, though it is observed in FAP families with higher incidence than the general populations. Surveillance for FAP-related cancer include an intensive medical regimen consisting of yearly colonoscopies starting in the second decade until the presence of polyps is too numerous to remove via polypectomy. Total colectomy is recommended for treatment of polyps and prevention of colon cancer. Esophagogastroduodenoscopy (EGD) is recommended starting by age 25 years every one to three years or before colectomy. Extracolonic surveillance includes hepatoblastoma evaluations for pediatric patients and complete physical examination annually³⁶. Pancreas surveillance may be considered for such families where pancreatic cancer is present.

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer)

Lynch syndrome accounts for approximately 2–5% of all colorectal cancers diagnoses and is the most common cause of inherited colon cancer. Substantially increased cancer risks for colon and extra-colonic tumors exist in patients with Lynch syndrome. The lifetime colorectal cancer risk ranges from 52–82% with a mean diagnosis age of 44 years. Other lifetime cancer risks include endometrial cancer (25–60%), ovarian cancer (4–12%), gastric (6–13%) and pancreatic cancer (1.3–4%)^37,38. Pancreatic cancer was observed in 2 out of 282 cancers diagnosed in a series of 121 families with known germline mutations. While this report identified a low cumulative incidence, others have identified higher risks for Lynch syndrome associated pancreatic cancer. Geary and coworkers³⁹ identified a 30-fold increased risk for pancreatic cancer before the age of 50 years and an almost nine times as likely overall risk in a cohort of 147 families with Lynch syndrome.

Lynch syndrome tumors arise from germline mutations in mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2. As such, the mismatch repair dysfunction results in loss of protein expression and microsatellite instability (MSI) in tumors. Analysis of tumor tissue may establish or exclude a Lynch syndrome diagnosis. However, approximately 10–15% of sporadic colon tumors display this phenotype, leaving clinicians to utilize family history as a means for risk assessment in some cases. It is anticipated that with the growing practice of universal testing of newly diagnosed colon cancers, many new cases of Lynch syndrome will be diagnosed.

Hereditary Pancreatitis (HP)

PRSS1

While rare, hereditary pancreatitis (HP) is among the only known inherited cancer predisposition syndrome for which pancreatic cancer is the sole cancer risk factor. HP is an inherited form of chronic pancreatitis, in which a subset of families carries gain-of-function mutations in PRSS1⁴³. Symptom onset begins in the first to second decade of life, though penetrance is estimated at 80%⁴⁴. Recurrent acute pancreatitis attacks develop into chronic pancreatitis and pain leading to pancreas dysfunction, diabetes and pancreatic cancer risk. Rebours et al. described that the pancreatic cancer risk ranges from 18–53% in a French cohort ⁴⁵.

PRSS1 codes for cationic trypsinogen, a digestive enzyme. Premature activation of trypsin within the pancreas is believed to cause activation of the other digestive enzymes, resulting in pancreatic auto-digestion and chronic inflammation⁴⁶. The incidence of pancreatic cancer in these families increases after 20–40 years of chronic pancreatitis, with earlier onset and higher incidence in smokers and diabetics^47,48. The importance of inflammation in initiating the epithelial to mesenchymal transition and pancreatic cancer, especially in the presences of KRAS G12D mutations has recently been published^49,50.

The challenge with surveillance of HP patients for pancreatic cancer is the gross distortion of the pancreatic architecture by chronic pancreatitis. One option for patients at high risk is total pancreatectomy⁵¹, with or without islet autotransplantation (TPIAT)⁵². With recognition that risk is markedly reduced in non-smokers and in non-diabetics, and that some large HP families have never had a case of pancreatic cancer, caution is required in recommending this irreversible and potentially dangerous procedure.

Peutz-Jeghers Syndrome (PJS)

STK11

Peutz-Jeghers syndrome (PJS) is caused by mutations in STK11 and presents with mucocutaneous hyperpigmentation and hamartomatous polyposis. Pancreatic cancer risk has been reported as high as a 132-fold risk in patients with PJS⁵³. Though a rare syndrome, PJS currently confers the greatest defined inherited risk factor for pancreatic cancer.

Genetic Counseling and Risk Assessment

Patient identification for pancreatic cancer risk stratification due to inherited factors is complex (Table 2). Pedigree analysis, molecular tumor studies and germline mutation testing collectively offer patients the most accurate risk assessment. In addition to the medical complexities, a family history of pancreatic cancer can be emotionally trying for the high risk healthy relative. In a series of high risk family members, Maheu and coworkers ⁵⁴ evaluated perception of cancer risk and identified that relatives who had increased worry prior to beginning pancreatic cancer surveillance may benefit from a comprehensive risk assessment and counseling program. Because no consensus guidelines exist for patients at high risk for inherited pancreatic cancer syndromes, clinical judgment and personalized counseling may be considered for this population. At the time of publication, patients meeting the FPC definition or those with known inherited cancer syndromes with a family history pancreatic cancer may consider a pancreatic cancer surveillance program. Thus it is generally recommended that surveillance of these patients only be performed in centers experienced in caring for these high-risk patients, ideally enrolling them into research protocols.