title: Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.
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.
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Medicine, University of Adelaide and Cancer Theme, SAHMRI, Adelaide, SA 5000, Australia.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Woods
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Healey
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beesley
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Haran
authors.initials: H
authors.lastname: Sivakumaran
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Nicci
authors.initials: N
authors.lastname: Wayte
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Katia
authors.initials: K
authors.lastname: Nones
authors.affiliation: Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Waterfall
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Pearson
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Patch
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Ferreira
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: Pardeep
authors.initials: P
authors.lastname: Kaurah
authors.affiliation: Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Robertson
authors.initials: R
authors.lastname: Mackenzie
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, Vancouver, BC V5Z 4S6, Canada.
authors.forename: Alireza
authors.initials: A
authors.lastname: Heravi-Moussavi
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Hansford
authors.affiliation: School of Medicine, University of Adelaide and Cancer Theme, SAHMRI, Adelaide, SA 5000, Australia.
authors.forename: Tamsin R M
authors.initials: TRM
authors.lastname: Lannagan
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia; School of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia; School of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia.
authors.forename: Leonard
authors.initials: L
authors.lastname: da Silva
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia; School of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia; Anatomical Pathology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: Centre for Liver Disease Research, TRI Building, University of Queensland, Woolloongabba, QLD 4102, Australia; Envoi Specialist Pathologists, Bishop Street, Kelvin Grove, QLD 4059, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia; Envoi Specialist Pathologists, Bishop Street, Kelvin Grove, QLD 4059, Australia; The Conjoint Gastroenterology Laboratory, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Bettington
authors.affiliation: Departments of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4006, Australia.
authors.forename: Florian
authors.initials: F
authors.lastname: Grimpen
authors.affiliation: Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, Melbourne, VIC 8006, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Busuttil
authors.affiliation: Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, Melbourne, VIC 8006, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Di Costanzo
authors.affiliation: Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, Melbourne, VIC 8006, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Gastroenterology, Royal Melbourne Hospital, Parkville, VIC 3010, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.affiliation: Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Jeanjean
authors.affiliation: Molecular Pathology Centre, Department of Pathology, Jewish General Hospital - McGill University, Montreal, QC H3T 1E2, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Chong
authors.affiliation: AP-HM Timone, Medical Genetics Department, 13385 Marseille, France; Aix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, France; Oncology Unit, Generale de Sante, Clairval Hospital, 13009 Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fabre
authors.affiliation: AP-HM Timone, Medical Genetics Department, 13385 Marseille, France; Aix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, France; Oncology Unit, Generale de Sante, Clairval Hospital, 13009 Marseille, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Olschwang
authors.affiliation: Mater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Faulkner
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia; Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Bellos
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Lachlan
authors.initials: L
authors.lastname: Coin
authors.affiliation: Department of Medicine, Division of Gastroenterology, Department of Microbiology and Infectious Diseases, Gastrointestinal Research Group, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rioux
authors.affiliation: Departments of Surgery and Oncology, University of Calgary, Calgary, AB T2N 4N1, Canada; Division of Surgical Oncology, Tom Baker Cancer Centre, 1331 29(th) St NW, Calgary, AB T2N 4N1, Canada.
authors.forename: Oliver F
authors.initials: OF
authors.lastname: Bathe
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)/Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; Centro Hospitalar Vila Nova de Gaia/Espinho, Porto 4430-027, Portugal.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Wen
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Hilary C
authors.initials: HC
authors.lastname: Martin
authors.affiliation: Department of Internal Medicine, Huntsman Cancer Institute at University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Deborah W
authors.initials: DW
authors.lastname: Neklason
authors.affiliation: Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Davis
authors.affiliation: Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.affiliation: Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Calzone
authors.affiliation: Department of Surgery, Saint Peter's University Hospital, Rutgers University, New Brunswick, NJ 08901, USA.
authors.forename: Itzhak
authors.initials: I
authors.lastname: Avital
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), NIH, Bethesda, MD 20892, USA.
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), NIH, Bethesda, MD 20892, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Koh
authors.affiliation: Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
authors.forename: Marbin
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
authors.forename: Udo
authors.initials: U
authors.lastname: Rudloff
authors.affiliation: Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.affiliation: Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Pavel N
authors.initials: PN
authors.lastname: Pichurin
authors.affiliation: Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hulick
authors.affiliation: GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Weissman
authors.affiliation: Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Newlin
authors.affiliation: National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), NIH, Bethesda, MD 20892, USA.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Rubinstein
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Jone E
authors.initials: JE
authors.lastname: Sampson
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamman
authors.affiliation: Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.affiliation: Adult Genetics Unit, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA 5006, Australia; University Department of Paediatrics, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Poplawski
authors.affiliation: Adult Genetics Unit, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA 5006, Australia; University Department of Paediatrics, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Kerry
authors.initials: K
authors.lastname: Phillips
authors.affiliation: Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, WA 6008, Australia.
authors.forename: Lyn
authors.initials: L
authors.lastname: Schofield
authors.affiliation: Adult Genetics Unit, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA 5006, Australia.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, WA 6008, Australia.
authors.forename: Cathy
authors.initials: C
authors.lastname: Kiraly-Borri
authors.affiliation: University Department of Paediatrics, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Graeme K
authors.initials: GK
authors.lastname: Suthers
authors.affiliation: Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6Z 2K5, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.affiliation: Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)/Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; Medical Faculty of the University of Porto/Centro Hospitalar São João, Porto 4200-319, Portugal.
authors.forename: Fatima
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ 85259, USA.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Edwards
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
authors.forename: Juliet D
authors.initials: JD
authors.lastname: French
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: School of Medicine, University of Adelaide and Cancer Theme, SAHMRI, Adelaide, SA 5000, Australia.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Kasmintan A
authors.initials: KA
authors.lastname: Schrader
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia. Electronic address: georgia.trench@qimrberghofer.edu.au.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D018256:Adenomatous Polyps / Q000235:genetics*; D022981:Allelic Imbalance / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D008040:Genetic Linkage / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein