Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 2360-2372 |
| Number of pages | 13 |
| Journal | JAMA - Journal of the American Medical Association |
| Volume | 297 |
| Issue number | 21 |
| DOIs | |
| State | Published - Jun 6 2007 |
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All Science Journal Classification (ASJC) codes
- Medicine(all)
Cite this
Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. / Kaurah, Pardeep; MacMillan, Andrée; Boyd, Niki; Senz, Janine; De Luca, Alessandro; Chun, Nicki; Suriano, Gianpaolo; Zaor, Sonya; Van Manen, Lori; Gilpin, Cathy; Nikkel, Sarah; Connolly-Wilson, Mary; Weissman, Scott; Rubinstein, Wendy S.; Sebold, Courtney; Greenstein, Robert; Stroop, Jennifer; Yim, Dwight; Panzini, Benoit; McKinnon, Wendy; Greenblatt, Marc; Wirtzfeld, Debrah; Fontaine, Daniel; Coit, Daniel; Yoon, Sam; Chung, Daniel; Lauwers, Gregory; Pizzuti, Antonio; Vaccaro, Carlos; Redal, Maria Ana; Oliveira, Carla; Tischkowitz, Marc; Olschwang, Sylviane; Gallinger, Steven; Lynch, Henry T.; Green, Jane; Ford, James; Pharoah, Paul; Fernandez, Bridget; Huntsman, David.
In: JAMA - Journal of the American Medical Association, Vol. 297, No. 21, 06.06.2007, p. 2360-2372.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer
AU - Kaurah, Pardeep
AU - MacMillan, Andrée
AU - Boyd, Niki
AU - Senz, Janine
AU - De Luca, Alessandro
AU - Chun, Nicki
AU - Suriano, Gianpaolo
AU - Zaor, Sonya
AU - Van Manen, Lori
AU - Gilpin, Cathy
AU - Nikkel, Sarah
AU - Connolly-Wilson, Mary
AU - Weissman, Scott
AU - Rubinstein, Wendy S.
AU - Sebold, Courtney
AU - Greenstein, Robert
AU - Stroop, Jennifer
AU - Yim, Dwight
AU - Panzini, Benoit
AU - McKinnon, Wendy
AU - Greenblatt, Marc
AU - Wirtzfeld, Debrah
AU - Fontaine, Daniel
AU - Coit, Daniel
AU - Yoon, Sam
AU - Chung, Daniel
AU - Lauwers, Gregory
AU - Pizzuti, Antonio
AU - Vaccaro, Carlos
AU - Redal, Maria Ana
AU - Oliveira, Carla
AU - Tischkowitz, Marc
AU - Olschwang, Sylviane
AU - Gallinger, Steven
AU - Lynch, Henry T.
AU - Green, Jane
AU - Ford, James
AU - Pharoah, Paul
AU - Fernandez, Bridget
AU - Huntsman, David
PY - 2007/6/6
Y1 - 2007/6/6
N2 - 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.
AB - 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.
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U2 - 10.1001/jama.297.21.2360
DO - 10.1001/jama.297.21.2360
M3 - Article
VL - 297
SP - 2360
EP - 2372
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
SN - 0002-9955
IS - 21
ER -