Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer

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 & 20 others 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 T. Lynch, Jane Green, James Ford, Paul Pharoah, Bridget Fernandez, David Huntsman

Research output: Contribution to journalArticle

273 Citations (Scopus)

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 languageEnglish
Pages (from-to)2360-2372
Number of pages13
JournalJAMA - Journal of the American Medical Association
Volume297
Issue number21
DOIs
StatePublished - Jun 6 2007

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Stomach Neoplasms
Mutation
Haplotypes
Breast Neoplasms
Newfoundland and Labrador
Germ-Line Mutation
Missense Mutation
Confidence Intervals
Founder Effect
British Columbia
Cadherins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Kaurah, P., MacMillan, A., Boyd, N., Senz, J., De Luca, A., Chun, N., ... Huntsman, D. (2007). Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA - Journal of the American Medical Association, 297(21), 2360-2372. https://doi.org/10.1001/jama.297.21.2360

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 journalArticle

Kaurah, P, MacMillan, A, Boyd, N, Senz, J, De Luca, A, Chun, N, Suriano, G, Zaor, S, Van Manen, L, Gilpin, C, Nikkel, S, Connolly-Wilson, M, Weissman, S, Rubinstein, WS, Sebold, C, Greenstein, R, Stroop, J, Yim, D, Panzini, B, McKinnon, W, Greenblatt, M, Wirtzfeld, D, Fontaine, D, Coit, D, Yoon, S, Chung, D, Lauwers, G, Pizzuti, A, Vaccaro, C, Redal, MA, Oliveira, C, Tischkowitz, M, Olschwang, S, Gallinger, S, Lynch, HT, Green, J, Ford, J, Pharoah, P, Fernandez, B & Huntsman, D 2007, 'Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer', JAMA - Journal of the American Medical Association, vol. 297, no. 21, pp. 2360-2372. https://doi.org/10.1001/jama.297.21.2360
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. / Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. In: JAMA - Journal of the American Medical Association. 2007 ; Vol. 297, No. 21. pp. 2360-2372.
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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.",
author = "Pardeep Kaurah and Andr{\'e}e MacMillan and Niki Boyd and Janine Senz and {De Luca}, Alessandro and Nicki Chun and Gianpaolo Suriano and Sonya Zaor and {Van Manen}, Lori and Cathy Gilpin and Sarah Nikkel and Mary Connolly-Wilson and Scott Weissman and Rubinstein, {Wendy S.} and Courtney Sebold and Robert Greenstein and Jennifer Stroop and Dwight Yim and Benoit Panzini and Wendy McKinnon and Marc Greenblatt and Debrah Wirtzfeld and Daniel Fontaine and Daniel Coit and Sam Yoon and Daniel Chung and Gregory Lauwers and Antonio Pizzuti and Carlos Vaccaro and Redal, {Maria Ana} and Carla Oliveira and Marc Tischkowitz and Sylviane Olschwang and Steven Gallinger and Lynch, {Henry T.} and Jane Green and James Ford and Paul Pharoah and Bridget Fernandez and David Huntsman",
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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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