title: Mutation spectrum in the Wnt/β-catenin signaling pathway in gastric fundic gland-associated neoplasms/polyps.
abstract: Frequent activation of the Wnt/β-catenin signaling pathway has recently been demonstrated in gastric adenocarcinoma/neoplasia of chief cell predominant type (GA-CCP/GN-CCP) with submucosal involvement. In this study, we examined the activation status of the Wnt/β-catenin signaling pathway in GN-CCP without submucosal involvement, which is referred to as gastric dysplasia-CCP (GD-CCP). We also examined β-catenin expression and the mutation spectrum of PPP2R1A and Wnt pathway genes in 11 cases of GD-CCP, 25 cases of gastric polyps of fundic gland type (GPs-FG), and 21 cases of GPs-FG with dysplasia (GP-FGD). β-catenin nuclear staining was observed in 3 cases of GD-CCP, none of GPs-FG, and 6 cases of GPs-FGD. Mutations in Wnt pathway genes, including PPP2R1A, were observed in 4 cases of GDs-CCP, 10 cases of GPs-FG, and 7 cases of GPs-FGD. Two of these seven GPs-FGD cases showed β-catenin nuclear staining. However, none of the 4 GD-CCP cases with mutations or the 10 GPs-FG cases with mutations showed β-catenin nuclear staining. PPP2R1A mutations were observed in 1 GD-CCP case and 1 GPs-FGD case. Although the mutation spectra of the Wnt pathway genes in GD-CCP and GP-FG differed, based on the absence of β-catenin nuclear staining despite the genetic alterations, GD-CCP is more similar to GP-FG than to GN-CCP, which shows β-catenin nuclear staining and submucosal involvement. Activation of the Wnt/β-catenin signaling by the β-catenin nuclear transition may be required during progression from GD-CCP to GN-CCP. Furthermore, this is the first report describing PPP2R1A mutations in gastric fundic gland-associated neoplasms.
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Se-Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mitomi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hidaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nomura
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
mesh_terms: D018256:Adenomatous Polyps / Q000235:genetics / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005748:Gastric Fundus / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054648:Protein Phosphatase 2 / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000032:analysis / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; C517191:PPP2R1A protein, human; D051176:beta Catenin; D054648:Protein Phosphatase 2
references.citation: Am J Surg Pathol. 1998 Mar;22(3):293-8
references.pmid: 9500770
references.citation: Hum Pathol. 2004 Mar;35(3):328-34
references.pmid: 15017589
references.citation: Science. 2010 Oct 8;330(6001):228-31
references.pmid: 20826764
references.citation: Am J Pathol. 2011 Apr;178(4):1442-7
references.pmid: 21435433
references.citation: Dig Endosc. 2011 Jul;23(3):244-6
references.pmid: 21699569
references.citation: Am J Pathol. 2002 Nov;161(5):1735-42
references.pmid: 12414520
references.citation: Mod Pathol. 2004 Nov;17(11):1421-6
references.pmid: 15494708
references.citation: Oncogene. 2006 Oct 19;25(49):6447-56
references.pmid: 16878161
references.citation: Am J Surg Pathol. 2010 May;34(5):609-19
references.pmid: 20410811
references.citation: J Biol Chem. 1999 Feb 5;274(6):3439-45
references.pmid: 9920888
references.citation: Curr Biol. 1998 May 7;8(10):591-4
references.pmid: 9601644
references.citation: J Med Genet. 2010 Oct;47(10):721-2
references.pmid: 20685668
references.citation: Hum Pathol. 2013 Nov;44(11):2438-48
references.pmid: 24011952
references.citation: Biochem J. 2001 Feb 1;353(Pt 3):417-39
references.pmid: 11171037
references.citation: EMBO J. 1998 Mar 2;17(5):1371-84
references.pmid: 9482734
references.citation: EMBO J. 1999 Aug 2;18(15):4233-40
references.pmid: 10428961
references.citation: Cancer Metastasis Rev. 1999;18(2):215-30
references.pmid: 10728985
references.citation: Oncol Rep. 2014 Aug;32(2):513-22
references.pmid: 24926961
references.citation: J Gastrointest Cancer. 2012 Sep;43 Suppl 1:S262-5
references.pmid: 22791069
references.citation: Curr Biol. 1996 Oct 1;6(10 ):1302-6
references.pmid: 8939578
references.citation: Am J Surg Pathol. 2012 Jul;36(7):1030-5
references.pmid: 22472957
references.citation: Cell. 2007 Jul 13;130(1):21-4
references.pmid: 17632053
references.citation: Virchows Arch. 2002 Apr;440(4):381-6
references.pmid: 11956818
references.citation: Endoscopy. 2014 Feb;46(2):153-7
references.pmid: 24338239
references.citation: Genes Dev. 1997 Dec 15;11(24):3286-305
references.pmid: 9407023
references.citation: Hum Pathol. 2014 Dec;45(12 ):2488-96
references.pmid: 25288233
references.citation: Scand J Gastroenterol. 2003 Sep;38(9):916-22
references.pmid: 14531526
references.citation: Am J Pathol. 2000 Sep;157(3):747-54
references.pmid: 10980114
references.citation: Gastroenterology. 2003 Nov;125(5):1462-9
references.pmid: 14598262
references.citation: FEBS Lett. 2006 Jun 26;580(15):3665-70
references.pmid: 16764864
references.citation: J Biol Chem. 2000 Nov 17;275(46):35680-3
references.pmid: 11007767
references.citation: Cancer Res. 2002 Jun 15;62(12):3503-6
references.pmid: 12067995
references.citation: Mol Cell Biol. 2000 Mar;20(6):2228-38
references.pmid: 10688669
references.citation: Anticancer Res. 2013 Jan;33(1):113-8
references.pmid: 23267135
references.citation: Curr Opin Genet Dev. 2005 Feb;15(1):34-41
references.pmid: 15661531
references.citation: Genes Cells. 1998 Jun;3(6):395-403
references.pmid: 9734785
references.citation: Histopathology. 2006 Dec;49(6):612-21
references.pmid: 17163846
references.citation: Tumour Biol. 2001 Mar-Apr;22(2):123-30
references.pmid: 11125285
references.citation: Int J Cancer. 2001 Mar 20;95(2):108-13
references.pmid: 11241321
references.citation: Jpn J Cancer Res. 1997 Aug;88(8):718-24
references.pmid: 9330602
references.citation: Oncogene. 1999 Jan 28;18(4):979-85
references.pmid: 10023673
references.citation: Science. 1997 Mar 14;275(5306):1652-4
references.pmid: 9054360
references.citation: Am J Pathol. 2001 Mar;158(3):1005-10
references.pmid: 11238048