Document Detail

Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer.
MedLine Citation:
PMID:  17545690     Owner:  NLM     Status:  MEDLINE    
CONTEXT: Hereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer.
OBJECTIVE: To determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry.
DESIGN, SETTING, AND PATIENTS: Thirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.
MAIN OUTCOME MEASURES: Classification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations.
RESULTS: Thirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%).
CONCLUSIONS: Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.
Pardeep Kaurah; Andrée MacMillan; Niki Boyd; Janine Senz; Alessandro De Luca; Nicki Chun; Gianpaolo Suriano; Sonya Zaor; Lori Van Manen; Cathy Gilpin; Sarah Nikkel; Mary Connolly-Wilson; Scott Weissman; Wendy S Rubinstein; Courtney Sebold; Robert Greenstein; Jennifer Stroop; Dwight Yim; Benoit Panzini; Wendy McKinnon; Marc Greenblatt; Debrah Wirtzfeld; Daniel Fontaine; Daniel Coit; Sam Yoon; Daniel Chung; Gregory Lauwers; Antonio Pizzuti; Carlos Vaccaro; Maria Ana Redal; Carla Oliveira; Marc Tischkowitz; Sylviane Olschwang; Steven Gallinger; Henry Lynch; Jane Green; James Ford; Paul Pharoah; Bridget Fernandez; David Huntsman
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-06-03
Journal Detail:
Title:  JAMA     Volume:  297     ISSN:  1538-3598     ISO Abbreviation:  JAMA     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-06-06     Completed Date:  2007-06-11     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  7501160     Medline TA:  JAMA     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2360-72     Citation Subset:  AIM; IM    
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MeSH Terms
Age of Onset
Aged, 80 and over
Cadherins / genetics*
DNA Mutational Analysis
Founder Effect*
Genetic Counseling
Germ-Line Mutation*
Heterozygote Detection
Middle Aged
Newfoundland and Labrador / epidemiology
Stomach Neoplasms / genetics*,  mortality
Grant Support
Reg. No./Substance:
0/CDH1 protein, human; 0/Cadherins
Comment In:
Gastroenterology. 2007 Nov;133(5):1730-2; discussion 1732-3   [PMID:  17983818 ]
JAMA. 2007 Jun 6;297(21):2410-1   [PMID:  17545691 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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