Original article Clinical endoscopy| Volume 97, ISSUE 1, P59-68.e7, January 2023

Genotype–phenotype correlation of small-intestinal polyps on small-bowel capsule endoscopy in familial adenomatous polyposis

Published:September 06, 2022DOI:

      Background and Aims

      In familial adenomatous polyposis (FAP), neoplastic lesions outside the colon have become increasingly important. The genotype–phenotype correlation has been established for duodenal polyps, and regular screening is recommended. However, this correlation remains unclear for small-intestinal lesions, except for reports on the relationship between their occurrence and Spigelman stage. Here, we used small-bowel capsule endoscopy (SBCE) to investigate the genotype–phenotype correlation of small-intestinal polyps in FAP.


      The genotype–phenotype correlation of small-intestinal polyps was investigated in patients with FAP who underwent SBCE, Esophagogastroduodenoscopy (EGD), and adenomatous polyposis coli (APC) gene analysis. Of 64 patients with FAP who underwent SBCE, 41 were included in the final analysis, 4 did not undergo a complete small intestine examination, and 19 did not undergo genetic analysis.


      The prevalence (median number) of small-intestinal polyps by Spigelman stage was 26% (1.5), 0% (0), 44% (5), 60% (4), and 73% (25.5) for stages 0 to IV, respectively. Significantly more small-intestinal polyps were found in Spigelman stage III and IV groups than in the stage 0 group (P < .05). The APC variant was negative for 6 patients (15%), and the sites associated with more than 5 small-intestinal polyps were codons 278, 1062, 1114, 1281, 1307, 1314, and 1504.


      In FAP patients, SBCE surveillance is potentially recommended for patients with pathogenic variants in the APC gene at codons 278 and 1062 to 1504 or with Spigelman stage III or higher.

      Graphical abstract


      APC (adenomatous polyposis coli), DBE (double-balloon endoscopy), EGD (esophagogastroduodenoscopy), FAP (familial adenomatous polyposis), PGV (pathogenic germline variant), SBCE (small-bowel capsule endoscopy), TCS (total colonoscopy)
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        • Kanth P.
        • Grimmett J.
        • Champine M.
        • et al.
        Hereditary colorectal polyposis and cancer syndromes: a primer on diagnosis and management.
        Am J Gastroenterol. 2017; 112: 1509-1525
        • Belchetz L.A.
        • Berk T.
        • Bapat B.V.
        • et al.
        Changing causes of mortality in patients with familial adenomatous polyposis.
        Dis Colon Rectum. 1996; 39: 384-387
        • Bjork J.
        • Akerbrant H.
        • Iselius L.
        • et al.
        Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: cumulative risks and APC gene mutations.
        Gastroenterology. 2001; 121: 1127-1135
        • Vasen H.F.
        • Moslein G.
        • Alonso A.
        • et al.
        Guidelines for the clinical management of familial adenomatous polyposis (FAP).
        Gut. 2008; 57: 704-713
        • Iwama T.
        • Tamura K.
        • Morita T.
        • et al.
        A clinical overview of familial adenomatous polyposis derived from the database of the Polyposis Registry of Japan.
        Int J Clin Oncol. 2004; 9: 308-316
        • Jagelman D.G.
        • DeCosse J.J.
        • Bussey H.J.
        Upper gastrointestinal cancer in familial adenomatous polyposis.
        Lancet. 1988; 1: 1149-1151
        • Yang J.
        • Gurudu S.R.
        • Koptiuch C.
        • et al.
        American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in familial adenomatous polyposis syndromes.
        Gastrointest Endosc. 2020; 91: 963-982
        • Ruys A.T.
        • Alderlieste Y.A.
        • Gouma D.J.
        • et al.
        Jejunal cancer in patients with familial adenomatous polyposis.
        Clin Gastroenterol Hepatol. 2010; 8: 731-733
        • Zuidema M.F.
        • Dekker W.
        A patient with a metastasizing jejunal carcinoma 17 years after colectomy for familial polyposis coli.
        Neth J Med. 1989; 34: 317-321
        • Eigenbrod T.
        • Kullmann F.
        • Klebl F.
        Resection of small bowel adenocarcinoma liver metastasis combined with neoadjuvant and adjuvant chemotherapy results in extended disease-free period—a case report.
        Int J Gastrointest Cancer. 2006; 37: 94-97
        • Li N.
        • Kang Q.
        • Yang L.
        • et al.
        Clinical characterization and mutation spectrum in patients with familial adenomatous polyposis in China.
        J Gastroenterol Hepatol. 2019; 34: 1497-1503
        • Papp J.
        • Kovacs M.E.
        • Matrai Z.
        • et al.
        Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary.
        Fam Cancer. 2016; 15: 85-97
        • Bertario L.
        • Russo A.
        • Sala P.
        • et al.
        Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis.
        J Clin Oncol. 2003; 21: 1698-1707
        • Worthley D.L.
        • Phillips K.D.
        • Wayte N.
        • et al.
        Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome.
        Gut. 2012; 61: 774-779
        • Li J.
        • Woods S.L.
        • Healey S.
        • et al.
        Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant.
        Am J Hum Genet. 2016; 98: 830-842
        • Miyaki M.
        • Yamaguchi T.
        • Iijima T.
        • et al.
        Difference in characteristics of APC mutations between colonic and extracolonic tumors of FAP patients: variations with phenotype.
        Int J Cancer. 2008; 122: 2491-2497
        • Matsumoto M.
        • Nakajima T.
        • Kakugawa Y.
        • et al.
        Surveillance using capsule endoscopy is safe in post-colectomy patients with familial adenomatous polyposis: a prospective Japanese study.
        Fam Cancer. 2016; 15: 75-83
        • Purchiaroni F.
        • Nakajima T.
        • Sakamoto T.
        • et al.
        Over-the-scope-clip pre-mounted onto a double balloon enteroscope for fast and successful closure of post-EMR jejunal perforation: case report.
        BMC Gastroenterol. 2017; 17: 152
        • Gao J.
        • Aksoy B.A.
        • Dogrusoz U.
        • et al.
        Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
        Sci Signal. 2013; 6: pl1
        • Cerami E.
        • Gao J.
        • Dogrusoz U.
        • et al.
        The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
        Cancer Discov. 2012; 2: 401-404
        • Monkemuller K.
        • Fry L.C.
        • Ebert M.
        • et al.
        Feasibility of double-balloon enteroscopy-assisted chromoendoscopy of the small bowel in patients with familial adenomatous polyposis.
        Endoscopy. 2007; 39: 52-57
        • Schulmann K.
        • Hollerbach S.
        • Kraus K.
        • et al.
        Feasibility and diagnostic utility of video capsule endoscopy for the detection of small bowel polyps in patients with hereditary polyposis syndromes.
        Am J Gastroenterol. 2005; 100: 27-37
        • Saurin J.C.
        • Gutknecht C.
        • Napoleon B.
        • et al.
        Surveillance of duodenal adenomas in familial adenomatous polyposis reveals high cumulative risk of advanced disease.
        J Clin Oncol. 2004; 22: 493-498
        • Matsumoto T.
        • Esaki M.
        • Yanaru-Fujisawa R.
        • et al.
        Small-intestinal involvement in familial adenomatous polyposis: evaluation by double-balloon endoscopy and intraoperative enteroscopy.
        Gastrointest Endosc. 2008; 68: 911-919
        • Saurin J.C.
        • Ligneau B.
        • Ponchon T.
        • et al.
        The influence of mutation site and age on the severity of duodenal polyposis in patients with familial adenomatous polyposis.
        Gastrointest Endosc. 2002; 55: 342-347
        • Tanaka K.
        • Sato Y.
        • Ishikawa H.
        • et al.
        Small intestinal involvement and genotype-phenotype correlation in familial adenomatous polyposis.
        Techn Innovat Gastrointest Endosc. 2022; 24: 26-34
        • Galiatsatos P.
        • Foulkes W.D.
        Familial adenomatous polyposis.
        Am J Gastroenterol. 2006; 101: 385-398
        • Fearon E.R.
        • Vogelstein B.
        A genetic model for colorectal tumorigenesis.
        Cell. 1990; 61: 759-767
        • Ishizu K.
        • Hashimoto T.
        • Naka T.
        • et al.
        APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum.
        J Gastroenterol. 2021; 56: 988-998
        • Groves C.
        • Lamlum H.
        • Crabtree M.
        • et al.
        Mutation cluster region, association between germline and somatic mutations and genotype-phenotype correlation in upper gastrointestinal familial adenomatous polyposis.
        Am J Pathol. 2002; 160: 2055-2061

      Supplementary References

        • Spigelman A.D.
        • Williams C.B.
        • Talbot I.C.
        • et al.
        Upper gastrointestinal cancer in patients with familial adenomatous polyposis.
        Lancet. 1989; 2: 783-785
        • Saurin J.C.
        • Gutknecht C.
        • Napoleon B.
        • et al.
        Surveillance of duodenal adenomas in familial adenomatous polyposis reveals high cumulative risk of advanced disease.
        J Clin Oncol. 2004; 22: 493-498
        • Nomura S.
        • Sugano K.
        • Kashiwabara H.
        • et al.
        Enhanced detection of deleterious and other germline mutations of hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds.
        Biochem Biophys Res Commun. 2000; 271: 120-129
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-423