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Founder and Recurrent CDH1 Mutations in Families With Hereditary Diffuse Gastric Cancer
Pardeep Kaurah, MSc;
Andrée MacMillan, MSc;
Niki Boyd, MSc, PhD;
Janine Senz, BSc;
Alessandro De Luca, BSc;
Nicki Chun, MS;
Gianpaolo Suriano, PhD;
Sonya Zaor, MSc;
Lori Van Manen, MS;
Cathy Gilpin, MS;
Sarah Nikkel, MD;
Mary Connolly-Wilson, Med;
Scott Weissman, MS;
Wendy S. Rubinstein, MD;
Courtney Sebold, MS;
Robert Greenstein, MD;
Jennifer Stroop, MS;
Dwight Yim, MD;
Benoit Panzini, MD;
Wendy McKinnon, MS;
Marc Greenblatt, MD;
Debrah Wirtzfeld, MD;
Daniel Fontaine, MD;
Daniel Coit, MD;
Sam Yoon, MD;
Daniel Chung, MD;
Gregory Lauwers, MD;
Antonio Pizzuti, MD;
Carlos Vaccaro, MD;
Maria Ana Redal, PhD;
Carla Oliveira, PhD;
Marc Tischkowitz, MD;
Sylviane Olschwang, MD;
Steven Gallinger, MD;
Henry Lynch, MD;
Jane Green, PhD;
James Ford, MD;
Paul Pharoah, PhD;
Bridget Fernandez, MD;
David Huntsman, MD
JAMA. 2007;297:2360-2372. Published online June 3, 2007 (doi:10.1001/jama.297.21.2360).
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 Affiliations: Hereditary Cancer Program (Ms Kaurah and Dr Huntsman), Centre for Translational and Applied Genomics (Ms Senz, Mr De Luca, and Drs Boyd and Huntsman), British Columbia Cancer Agency, Vancouver; Provincial Medical Genetics Program, Health Sciences Centre, St Johns, Newfoundland (Ms MacMillan, Ms Connolly-Wilson, and Dr Fernandez); Cancer Genetics Program, Division of Oncology, Stanford University School of Medicine, Stanford, Calif (Ms Chun and Dr Ford); Institute of Molecular Pathology and Immunology (Drs Suriano and Oliveira), Faculty of Medicine (Dr Oliveira), University of Porto, Porto, Portugal; Cancer Prevention Center, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec (Ms Zaor and Dr Tischkowitz); Familial Oncology Program, Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston (Ms Van Manen); Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa (Ms Gilpin and Dr Nikkel); Center for Medical Genetics, Evanston Northwestern Healthcare, Evanston, Ill (Mr Weissman and Dr Rubinstein); Pediatric Subspecialty Clinic, Wilford Hall Medical Center, San Antonio, Tex (Ms Sebold); Hereditary Cancer Program, Division of Medical Genetics, University of Connecticut Health Center, Farmington (Dr Greenstein and Ms Stroop); Department of Pediatrics, Kaiser Permanante, Honolulu, Hawaii (Dr Yim); Clinique des Cancers Héréditaires, CHUM Hôtel-Dieu, Montreal, Quebec (Dr Panzini); Service de Gastroenterology, CHUM Hôpital Notre-Dame, Montreal, Quebec (Dr Panzini); Familial Cancer Program, University of Vermont College of Medicine, Burlington (Ms McKinnon and Dr Greenblatt); Divisions of Surgery and Clinical Genetics (Dr Wirtzfeld), Department of Anatomical Pathology (Dr Fontaine), and Discipline of Genetics, Faculty of Medicine (Drs Green and Fernandez), Memorial University of Newfoundland, St John’s, Newfoundland; Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY (Dr Coit); Surgical Oncology, Department of Surgery (Dr Yoon), Gastrointestinal Unit and Cancer Center (Dr Chung), and Gastrointestinal Pathology Service, Department of Pathology (Dr Lauwers), Massachusetts General Hospital and Harvard Medical School, Boston; IRCCS-CSS Hospital, San Giovanni Rotondo and CSS-Mendel Institute, Rome, Italy (Dr Pizzuti); Service of General Surgery (Dr Vaccaro), Instituto de Ciencias Basicas y Medicina Experimental (Dr Redal), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec (Dr Tischkowitz); INSERM U599, Institut Paoli Calmettes, Marseille, France (Dr Olschwang); Hepatobiliary and Pancreatic Surgical Group, Division of General Surgery, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario (Dr Gallinger); Department of Preventive Medicine and Public Health, Creighton University, Omaha, Neb (Dr Lynch); and Department of Oncology, University of Cambridge, Cambridge, England (Dr Pharoah). Ms Sebold is now with the Chromosome 18 Clinical Research Center, University of Texas Health Science Center, San Antonio.
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