Advertisement

KLF4 mutation shapes pathologic characteristics of foveolar-type gastric adenoma in Helicobacter pylori-naïve patients

      Abstract

      Along with a recent remarkable decrease in Helicobacter pylori (Hp)-infected individuals, reports of gastric neoplasms in Hp-naïve patients have been increasing. A sporadic foveolar-type gastric adenoma (FGA) is one such type, and we recently reported that occurrence of this tumor is not rare in Hp-naïve gastric mucosa and its raspberry-like appearance. This study was conducted to investigate the genomic features of sporadic FGA.
      Fresh-frozen sporadic FGA tissue samples from Hp-naïve patients underwent whole-genome analysis performed using a next-generation sequencer. Proliferation ability and apoptotic profiles of human gastric epithelial cells, along with plasmid transfection of candidate variants were then examined.
      An average 6.65×108 total reads were obtained for each sample. Common genetic abnormalities in well-known proliferation driver genes of conventional gastric dysplasia/cancer were not found. However, a common single nucleotide variation (SNV) was noted within the DNA binding domain of the tumor suppressor gene Krüppel-like factor 4 (KLF4). This novel SNV was located in the zinc finger 2 region and additional experiments showed that it significantly suppressed proliferation of gastric epithelial cells as compared with wild-type-KLF4 plasmid transfection cells, though suppression was reduced in early apoptotic phase-related genes.
      A novel SNV in the KLF4 zinc finger 2 region was commonly found in sporadic FGA tissue samples, which may explain the slow growing properties of this neoplasm.

      Keywords

      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:

      Subscribe to The American Journal of Pathology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Uemura N.
        • Okamoto S.
        • Yamamoto S.
        • Matsumura N.
        • Yamaguchi S.
        • Yamakido M.
        • Taniyama K.
        • Sasaki N.
        • Schlemper R.J.
        Helicobacter pylori infection and the development of gastric cancer.
        N Engl J Med. 2001; 345: 784-789
        • Inoue M.
        Changing epidemiology of Helicobacter pylori in Japan.
        Gastric Cancer. 2017; 20: 3-7
      1. The WHO classification of tumors editorial board. WHO classification of tumors of the digestive system tumors, 5th ed. 2019.

      2. Rebecca Wilcox (2017) The Neoplastic Stomach. In: Noffsinger AE (ed) Fenoglio-Preiser’s Gastrointestinal Pathology, 4th edn. Wolters Kluwer, Philadelphia, pp 233-234.

        • Shibagaki K.
        • Fukuyama C.
        • Mikami H.
        • Izumi D.
        • Yamashita N.
        • Mishiro T.
        • Oshima N.
        • Ishimura N.
        • Sato S.
        • Ishihara S.
        • Nagase M.
        • Araki A.
        • Ishikawa N.
        • Maruyama R.
        • Kushima R.
        • Kinoshita Y.
        Gastric foveolar-type adenomas endoscopically showing a raspberry-like appearance in the Helicobacter pylori-uninfected stomach.
        Endosc Int Open. 2019; 7: E784-E791
        • Shibagaki K.
        • Mishiro T.
        • Fukuyama C.
        • Takahashi Y.
        • Itawaki A.
        • Nonumura S.
        • Yamashita N.
        • Kotani S.
        • Mikami H.
        • Izumi D.
        • Kawashima K.
        • Ishimura N.
        • Nagase M.
        • Araki A.
        • Ishikawa N.
        • Maruyama R.
        • Kushima R.
        • Ishihara S.
        Sporadic foveolar-type gastric adenoma with a raspberry-like appearance in the Helicobacter pylori-naïve-patients.
        Virchows Archiv. 2021; : 27
      3. Sekine S, Yoshida H, Jansen M, and Kushima R. The Japanese Viewpoint on the Histopathology of Early Gastric Cancer. In: M. Jansen, N.A. Wright (eds) Stem Cells, Pre-neoplasia, and Early Cancer of the Upper Gastrointestinal Tract, Advances in Experimental Medicine and Biology 2016;908:331-346.

        • Kocer B.
        • Soran A.
        • Kiyak G.
        • Erdogan S.
        • Eroglu A.
        • Bozkurt B.
        • Solak C.
        • Cengiz O.
        Prognostic significance of mucin expression in gastric carcinoma.
        Dig Dis Sci. 2004; 49: 954-964
        • Koseki K.
        • Takizawa T.
        • Koike M.
        • Ito M.
        • Nihei Z.
        • Sugihara K.
        Distinction of differentiated type early gastric carcinoma with gastric type mucin expression.
        Cancer. 2000; 89: 724-732
        • Dixon M.F.
        • Genta R.M.
        • Yardley J.H.
        • Correa P.
        Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994.
        Am J Surg Pathol. 1996; 20: 1161-1181
        • Kishikawa H.
        • Kimura K.
        • Takarabe S.
        • Kaida S.
        • Nishida J.
        Helicobacter pylori antibody titer and gastric cancer screening.
        Dis Markers. 2015; 156719
        • Li H.
        • Durbin R.
        Fast and accurate short read alignment with Burrows-Wheeler transform.
        Bioinformatics. 2009; 25: 1754-1760
        • Cibulskis K.
        • Lawrence M.S.
        • Carter S.L.
        • Sivachenko A.
        • Jaffe D.
        • Sougnez C.
        • Gabriel S.
        • Meyerson M.
        • Lander E.S.
        • Gets G.
        Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples.
        Nat Biotechnol. 2013; 31: 213-219
        • Boeva V.
        • Popova T.
        • Bleakley K.
        • Chiche P.
        • Cappo J.
        • Schleiermacher G.
        • Janoueix-Lerosey I.
        • Delattre O.
        • Barillot E.
        Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data.
        Bioinformatics. 2012; 28: 423-425
        • Kazumori H.
        • Ishihara S.
        • Takahashi Y.
        • Amano Y.
        • Kinoshita Y.
        Roles of Krüppel-like factor 4 in oesophageal epithelial cells in Barrett’s epithelium development.
        Gut. 2010; 60: 608-617
        • Kimura K.
        • Takemoto T.
        An endoscopic recognition of the atrophic border and its significance in chronic gastritis.
        Endoscopy. 1969; 1: 87-97
        • Zhang J.
        • Qiu W.
        • Liu H.
        • Qian C.
        • Liu D.
        • Wang H.
        • Hu N.
        • Tang Y.T.
        • Sun J.
        • Shen Z.
        Genomic alterations in gastric cancers discovered via whole-exome sequencing.
        BMC Cancer. 2018; 18: 1270
        • Cancer Genome Atlas Research Network
        Comprehensive molecular characterization of gastric adenocarcinoma.
        Nature. 2014; 513: 202-209
        • Tate J.G.
        • Bamford S.
        • Jubb H.C.
        • Sondka Z.
        • Beare D.M.
        • Bindal N.
        • Boutselakis H.
        • Cole C.G.
        • Creatore C.
        • Dawson E.
        • Fish P.
        • Harsha B.
        • Hathaway C.
        • Jupe S.C.
        • Kok C.Y.
        • Noble K.
        • Ponting L.
        • Ramshaw C.C.
        • Rye C.E.
        • Speedy H.E.
        • Stefancsik R.
        • Thompson S.L.
        • Wang S.
        • Ward S.
        • Campbell P.J.
        • Forbes S.A.
        COSMIC: the Catalogue Of Somatic Mutations In Cancer.
        Nucleic Acids Res. 2019; 47: D941-D947
        • Ghaleb A.M.
        • Yang V.W.
        Krüppel-like factor 4 (KLF4): What we currently know.
        Gene. 2017; 611: 27-37
        • Hashimoto I.
        • Nagata T.
        • Sekine S.
        • Moriyama M.
        • Shibuya K.
        • Hojo S.
        • Matsui K.
        • Yoshioka I.
        • Okumura T.
        • Hori T.
        • Shimada Y.
        • Tsukada K.
        Prognostic significance of KLF4 expression in gastric cancer.
        Oncol Lett. 2017; 13: 819-826
        • Zhang J.
        • Zhu Z.
        • Wu H.
        • Yu Z.
        • Rong Z.
        • Luo Z.
        • Xu Y.
        • Huang K.
        • Qiu Z.
        • Huang C.
        PODXL, negatively regulated by KLF4, promotes the EMT and metastasis and serves as a novel prognostic indicator of gastric cancer.
        Gastric Cancer. 2019; 22: 48-59
        • Katz J.P.
        • Perreault N.
        • Goldstein B.G.
        • Actman L.
        • McNally S.R.
        • Silberg D.G.
        • Furth E.E.
        • Kaestner K.H.
        Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach.
        Gastroenterology. 2005; 128: 935-945
        • Shao L.
        • Chen Z.
        • Soutto M.
        • Zhu S.
        • Lu H.
        • Romero-Gallo J.
        • Peek R.
        • Zhang S.
        • El-Rifai W.
        Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer.
        FASEB J Off Publ Fed Am Soc Exp Biol. 2019; 33: 264-274
        • Ou Y.
        • Ren H.
        • Zhao R.
        • Song L.
        • Liu Z.
        • Xu W.
        • Liu Y.
        • Wang S.
        Helicobacter pylori CagA promotes the malignant transformation of gastric mucosal epithelial cells through the dysregulation of the miR-155/KLF4 signaling pathway.
        Mol Carcinog. 2019; 58: 1427-1437
        • Zhao R.
        • Liu Z.
        • Xu W.
        • Song L.
        • Ren H.
        • Ou Y.
        • Liu Y.
        • Wang S.
        Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1-mediated DNA methylation mechanism.
        Cancer Med. 2020; 9: 2551-2563
        • Schuetz A.
        • Nana D.
        • Rose C.
        • Zocher G.
        • Milanovic M.
        • Koenigsmann J.
        • Blasig R.
        • Heinemann U.
        • Carstanjen D.
        The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation.
        Cell Mol Life Sci. 2011; 68: 3121-3131
        • Fujikura K.
        • Hosoda W.
        • Felsenstein M.
        • Song Q.
        • Reiter J.G.
        • Zheng L.
        • Guthrie V.B.
        • Rincon N.
        • Molin M.D.
        • Dudley J.
        • Cohen J.D.
        • Wang P.
        • Fischer C.G.
        • Braxton A.M.
        • Noe M.
        • Jongepier M.
        • Castillo C.F.-D.
        • Mino-Kenudson M.
        • Schmidt C.M.
        • Yip-Schneider M.T.
        • Lawlor R.T.
        • Salvia R.
        • Roberts N.J.
        • Thompson E.D.
        • Karchin R.
        • Lennon A.M.
        • Jiao Y.
        • Wood L.D.
        Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.
        Gut. 2021; 70: 928-939