Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families.
OBJECTIVE
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.
Pharoah
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PD
Department of Oncology, Strangeways Research Laboratories, University of Cambridge, Worts Causeway, Cambridge, CB18RN England, UK. paul.pharoah@srl.cam.ac.uk
Guilford
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Caldas
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C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D013274:Stomach Neoplasms / Q000453:epidemiology* / Q000235:genetics*
D015820:Cadherins