Oncology| Volume 54, ISSUE 7, P905-910, July 2022

Download started.


Relationship between gene mutations and clinicopathological features in nonampullary duodenal epithelial tumors

Published:December 24, 2021DOI:



      Molecular features of nonampullary duodenal epithelial tumors (NADETs) remain unclear.


      The aim of this study is to determine the association between the genetic features and clinicopathological findings of NADETs.


      In total, 75 NADETs were enrolled in this study, and was performed targeted DNA sequencing of the GNAS, KRAS, TP53, and APC genes. Histological grade was classified as category 3 or category 4/5 according to the Vienna classification, and the immunophenotype was categorized as the gastric phenotype (G type), gastrointestinal phenotype (GI type), or the intestinal phenotype (I type).


      The prevalence of GNAS and KRAS mutations was significantly higher in the G type than in the GI/I type (GNAS, P = 0.027; KRAS, P = 0.005). In contrast, the frequency of TP53 mutations was significantly higher in the GI/I type than in the G type (P = 0.049). Notably, APC mutations, excluding c.4479 G>A which was synonymous mutation, were more frequently identified in category 4/5 tumors than in category 3 tumors (50% vs. 24.5%; P = 0.039).


      G-type NADETs harbored frequent GNAS and KRAS mutations, whereas TP53 mutations are common in NADETs with intestinal features. APC mutations were significantly associated with high-grade neoplasia and invasive carcinoma.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Digestive and Liver Disease
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kakushima N.
        • Ono H.
        • Takao T.
        • et al.
        Method and timing of resection of superficial non-ampullary duodenal epithelial tumors.
        Dig Endosc. 2014; 26: 35-40
        • Jepsen J.M.
        • Persson M.
        • Jakobsen N.O.
        • et al.
        Prospective study of prevalence and endoscopic and histopathologic characteristics of duodenal polyps in patients submitted to upper endoscopy.
        Scand J Gastroenterol. 1994; 29: 483-487
        • Schottenfeld D.
        • Beebe-Dimmer J.L.
        • Vigneau F.D.
        The epidemiology and pathogenesis of neoplasia in the small intestine.
        Ann Epidemiol. 2009; 19: 58-69
        • Fukusada S.
        • Shimura T.
        • Iwasaki H.
        • et al.
        Relationship between immunophenotype and clinicopathological findings for superficial nonampullary duodenal epithelial tumor.
        Digestion. 2021; : 1-8
        • Nguyen H.T.
        • Duong H.Q.
        The molecular characteristics of colorectal cancer: implications for diagnosis and therapy.
        Oncol Lett. 2018; 16: 9-18
        • Smit W.L.
        • Spaan C.N.
        • Johannes de Boer R.
        • et al.
        Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity.
        Proc Natl Acad Sci USA. 2020; 117: 25560-25570
        • Fearon E.R.
        • Vogelstein B.
        A genetic model for colorectal tumorigenesis.
        Cell. 1990; 61: 759-767
        • Rad R.
        • Cadinanos J.
        • Rad L.
        • et al.
        A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.
        Cancer Cell. 2013; 24: 15-29
      1. Cancer genome atlas research N. comprehensive molecular characterization of gastric adenocarcinoma.
        Nature. 2014; 513: 202-209
        • Schrock A.B.
        • Devoe C.E.
        • McWilliams R.
        • et al.
        Genomic profiling of small-bowel adenocarcinoma.
        JAMA Oncol. 2017; 3: 1546-1553
        • Matsubara A.
        • Ogawa R.
        • Suzuki H.
        • et al.
        Activating GNAS and KRAS mutations in gastric foveolar metaplasia, gastric heterotopia, and adenocarcinoma of the duodenum.
        Br J Cancer. 2015; 112: 1398-1404
        • Wagner P.L.
        • Chen Y.T.
        • Yantiss R.K.
        Immunohistochemical and molecular features of sporadic and FAP-associated duodenal adenomas of the ampullary and nonampullary mucosa.
        Am J Surg Pathol. 2008; 32: 1388-1395
        • Vandenbroucke J.P.
        • von Elm E.
        • Altman D.G.
        • et al.
        Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration.
        Epidemiology. 2007; 18: 805-835
        • Shimura T.
        • Sasaki M.
        • Kataoka H.
        • et al.
        Advantages of endoscopic submucosal dissection over conventional endoscopic mucosal resection.
        J Gastroenterol Hepatol. 2007; 22: 821-826
        • Schlemper R.J.
        • Riddell R.H.
        • Kato Y.
        • et al.
        The Vienna classification of gastrointestinal epithelial neoplasia.
        Gut. 2000; 47: 251-255
        • Kanda Y.
        Investigation of the freely available easy-to-use software 'EZR' for medical statistics.
        Bone Marrow Transplant. 2013; 48: 452-458
        • Kojima Y.
        • Ohtsuka K.
        • Ohnishi H.
        • et al.
        APC:T1556fs and STK11 mutations in duodenal adenomas and adenocarcinomas.
        Surg Today. 2018; 48: 765-772
        • Yamaguchi K.
        • Nagayama S.
        • Shimizu E.
        • et al.
        Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis.
        Sci Rep. 2016; 6: 26011
        • Hida R.
        • Yamamoto H.
        • Hirahashi M.
        • et al.
        Duodenal Neoplasms of gastric phenotype: an immunohistochemical and genetic study with a practical approach to the classification.
        Am J Surg Pathol. 2017; 41: 343-353
        • Matsubara A.
        • Sekine S.
        • Kushima R.
        • et al.
        Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum.
        J Pathol. 2013; 229: 579-587
        • Ota R.
        • Sawada T.
        • Tsuyama S.
        • et al.
        Integrated genetic and epigenetic analysis of cancer-related genes in non-ampullary duodenal adenomas and intramucosal adenocarcinomas.
        J Pathol. 2020;
        • Molin M.D.
        • Matthaei H.
        • Wu J.
        • et al.
        Clinicopathological correlates of activating GNAS mutations in intraductal papillary mucinous neoplasm (IPMN) of the pancreas.
        Ann Surg Oncol. 2013; 20: 3802-3808
        • Furukawa T.
        • Kuboki Y.
        • Tanji E.
        • et al.
        Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas.
        Sci Rep. 2011; 1: 161
        • Yamada M.
        • Sekine S.
        • Ogawa R.
        • et al.
        Frequent activating GNAS mutations in villous adenoma of the colorectum.
        J Pathol. 2012; 228: 113-118
        • Taki K.
        • Ohmuraya M.
        • Tanji E.
        • et al.
        GNAS(R201H) and Kras(G12D) cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm.
        Oncogene. 2016; 35: 2407-2412
        • Goh A.M.
        • Coffill C.R.
        • Lane D.P.
        The role of mutant p53 in human cancer.
        J Pathol. 2011; 223: 116-126
        • Rodrigues N.R.
        • Rowan A.
        • Smith M.E.
        • et al.
        p53 mutations in colorectal cancer.
        Proc Natl Acad Sci USA. 1990; 87: 7555-7559
        • Baker S.J.
        • Fearon E.R.
        • Nigro J.M.
        • et al.
        Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas.
        Science. 1989; 244: 217-221
        • Yuan W.
        • Zhang Z.
        • Dai B.
        • et al.
        Whole-exome sequencing of duodenal adenocarcinoma identifies recurrent Wnt/beta-catenin signaling pathway mutations.
        Cancer. 2016; 122: 1689-1696
        • Malhotra P.
        • Anwar M.
        • Nanda N.
        • et al.
        Alterations in K-ras, APC and p53-multiple genetic pathway in colorectal cancer among Indians.
        Tumour Biol. 2013; 34: 1901-1911
        • Deissler H.
        • Kafka A.
        • Schuster E.
        • et al.
        Spectrum of p53 mutations in biopsies from breast cancer patients selected for preoperative chemotherapy analysed by the functional yeast assay to predict therapeutic response.
        Oncol Rep. 2004; 11: 1281-1286
        • Vega F.J.
        • Iniesta P.
        • Caldes T.
        • et al.
        p53 exon 5 mutations as a prognostic indicator of shortened survival in non-small-cell lung cancer.
        Br J Cancer. 1997; 76: 44-51
        • Kato S.
        • Han S.Y.
        • Liu W.
        • et al.
        Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
        Proc Natl Acad Sci USA. 2003; 100: 8424-8429
        • Yoshie T.
        • Nishiumi S.
        • Izumi Y.
        • et al.
        Regulation of the metabolite profile by an APC gene mutation in colorectal cancer.
        Cancer Sci. 2012; 103: 1010-1021
        • Chang Y.S.
        • Lin C.Y.
        • Yang S.F.
        • et al.
        Analysing the mutational status of adenomatous polyposis coli (APC) gene in breast cancer.
        Cancer Cell Int. 2016; 16: 23