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Am J Hum Genet. 2016 May 5;98(5):830-842. doi: 10.1016/j.ajhg.2016.03.001. Epub 2016 Apr 14.

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

Author information

1
Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia.
2
School of Medicine, University of Adelaide and Cancer Theme, SAHMRI, Adelaide, SA 5000, Australia.
3
Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
4
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.
5
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
6
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
7
Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
8
Canada's Michael Smith Genome Sciences Centre, Vancouver, BC V5Z 4S6, Canada.
9
UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia; School of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia.
10
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.
11
Centre for Liver Disease Research, TRI Building, University of Queensland, Woolloongabba, QLD 4102, Australia; Envoi Specialist Pathologists, Bishop Street, Kelvin Grove, QLD 4059, Australia.
12
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.
13
Departments of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4006, Australia.
14
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.
15
Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, Melbourne, VIC 8006, Australia.
16
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.
17
Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
18
Molecular Pathology Centre, Department of Pathology, Jewish General Hospital - McGill University, Montreal, QC H3T 1E2, Canada.
19
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.
20
Mater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia.
21
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.
22
Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
23
Department of Medicine, Division of Gastroenterology, Department of Microbiology and Infectious Diseases, Gastrointestinal Research Group, University of Calgary, Calgary, AB T2N 4N1, Canada.
24
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.
25
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.
26
Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
27
Department of Internal Medicine, Huntsman Cancer Institute at University of Utah, Salt Lake City, UT 84112, USA.
28
Department of Surgery, Saint Peter's University Hospital, Rutgers University, New Brunswick, NJ 08901, USA.
29
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), NIH, Bethesda, MD 20892, USA.
30
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
31
Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
32
Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA.
33
Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
34
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
35
National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), NIH, Bethesda, MD 20892, USA.
36
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
37
Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
38
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.
39
Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, WA 6008, Australia.
40
Adult Genetics Unit, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA 5006, Australia.
41
University Department of Paediatrics, University of Adelaide, Adelaide, SA 5005, Australia.
42
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.
43
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.
44
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.
45
Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ 85259, USA.
46
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.
47
Department of Genetics and Computational Biology, QIMR Berghofer, Herston, QLD 4029, Australia. Electronic address: georgia.trench@qimrberghofer.edu.au.

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.

PMID:
27087319
PMCID:
PMC4863475
DOI:
10.1016/j.ajhg.2016.03.001
[Indexed for MEDLINE]
Free PMC Article

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