Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant

J Li; SL Woods; S Healey; J Beesley; X Chen; JS Lee; H Sivakumaran; N Wayte; K Nones; JJ Waterfall; J Pearson; AM Patch; J Senz; MA Ferreira; P Kaurah; R MacKenzie; A Heravi-Moussavi; S Hansford; TRM Lannagan; AB Spurdle; PT Simpson; L Da Silva; SR Lakhani; AD Clouston; M Bettington; F Grimpen; RA Busuttil; N Di Costanzo; A Boussioutas; M Jeanjean; G Chong; A Fabre; S Olschwang; GJ Faulkner; E Bellos; L Coin; K Rioux; OF Bathe; X Wen; HC Martin; DW Neklason; SR Davis; RL Walker; KA Calzone; I Avital; T Heller; C Koh; M Pineda; U Rudloff; M Quezado; PN Pichurin; PJ Hulick; SM Weissman; A Newlin; WS Rubinstein; JE Sampson; K Hamman; D Goldgar; N Poplawski; K Phillips; L Schofield; J Armstrong; C Kiraly-Borri; GK Suthers; DG Huntsman; WD Foulkes; F Carneiro; NM Lindor; SL Edwards; JD French; N Waddell; PS Meltzer; DL Worthley; KA Schrader; G Chenevix-Trench

Journal article

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant

J Li, SL Woods, S Healey, J Beesley, X Chen, JS Lee, H Sivakumaran, N Wayte, K Nones, JJ Waterfall, J Pearson, AM Patch, J Senz, MA Ferreira, P Kaurah, R MacKenzie, A Heravi-Moussavi, S Hansford, TRM Lannagan, AB Spurdle Show all

American Journal of Human Genetics | CELL PRESS | Published : 2016

DOI: 10.1016/j.ajhg.2016.03.001

Abstract

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed a..

View full abstract

University of Melbourne Researchers

Alex Boussioutas Author

Lachlan Coin Author

Grants

Awarded by Michael Smith Foundation for Health Research

Funding Acknowledgements

We thank all the individuals from the GAPPS-affected families who took part in this study, Andrew Giraud for providing the AGS and MKN74 cell lines, and Vicki Whitehall for HCT116 and RKO. The work was funded by the NHMRC, NIH (PO1-CA073992), and grant MOP-123517 from the Canadian Institutes of Health Research and the Ride to Conquer Cancer. G.J.F. acknowledges the support of an NHMRC Career Development Fellowship (GNT1045237); D.L.W., T.R.M.L., and S.L.W. are funded by Cancer Council South Australia Beat Cancer Project; G.C.-T. and A.B.S. by NHMRC Research Fellowships; and K.A.S. by the Canadian Institutes of Health Research, Michael Smith Foundation for Health Research, and BC Cancer Foundation. W.D.F. thanks Ms. N. Wong for clinical contributions. We acknowledge the support provided by the following pathology labs: Perth Pathology, St John of God Pathology, Western Diagnostics, and PathWest (Royal Perth Hospital, Fremantle Hospital, King Edward Memorial Hospital, and Sir Charles Gairdner Hospital). The authors are very grateful to staff at the Australian Red Cross Blood Services for their assistance with the collection of risk factor information and blood samples of healthy donor control subjects and thank members of the QIMR Molecular Cancer Epidemiology Laboratory for their assistance with recruitment and biospecimen processing. This study was in part (P.S.M., U.R.) supported by the Intramural Research Program of the NIH. O.F.B. has been paid consultancy fees by Amgen and Sanofi Canada.