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. Author manuscript; available in PMC: 2022 Jul 21.
Published in final edited form as: J Gastroenterol Hepatol. 2022 Apr 13;37(6):973–982. doi: 10.1111/jgh.15848

Immunogenetics of gastrointestinal cancers: A systematic review and retrospective survey of inborn errors of immunity in humans

Beishi Zheng *,†, Michael G Artin *, Howard Chung *, Bing Chen *, Siming Sun *, Benjamin L May *, Chin Hur *, Peter H R Green *, Timothy C Wang *, Jiheum Park *, Xiao-Fei Kong *
PMCID: PMC9301767  NIHMSID: NIHMS1820550  PMID: 35384041

Abstract

Background and Aim:

Humans with inborn errors of immunity (IEI), or primary immunodeficiencies, may be associated with a potential risk factor for early-onset gastrointestinal (GI) cancer.

Methods:

We systematically reviewed all cases with clinical diagnoses of both an IEI and a GI cancer in three databases (MEDLINE, SCOPUS, and EMBASE). In total, 76 publications satisfying our inclusion criteria were identified, and data for 149 cases were analyzed. We also searched our institutional cancer registry for such cases.

Results:

We identified 149 patients with both an IEI and a GI cancer, 95 presented gastric cancer, 13 small bowel cancer, 35 colorectal cancer, and 6 had an unspecified cancer or cancer at another site. Gastric and colon adenocarcinomas were the most common. For both gastric and colorectal cancers, age at onset was significantly earlier in patients with IEIs than in the general population, based on the SEER database. Common variable immunodeficiency (CVID) was the most common IEI associated with gastrointestinal cancer. About 12% of patients had molecular genetic diagnoses, the three most frequently implicated genes being ATM, CARMIL2, and CTLA4. Impaired humoral immunity and Epstein–Barr virus (EBV) infection were frequently reported as factors potentially underlying early-onset GI cancers in patients with IEIs. We identified one patient with CVID and early-onset gastric adenocarcinoma, recurrent diarrhea, and gastrointestinal CMV infection from a retrospective survey.

Conclusion:

Patients with IEIs should be considered at risk of early-onset GI cancers and should therefore undergo cancer screening at an earlier age.

Keywords: gastrointestinal cancer, human genetics, immunosurveillance, inborn errors of immunity

Introduction

Cancer immunosurveillance, first proposed by Frank Macfarlane Burnet and Lewis Thomas in 1957, plays an indispensable role in preventing gastrointestinal cancers.1 Studies of AIDS patients or organ transplant recipients have shown that cancers generally, and non-melanoma skin cancers, in particular, occur more frequently in immunocompromised individuals.2,3 Studies of transgenic mice with defects of crucial components of the immune system have improved our understanding of the effector molecules involved in immunosurveillance and have led to the development of immune checkpoint inhibitors, a key breakthrough in immunotherapy for cancer treatment.4,5 Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, manifest as recurrent infections, autoimmunity, autoinflammatory diseases, allergy, and cancer.6 Humans with IEIs constitute experiments of nature that provide us with a unique angle from which to study immunosurveillance of GI cancers and interaction between environment and host. However, the rare cases of GI cancer in patients with IEIs can prove challenging for the physicians responsible for patient care. For instance, IEIs can manifest as early-onset GI cancers but are not yet generally considered to be a risk factor for such cancers. Thus, contrary to other hereditary factors conferring a high risk of GI cancer, there are currently no practice guidelines for screening for gastrointestinal cancers in patients with IEIs.7,8

The diagnosis of an early-onset (before the age of 50 years) gastrointestinal cancer, whether gastric or colorectal cancer, is devastating for any patient.9–11 The field of primary immunodeficiencies has progressed considerably with recent advances in genetic sequencing technology, which are facilitating genetic diagnosis and discoveries. Defects of more than 400 genes, some dominant and others recessive, have been shown to cause wide-ranging immunodysregulation, with complete or incomplete penetrance.6 Epidemiological data suggest that inborn errors of immunity are more prevalent than previously thought, affecting about 1:8500 to 1:100 000 individuals in the general population.12 With earlier clinical recognition, appropriate treatment, and hematopoietic stem cell transplantation, many patients with IEIs now survive into adulthood, overcoming severe infections or inflammation. Given these improvements in the overall survival of patients with IEI, physicians may begin to see delayed clinical phenotypes with incomplete penetrance, including gastrointestinal cancers. It is often difficult to understand the human genetics and immunological basis of IEIs, due to phenotypic and allelic heterogeneity, differences in expressivity and incomplete penetrance. Due to the complexity of human genetics and immunology, and the rareness of individuals with both an identified IEI and a gastrointestinal cancer, we systematically reviewed all reported cases with diagnoses of both an IEI and a gastrointestinal cancer. We summarized their genetic and immunological features and highlighted the elements of importance for the clinical surveillance and management of this particular population.

Methods

Case identification and literature search.

We followed a Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA)13 flow chart for the literature search and data collection for this systematic review (Fig. S1). Briefly, we conducted a search of the MEDLINE, SCOPUS, and EMBASE databases for all publications up to December 1, 2020, focusing on IEIs and GI cancers. We focused on luminal GI cancers and excluded pancreatic or hepatobiliary cancers. We followed the International Union of Immunological Societies (IUIS) guidelines6 to ensure the inclusion of all IEIs. We searched three databases for the following terms: “gastrointestinal neoplasms,” “primary immunodeficiency,” “agammaglobulinemia,” “common variable immunodeficiency,” “dysgammaglobulinemia,” “lymphopenia,” “immune dysregulation,” and 14 additional Medical Subject Headings (MeSH) terms relating to IEIs in the title, abstract, or keywords of articles (Table S1). The results of three database searches (n = 1146) were then carefully reviewed, as illustrated in Figure S1. Additional publications (n = 24) were identified and included manually if missed by the search strategy described earlier. Duplicate articles were eliminated. All records (n = 1099) were then reviewed independently by two authors (B. Z. and H. C.) by comprehensive reading, and any discrepancies were resolved by a third author (X.-F. K.). The inclusion criteria for cases were as follows: (i) clinical diagnosis of IEI and (ii) clinical diagnosis of a gastrointestinal cancer. The exclusion criteria were (i) article not written in English and (ii) lack of detailed clinical information, such as age, sex, and age-at-onset data for the patient. In total, 76 articles satisfied our inclusion criteria and did not meet the criteria for exclusion.

Data curation, quality assessment, and statistical analysis.

We collected information by scrutinizing the publications identified to generate a dataset with the following information: author and year of publication of the article and, for the patients, sex, ethnicity, age at cancer diagnosis, genetic defects, immunological dysfunctions, IEI diagnosis, cancer histology, and prognosis. Standardized forms were used to extract the required information from the articles. A quality assessment form was developed based on the CARE (CAse REports)13 tool for quality assessment (Table S2). The expected distributions of age, sex, and survival interval for GI cancers were calculated from the data in the SEER (Surveillance, Epidemiology, and End Results) database. Time-to-event and survival analyses (log rank tests) were performed in GraphPad Prism 8.0 to calculate the hazard ratio. Categorical variables were analyzed with Fisher’s exact tests or χ2 tests. Continuous variables were analyzed with t-tests. All data were analyzed with the statistical packages in R software (4.0.0).

Retrospective survey.

We performed a retrospective survey of the Columbia University Irving Medical Center (CUIMC) tumor registry to search for GI cancer patients with IEIs. We searched for all patients with a matching ICD-O-3 code for esophageal, gastric, small bowel, or colon cancer. For these patients, laboratory test results, medication, and ICD-9/10 code data were extracted from institutional electronic health records (EHR). Potential IEI patients were identified on the basis of the presence of an immunodeficiency-related ICD-9/10 code (D80, D81, D82, D83, D84, D89, 279, and 279.5) with the exclusion of patients with graft versus host disease. Age at diagnosis was retrieved from tumor registry data. Data on immunoglobulin levels and intravenous immunoglobulin (IVIG) treatment were retrieved to investigate. The data for the candidate patients were carefully reviewed by an experienced physician to determine the clinical phenotypes of GI cancer and IEI. This study was approved by the CUIMC institutional review boards.

Results

A clinical summary of gastrointestinal cancers in patients with inborn errors of immunity.

The 76 publications identified14–89 included 149 cases in which both IEIs and gastrointestinal cancers had been diagnosed. A summary of the clinical characteristics of the patients concerned is provided in Figure 1. Briefly, 95 cases were diagnosed with gastric cancer, 13 cases presented with small bowel cancer, 35 cases with colorectal cancer, 3 cases with esophageal cancer, and 3 cases with a GI tract tumor at an unspecified location (Fig. 1a). In total, 59 cases (40%) were reported after 2010 (Fig. 1b). The dataset consisted of 84 (56.4%) male patients, 58 (38.9%) female patients, and 7 patients for whom sex was not specified (Fig. 1c). Age at onset for the cancer ranged from 3 to 82 years, with a median age at onset of 42 years (Fig. 1d). Most of the reported cases (64.4%) were diagnosed before the age of 50 years, and their cancers should therefore be considered early-onset. Age at onset for GI was normally distributed, contrasting with the left-skewed distribution in the general population. Fisher’s exact test showed that the proportion of male patients was higher in the younger age groups (ages 0–40) than the older age groups (ages above 40, P = 0.034) (Fig. 1d). Age at onset of the GI cancer was 26 to 30 years lower for the individuals with IEIs than for the general population (42 vs 68–72 years), according to the data of the SEER database. Ethnicity data were available for only 18 patients: seven were classified as white, four as non-Hispanic, three as Asian, two as African American, and two as Hispanic or Latino. The IEI diagnosis was common variable immunodeficiency (CVID) for 88 patients in the cohort. The other IEI diagnoses included X-linked agammaglobulinemia (XLA) in 11 patients, selective IgA deficiency (SIgAD) in 10 patients, and ataxia-telangiectasia mutated gene deficiency (ATM) in 10 patients. The rate of molecular genetic diagnosis for IEIs was low, with disease-causing genotypes reported for only 18/149 (12.1%).

Figure 1.

Figure 1

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A descriptive summary of patients with inborn errors of immunity and GI cancers. (a) A schematic presentation of the numbers of esophageal, gastric, small bowel, and colon cancers reported in patients with IEIs. (b) The table describes the number of cases published over the last six decades. (c) A pie chart of the sex distribution for this cohort. (d) Histogram presenting the age and sex distributions of the cohort. NA, not available.

Gastric cancers in patients with inborn errors of immunity.

Our literature search identified 95 patients with an IEI and gastric cancer, which was the most common GI cancer in this cohort (Table S3). Most (87/95, 91.5%) of the patients were diagnosed with gastric adenocarcinoma. The other cancer diagnosed were lymphoma (7/95, 7.4%) and neuroendocrine carcinoma (1/95, 1.1%) (Fig. 2a). Mean age at gastric cancer diagnosis was 45.86 years: male patients outnumbered female patients in this group (55.8% vs 43.2%), and there were no significant differences with respect to the expected value (Fig. 2b). Age at onset of gastric cancer in patients with IEIs was significantly different from that in the general population, with most patients with IEIs diagnosed with gastric cancer before the age of 65 years (Fig. 2b). Gastric cancer was diagnosed between the ages of 25 and 44 years in 32.6% of IEI cases, whereas such early diagnosis was uncommon in the general population (Fig. 2b). A time-to-event data analysis based on the observed and expected age at onset for gastric cancer yielded a hazard ratio (HR) of 3.57 for the IEI group, indicating a significantly earlier than expected age at onset for this group (Fig. 2c). Prognosis was as follows: 31 (32.6%) patients died within 1 year, and 9 (9.5%) patients died within 5 years of a gastric cancer diagnosis. The 5-year survival rate in IEI patients with gastric cancer was 27.3%, which is close to the value reported for the general population, as shown by the survival analysis (Fig. 2d). CVID was the most common IEI and was found in 69 cases (72.6%) of gastric cancer. ATM defects and XLA were the next most frequent IEIs (Fig. 2e). Four patients with CTLA4 deficiency and one patient with LRBA deficiency were reported to have gastric cancer. However, most of the publications did not report the history of Helicobacter pylori infection. In summary, inborn errors resulting in B-cell defects or dysfunctions of humoral immunity were the most common IEIs associated with gastric cancer.

Figure 2.

Figure 2

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Gastric cancers reported in patients with IEIs. (a) Cellular types of gastric cancer reported in patients with IEIs. Adenoca, adenocarcinoma; NET, neuroendocrine tumor. (b) The table shows the sex and age distributions of gastric cancer patients from the IEI cohort relative to the expected numbers in the general population imputed from the SEER database. OR, odds ratio. (c) Pie chart of the different types of IEI and numbers of cases with gastric cancer. CVID, common variable immunodeficiency; ATM, ataxia-telangiectasia mutated; XLA, X-linked agammaglobulinemia; CTLA4, cytotoxic T-lymphocyte associated protein 4; SIgAD, selective IgA deficiency; FMF, familial Mediterranean fever; LRBA, LPS-responsive beige-like anchor protein. (d) Survival curve for gastric cancer comparing patients with and without IEIs. (e) The genetic and clinical diagnosis of IEIs in patients with gastric cancer. NA, not available. (c, d) Inline graphic, IEIs; Inline graphic, General.

Small bowel cancers reported in patients with inborn errors of immunity.

The small bowel is an uncommon site for cancers. To date, 13 patients with IEIs and small bowel cancer have been reported (Table S4). Lymphoma was the most common type of cancer (11/13, 84.6%) affecting the small bowel, with 10 cases of B-cell lymphoma, and one of T-cell lymphoma. Neuroendocrine carcinoma and reticular lymphosarcoma were reported in one case each. Mean age at cancer diagnosis was 43.92 years, and there were seven male patients and six female patients. CVID (41.6%, 6/13) was the most common IEI associated with small bowel cancer, consistent with the recent meta-analysis of CVID patients showing that lymphoma was the cancer most frequently reported in these patients.90 One patient with Wiskott–Aldrich syndrome and another with familial Mediterranean fever were reported. Overall, 41.6% (6/13) of the patients survived for more than 5 years, 15.4% (2/13) survived for less than 3 years, and 23.1% (3/13) died within 1 year. The genetic etiology of small-bowel lymphoma in CVID remains to be explored.

Colorectal cancers in patients with inborn errors of immunity.

There were 35 cases of colorectal cancer reported in patients with IEIs (Table S5). The most common type of cancer was adenocarcinoma (68.1%, 24/35), followed by lymphoma (11.4%, 4/35), and smooth-muscle tumors (5.7%, 2/35) (Fig. 3a). Cancer originating from other cell types, such as neuroendocrine carcinoma, rhabdomyosarcoma, and squamous cell carcinoma, was reported in one case each, including (Fig. 3a). Mean age at onset was 32.94 years, and this group comprised 60% (21/35) male and 28.6% (10/35) female patients. Most of the cases (71.4%, 25/35) were diagnosed before 45 years of age, which is significantly younger than expected (Fig. 3b). Time-to-event analysis (Fig. 3c) revealed a HR of 5.23 (95% CI 2.65–10.30) for the IEI group. Overall, 42.9% (15/35) of the patients with IEIs died within 1 year of colon cancer diagnosis, and the 5-year survival rate for IEI patients with colon cancer was 31.4% (11/35). A survival analysis showed prognosis to be worse for the IEI group than for the general population (HR = 2.55, P = 0.002) (Fig. 3d). The most common types of immune dysregulation were B-cell defects (71.4%, 25/35), including CVID, XLA or selective IgA deficiency. However, DNA repair defects, including BLM, NBS1, and ATM gene mutations, accounted for 20% (7/35) of IEI cases with colorectal cancer (Fig. 3e). In summary, colorectal cancer appeared to be more heterogeneous in terms of immunological dysfunction and to lead to worse outcomes in patients with IEIs than in the general population.

Figure 3.

Figure 3

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Colon cancer in patients with IEIs. (a) Cellular types of colon cancer reported in patients with IEIs. Adenoca, adenocarcinoma; NET, neuroendocrine tumor; SMT, smooth muscle tumor; RMS, rhabdomycosarcoma; GS, granulocytic sarcoma; SCC, squamous cell carcinoma. (b) The table shows the sex and age distribution of colon cancer patients from the IEI cohort relative to the expected numbers in the general population imputed from the SEER database. OR, odds ratio. (c) Pie chart of the different types of IEIs and numbers of cases with colon cancer. CVID, common variable immunodeficiency; ATM, ataxia-telangiectasia mutated; XLA, X-linked agammaglobulinemia; BLM, Bloom syndrome; SIgAD, selective IgA deficiency; CARMIL2, capping protein regulator and myosin 1 linker 2; ATM, ataxia-telangiectasia mutated; FMF, familial Mediterranean fever; NBS, Nijmegen breakage syndrome. (d) Survival curve for colon cancer comparing patients with and without IEIs. (e). The genetic and clinical diagnosis of IEIs in patients with colon cancer. NA, not available. (c, d) Inline graphic, IEIs; Inline graphic, General.

A retrospective survey and one case of early-onset gastric cancer and inborn errors of immunity.

A search of our institutional cancer registry identified 422 patients with a GI cancer diagnosis: 39 patients with esophageal cancer, 73 patients with gastric cancer, 36 patients with small bowel cancer, and 274 patients with colon cancer. We reviewed the EHRs of 40 patients with either an ICD code for immunodeficiency or hypogammaglobulinemia or on IVIG treatment. Immunosuppression was either transplant- or treatment-related in most cases, but we identified one patient with early-onset gastric cancer with a clinical IEI diagnosis (Fig. 4a). The patient was a 40-year-old South Asian woman with celiac disease, CVID on IVIG infusion, and adrenal insufficiency on steroids. She was born to non-consanguineous parents and her sister was also diagnosed with celiac disease (Fig. 4a). She had chronic diarrhea on a gluten-free diet, and recurrent CMV infections were detected on gastric and colonic biopsies. An endoscopic evaluation for celiac disease at the age of 36 years detected a 30 mm × 25 mm polypoid mass in the prepyloric region of the stomach (Fig. 4b, c). Endoscopic submucosal dissection was performed, and pathology analysis revealed a moderately differentiated, gland-forming adenocarcinoma invading the muscularis mucosae (pT1a). Immunohistological staining to detect mismatch repair defects, microsatellite instability tests, and common hereditary cancer panel testing (47 genes) all gave normal results. This patient currently undergoes annual endoscopic surveillance for gastric cancer but still has chronic diarrhea on a gluten-free diet (Fig. 4d). Further immunological and genetic investigations are required to determine the underlying causes of this unique GI cancer/IEI phenotype.

Figure 4.

Figure 4

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The clinical characteristics of one patient with early-onset gastric cancer and CVID identified from a retrospective survey. (a) Family pedigree of the index case with gastric adenocarcinoma; endoscopic appearance of gastric cancer (b, white light; c, narrow band imaging); (d) clinical course of the index case with gastric adenocarcinoma and CVID. ITP, idiopathic thrombocytopenic purpura; TTG, tissue transglutaminase; IEL, intraepithelial lymphocytes; CMV, cytomegalovirus; PEG, percutaneous endoscopic gastrostomy; EGD, esophagogastroduodenoscopy; ESD, endoscopic submucosal dissection.

Discussion

The Fearon–Volgelstein model has prevailed over the last few decades, and genetic practices for GI cancer have now emerged and can facilitate the management of about 3% to 5% of all colorectal cancer patients.91 Pathogenic variants with various degrees of clinical penetrance have been identified in 9–26% of patients with early-onset colorectal cancer.92 However, the detection of such mutations is limited by a lack of knowledge of the full genetic landscape for GI cancers. We investigated the immunogenetic determinants of GI cancers by performing a systemic review of cases in patients with IEIs, who usually have a genetic predisposition for cancer and abnormal immunological dysregulation. Even though IEIs are usually diagnosed during childhood and mortality rates are high at a young age, 2–10% of patients have been found to develop cancers with their short lifespans.78 Our analysis indicates that patients with IEIs may be prone to early-onset GI cancers. Longitudinal data from a large IEI cohort are lacking, but our findings are consistent with previous CVID studies.58,93 Further studies are required to delineate the clinical epidemiology of IEIs in patients with early-onset GI cancers, through immunological or genetic testing. A collaboration between clinical immunologists and pediatricians might facilitate GI cancer surveillance in individuals with IEIs. We need to address the question as to whether there is an association between clinical symptoms or biomarkers of IEIs and early-onset GI cancer. It would be intriguing to determine whether immunoglobulin level, lymphocytopenia, a clinical diagnosis of CVID, or a history of IVIG use is associated with early-onset GI cancer. Our retrospective study based on data from our institutional registry revealed that patients with IEIs are not common (1/422) among those with GI cancers, but it would also be interesting to increase the sample size and to perform more careful evaluations to detect potential IEIs.

Several factors could, conceivably, account for the early-onset gastrointestinal cancers observed in patients with IEIs. First, primary immunodeficiency may lead to chronic mucocutaneous infection (with H. pylori or EBV, for example) in the gastrointestinal tract, which is a risk factor for gastric cancer. CARMIL2 deficiency has been associated with EBV+ smooth muscle tumors in the GI tract.65 Previous studies on CVID have revealed a high prevalence of H. pylori infection and multifocal atrophic gastritis, but H. pylori infection rates in CVID patients vary between reports and may not, necessarily, explain the risk of GI cancer.67 Nevertheless, one recent large CVID cohort meta-analysis90 on 8123 CVID patients revealed an estimated prevalence of gastric cancer in CVID patients of about 1.5%, lower than the prevalence of 4.1% for lymphoma and consistent with another report suggesting that gastric cancer may be the leading cause of death in CVID patients.67 Gastrointestinal cancers may also arise due to defects of immune cells in the mucosa. As most reported cases have impaired humoral immunity, this suggests that B cells may play an important role in gastrointestinal mucosal surveillance. Only a few cases with genetic abnormalities have been reported, but several genetic disorders, including CTLA4, LBRA, and CARMIL2 mutations, result in well-defined B-cell abnormalities.

A third plausible explanation is related to intrinsic epithelium abnormalities due to the pleiotropic effects of some genes. Three disorders, such as ataxia-telangiectasia due to ATM mutations, Nijmegen breakage syndrome due to NBS1 defects, and Bloom syndrome due to BLM mutations, have been reported to cause heterogeneous clinical phenotypes and chromosomal instability. ATM is a serine/threonine kinase activated by DNA damage: it phosphorylates several tumor suppressors, including p53, NBS1, and H2AX. Eight patients (9.5%) with ataxia telangiectasia due to biallelic ATM gene mutations have been reported to have gastric cancer and immunodeficiency.33,50,76,82,83,85 Individuals with heterozygous germline ATM mutations may have a higher risk of early-onset gastric and pancreatic cancer.94 However, some IEIs characterized by impaired DNA repair, such as MCM4 and GINS1 deficiencies, have not been found to lead to cancers.95,96 It is possible that GI cancers in patients with DNA repair disorders are more strongly related to intrinsic epithelial cell defects than to compromised immunity. With advances in human genetics and immunological technologies, studies of humans with IEIs might improve our understanding of immune surveillance in the gastrointestinal tract in general.

Supplementary Material

Supplementary Material

Figure S1. Flow diagram for literature search and data extraction.

Table S1. Search Terms.

Table S2. Quality Assessment Form.

Table S3. Patients with gastric cancer.

Table S4. Patients with small-bowel cancers.

Table S5. Patients with colorectal cancers.

Acknowledgments

We thank Dr. Jean-Laurent Casanova, Laurent Abel, Anil K Rustgi, and Benjamin Lebwohl for their careful reading of the manuscript and suggestions. Figure 1 was created with BioRender.com.

Financial support:

The research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number K08DK128631 and the National Cancer Institute under Award Numbers R01 CA247790 (C. H.) and R21 CA265400 (C. H.). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Declaration of conflict of interest: Beishi Zheng, Michael G. Artin, Howard Chung, Bing Chen, Siming Sun, Benjamin L. May, Peter HR. Green, Timothy C. Wang, Jiheum Park, and Xiao-Fei Kong have no conflict of interest (financial, professional, or personal) to disclose. Chin Hur reports receiving consulting fees from Roche Diagnostics and Value Analytics Labs.

Supporting information

Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material

Figure S1. Flow diagram for literature search and data extraction.

Table S1. Search Terms.

Table S2. Quality Assessment Form.

Table S3. Patients with gastric cancer.

Table S4. Patients with small-bowel cancers.

Table S5. Patients with colorectal cancers.

NIHMS1820550-supplement-Supplementary_Material.pdf (807.8KB, pdf)

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