Point mutations in Exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant

Li, Jun, Woods, Susan L., Healey, Sue, Beesley, Jonathan, Chen, Xiaoqing, Lee, Jason S., Sivakumaran, Haran, Wayte, Nicci, Nones, Katia, Waterfall, Joshua J., Pearson, John, Patch, Anne-Marie, Senz, Janine, Ferreira, Manuel A., Kaurah, Pardeep, Mackenzie, Robertson, Heravi-Moussavi, Alireza, Hansford, Samantha, Lannagan, Tamsin R. M., Spurdle, Amanda B., Simpson, Peter T., da Silva, Leonard, Lakhani, Sunil R., Clouston, Andrew D., Bettington, Mark, Grimpen, Florian, Busuttil, Rita A., Di Costanzo, Natasha, Boussioutas, Alex, Jeanjean, Marie, Chong, George, Fabre, Aurelie, Olschwang, Sylviane, Faulkner, Geoffrey J., Bellos, Evangelos, Coin, Lachlan, Rioux, Kevin, Bathe, Oliver F., Wen, Xiaogang, Martin, Hilary C., Neklason, Deborah W., Davis, Sean R., Walker, Robert L., Calzone, Kathleen A., Avital, Itzhak, Heller, Theo, Koh, Christopher, Pineda, Marbin, Rudloff, Udo, Quezado, Martha, Pichurin Pavel N., Hulick, Peter J., Weissman, Scott M., Newlin, Anna, Rubinstein, Wendy S., Sampson, Jone E., Hamman, Kelly, Goldgar, David, Poplawski, Nicola, Phillips, Kerry, Schofield, Lyn, Armstrong, Jacqueline, Kiraly-Borri, Cathy, Suthers, Graeme K., Huntsman, David G., Foulkes, William D., Carneiro, Fatima, Lindor, Noralane M., Edwards, Stacey L., French, Juliet D., Waddell, Nicola, Meltzer, Paul S., Worthley, Daniel L., Schrader, Kasmintan A. and Chenevix-Trench, Georgia (2016) Point mutations in Exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant. American Journal of Human Genetics, 98 5: 830-842. doi:10.1016/j.ajhg.2016.03.001

Author Li, Jun
Woods, Susan L.
Healey, Sue
Beesley, Jonathan
Chen, Xiaoqing
Lee, Jason S.
Sivakumaran, Haran
Wayte, Nicci
Nones, Katia
Waterfall, Joshua J.
Pearson, John
Patch, Anne-Marie
Senz, Janine
Ferreira, Manuel A.
Kaurah, Pardeep
Mackenzie, Robertson
Heravi-Moussavi, Alireza
Hansford, Samantha
Lannagan, Tamsin R. M.
Spurdle, Amanda B.
Simpson, Peter T.
da Silva, Leonard
Lakhani, Sunil R.
Clouston, Andrew D.
Bettington, Mark
Grimpen, Florian
Busuttil, Rita A.
Di Costanzo, Natasha
Boussioutas, Alex
Jeanjean, Marie
Chong, George
Fabre, Aurelie
Olschwang, Sylviane
Faulkner, Geoffrey J.
Bellos, Evangelos
Coin, Lachlan
Rioux, Kevin
Bathe, Oliver F.
Wen, Xiaogang
Martin, Hilary C.
Neklason, Deborah W.
Davis, Sean R.
Walker, Robert L.
Calzone, Kathleen A.
Avital, Itzhak
Heller, Theo
Koh, Christopher
Pineda, Marbin
Rudloff, Udo
Quezado, Martha
Pichurin Pavel N.
Hulick, Peter J.
Weissman, Scott M.
Newlin, Anna
Rubinstein, Wendy S.
Sampson, Jone E.
Hamman, Kelly
Goldgar, David
Poplawski, Nicola
Phillips, Kerry
Schofield, Lyn
Armstrong, Jacqueline
Kiraly-Borri, Cathy
Suthers, Graeme K.
Huntsman, David G.
Foulkes, William D.
Carneiro, Fatima
Lindor, Noralane M.
Edwards, Stacey L.
French, Juliet D.
Waddell, Nicola
Meltzer, Paul S.
Worthley, Daniel L.
Schrader, Kasmintan A.
Chenevix-Trench, Georgia
Title Point mutations in Exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant
Formatted title
Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 1537-6605
Publication date 2016-05-05
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2016.03.001
Open Access Status Not Open Access
Volume 98
Issue 5
Start page 830
End page 842
Total pages 13
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2017
Language eng
Formatted 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 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.
Keyword Point mutations
Gastric adenocarcinoma
Gastric adenocarcinoma and proximal polyposis of the stomach
Whole-exome sequencing (WES)
Whole-genome sequencing (WGS)
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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