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. Spurdle & 55 others Peter 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 journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)830-842
Number of pages13
JournalAmerican Journal of Human Genetics
Volume98
Issue number5
DOIs
StatePublished - May 5 2016

Fingerprint

Adenomatous Polyposis Coli
Point Mutation
Exons
Stomach
Adenocarcinoma
Mutation
Polyps
YY1 Transcription Factor
Alleles
Allelic Imbalance
Exome
Gastric Mucosa
Luciferases
Saliva
Stomach Neoplasms
Protein Isoforms
Genome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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, Aurélie; 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.

In: American Journal of Human Genetics, Vol. 98, No. 5, 05.05.2016, p. 830-842.

Research output: Contribution to journalArticle

Li, J, Woods, SL, Healey, S, Beesley, J, Chen, X, Lee, JS, Sivakumaran, H, Wayte, N, Nones, K, Waterfall, JJ, Pearson, J, Patch, AM, Senz, J, Ferreira, MA, Kaurah, P, MacKenzie, R, Heravi-Moussavi, A, Hansford, S, Lannagan, TRM, Spurdle, AB, Simpson, PT, Da Silva, L, Lakhani, SR, Clouston, AD, Bettington, M, Grimpen, F, Busuttil, RA, Di Costanzo, N, Boussioutas, A, Jeanjean, M, Chong, G, Fabre, A, Olschwang, S, Faulkner, GJ, Bellos, E, Coin, L, Rioux, K, Bathe, OF, Wen, X, Martin, HC, Neklason, DW, Davis, SR, Walker, RL, Calzone, KA, Avital, I, Heller, T, Koh, C, Pineda, M, Rudloff, U, Quezado, M, Pichurin, PN, Hulick, PJ, Weissman, SM, Newlin, A, Rubinstein, WS, Sampson, JE, Hamman, K, Goldgar, D, Poplawski, N, Phillips, K, Schofield, L, Armstrong, J, Kiraly-Borri, C, Suthers, GK, Huntsman, DG, Foulkes, WD, Carneiro, F, Lindor, NM, Edwards, SL, French, JD, Waddell, N, Meltzer, PS, Worthley, DL, Schrader, KA & Chenevix-Trench, G 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, vol. 98, no. 5, pp. 830-842. https://doi.org/10.1016/j.ajhg.2016.03.001
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, Aurélie ; 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. / Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 5. pp. 830-842.
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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.",
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T1 - Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant

AU - Li, Jun

AU - Woods, Susan L.

AU - Healey, Sue

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Lee, Jason S.

AU - Sivakumaran, Haran

AU - Wayte, Nicci

AU - Nones, Katia

AU - Waterfall, Joshua J.

AU - Pearson, John

AU - Patch, Anne Marie

AU - Senz, Janine

AU - Ferreira, Manuel A.

AU - Kaurah, Pardeep

AU - MacKenzie, Robertson

AU - Heravi-Moussavi, Alireza

AU - Hansford, Samantha

AU - Lannagan, Tamsin R M

AU - Spurdle, Amanda B.

AU - Simpson, Peter T.

AU - Da Silva, Leonard

AU - Lakhani, Sunil R.

AU - Clouston, Andrew D.

AU - Bettington, Mark

AU - Grimpen, Florian

AU - Busuttil, Rita A.

AU - Di Costanzo, Natasha

AU - Boussioutas, Alex

AU - Jeanjean, Marie

AU - Chong, George

AU - Fabre, Aurélie

AU - Olschwang, Sylviane

AU - Faulkner, Geoffrey J.

AU - Bellos, Evangelos

AU - Coin, Lachlan

AU - Rioux, Kevin

AU - Bathe, Oliver F.

AU - Wen, Xiaogang

AU - Martin, Hilary C.

AU - Neklason, Deborah W.

AU - Davis, Sean R.

AU - Walker, Robert L.

AU - Calzone, Kathleen A.

AU - Avital, Itzhak

AU - Heller, Theo

AU - Koh, Christopher

AU - Pineda, Marbin

AU - Rudloff, Udo

AU - Quezado, Martha

AU - Pichurin, Pavel N.

AU - Hulick, Peter J.

AU - Weissman, Scott M.

AU - Newlin, Anna

AU - Rubinstein, Wendy S.

AU - Sampson, Jone E.

AU - Hamman, Kelly

AU - Goldgar, David

AU - Poplawski, Nicola

AU - Phillips, Kerry

AU - Schofield, Lyn

AU - Armstrong, Jacqueline

AU - Kiraly-Borri, Cathy

AU - Suthers, Graeme K.

AU - Huntsman, David G.

AU - Foulkes, William D.

AU - Carneiro, Fatima

AU - Lindor, Noralane M.

AU - Edwards, Stacey L.

AU - French, Juliet D.

AU - Waddell, Nicola

AU - Meltzer, Paul S.

AU - Worthley, Daniel L.

AU - Schrader, Kasmintan A.

AU - Chenevix-Trench, Georgia

PY - 2016/5/5

Y1 - 2016/5/5

N2 - 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.

AB - 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.

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