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

Jun Li, Susan L. Woods, Sue Healey, Jonathan Beesley, Xiaoqing Chen, Jason S. Lee, Haran Sivakumaran, Nicci Wayte, Katia Nones, Joshua J. Waterfall, John Pearson, Anne Marie Patch, Janine Senz, Manuel A. Ferreira, Pardeep Kaurah, Robertson MacKenzie, Alireza Heravi-Moussavi, Samantha Hansford, Tamsin R.M. Lannagan, Amanda B. SpurdlePeter T. Simpson, Leonard Da Silva, Sunil R. Lakhani, Andrew D. Clouston, Mark Bettington, Florian Grimpen, Rita A. Busuttil, Natasha Di Costanzo, Alex Boussioutas, Marie Jeanjean, George Chong, Aurélie Fabre, Sylviane Olschwang, Geoffrey J. Faulkner, Evangelos Bellos, Lachlan Coin, Kevin Rioux, Oliver F. Bathe, Xiaogang Wen, Hilary C. Martin, Deborah W. Neklason, Sean R. Davis, Robert L. Walker, Kathleen A. Calzone, Itzhak Avital, Theo Heller, Christopher Koh, Marbin Pineda, Udo Rudloff, Martha Quezado, Pavel N. Pichurin, Peter J. Hulick, Scott M. Weissman, Anna Newlin, Wendy S. Rubinstein, Jone E. Sampson, Kelly Hamman, David Goldgar, Nicola Poplawski, Kerry Phillips, Lyn Schofield, Jacqueline Armstrong, Cathy Kiraly-Borri, Graeme K. Suthers, David G. Huntsman, William D. Foulkes, Fatima Carneiro, Noralane M. Lindor, Stacey L. Edwards, Juliet D. French, Nicola Waddell, Paul S. Meltzer, Daniel L. Worthley, Kasmintan A. Schrader, Georgia Chenevix-Trench

Research output: Contribution to journalArticlepeer-review

161 Scopus citations


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 allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.

Original languageEnglish (US)
Pages (from-to)830-842
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - May 5 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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