Gastroenterology

Gastroenterology

Volume 121, Issue 6, December 2001, Pages 1348-1353
Gastroenterology

Clinical Science
Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families,☆☆,

https://doi.org/10.1053/gast.2001.29611Get rights and content

Abstract

Background & Aims: Germline mutations in CDH1 are known to cause hereditary diffuse gastric cancer (HDGC). Breast and colorectal cancer have also been reported in CDH1-associated HDGC. The purpose of this study was to estimate the cumulative risk of gastric and breast cancer in CDH1 mutation carriers. Methods: Family data were collected by member groups of the International Gastric Cancer Linkage Consortium. Eligible families had at least 3 cases of diffuse gastric cancer, and at least 1 affected member had tested positive for a mutation in CDH1. Eleven families met these criteria. We used the pedigree information to estimate penetrance using the MENDEL program. The conditional likelihood of the pedigree was maximized given the phenotype of the pedigree and genotype of the index case at ascertainment. We parameterized the model in terms of log relative risks for mutation carriers compared with risks in the general population of the United Kingdom. Noncarriers of the gene were assumed to develop the disease at population incidence rates. Results: The estimated cumulative risk of gastric cancer by age 80 years was 67% for men (95% confidence interval [95% CI], 39–99) and 83% for women (95% CI, 58–99). For women, the cumulative risk of breast cancer was 39% (95% CI, 12–84). The combined risk of gastric cancer and breast cancer in women was 90% by age 80 years. Conclusions: These penetrance estimates should be useful for genetic counseling in multiple-case families. However, they may not apply to individuals with a minimal family history, in whom the risks may be lower.

GASTROENTEROLOGY 2001;121:1348-1353

Section snippets

Patients and families

Family samples were collected by research groups that are members of the IGCLC. Families were eligible for the study if they included at least 3 cases of diffuse-type gastric cancer and at least 1 affected member had tested positive for a disease-associated mutation in CDH1. Gastric cancer families in which a missense mutation in CDH1 had been identified were excluded from the analysis because the pathogenic significance of these genetic variants is not known. Twelve families meeting these

Results

A summary of the 11 families used in this analysis is shown in Table 1. The families included data on 476 individuals (241 male, 235 female). Of these there were 80 cases of gastric cancer (38 male, 42 female) with an average age of diagnosis of 40 (range, 14–85) years. Age of diagnosis tended to be slightly earlier in women (mean, 39 years) than in men (mean, 42 years). Confirmation of gastric cancers from pathology records was available for 46 patients. Of these, 44 were diffuse-type gastric

Discussion

This study confirms that carriers of a germline mutation in CDH1 have a high lifetime risk of developing gastric cancer but that the risk is less than 100%. Huntsman et al.18 reported superficial infiltrates of malignant signet-ring cells identified in all surgical samples from 5 CDH1 mutation carriers who underwent prophylactic gastrectomy. These early diffuse gastric cancers were multifocal in 3 of 5 cases, and in 1 case infiltrates of malignant signet-ring cells were present in 65 of 140

Acknowledgements

The authors thank all families, clinicians, and pathologists who contributed to this study.

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    Address requests for reprints to: Paul D. P. Pharoah, M.D., Ph.D., University of Cambridge, Strangeways Research Laboratories, Worts Causeway, Cambridge, CB18RN England. e-mail: [email protected]; fax: (44) 1223-411609.

    ☆☆

    P.D.P.P. is a Cancer Research Campaign (CRC) Senior Clinical Research Fellow. P.H., M.M., and P.G. are funded by the Health Research Council of New Zealand. F.R. and E.M. are funded by the Birmingham Hospitals Endowment Research Fund and the British Digestive Foundation. Meetings of the IGCLC have been supported by grants from the Kathleen DuRoss Ford Foundation and the Bank of Siena.

    Contributing centers and principal investigators in the International Gastric Cancer Linkage Consortium (the number of families contributed by each center is shown in parentheses): Carlos Caldas and Paul Pharoah, Strangeways Research Laboratories and Department of Oncology, University of Cambridge, Cambridge, England (coordinating center); Tumi Toro and Parry Guilford, Cancer Genetics Laboratory, University of Otago, Dunedin, Aetearoa, New Zealand, and Maybelle McLeod and Pauline Harawira, Kimihauora Health and Research Clinic, Mt. Maunganui, New Zealand (1); Gisela Keller and Heinz Hofler, Institute of Pathology, and H. Vogelsang, Department of Surgery, Technische Universität München, Munich, Germany (1); Frances Richards and Eamonn Maher, Section of Medical and Molecular Genetics, University of Birmingham, Birmingham, England (2); Nicola Grehan and Carlos Caldas, Department of Oncology, University of Cambridge, Cambridge, England (1); Jean-Marc Limacher, Service d'Oncologie, Hopitaux Universitaires, Strasbourg, France (1); David Huntsman, British Columbia Cancer Agency, and Patrick MacLeod, Medical Genetics, Victoria General Hospital, Victoria, British Columbia, Canada (1); Charles E. Jackson, Henry Ford Hospital, Detroit, Michigan, (1); Georgia Wiesner, Department of Genetics, University Hospitals of Cleveland/Case Western Reserve University, Cleveland, Ohio, (1); Cindy Hunter and Gail Vance, Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana (1); Anne E. Harty and Henry Lynch, Department of Medicine, Creighton University Medical School, Omaha, Nebraska (1); Noralane M. Lindor and Larry J. Burgart, Mayo Clinic, Rochester, Minnesota (1).

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