Samantha Hansford1, Pardeep Kaurah2, Hector Li-Chang1, Michelle Woo1, Janine Senz1, Hugo Pinheiro3, Kasmintan A Schrader4, David F Schaeffer5, Karey Shumansky6, George Zogopoulos7, Teresa Almeida Santos8, Isabel Claro9, Joana Carvalho3, Cydney Nielsen10, Sarah Padilla11, Amy Lum11, Aline Talhouk1, Katie Baker-Lange12, Sue Richardson13, Ivy Lewis14, Noralane M Lindor15, Erin Pennell16, Andree MacMillan14, Bridget Fernandez14, Gisella Keller17, Henry Lynch18, Sohrab P Shah6, Parry Guilford19, Steven Gallinger20, Giovanni Corso21, Franco Roviello22, Carlos Caldas13, Carla Oliveira23, Paul D P Pharoah24, David G Huntsman25. 1. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 2. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada5Hereditary Cancer Program, BC Cancer Agency, Vancouver, British Columbia, Canada. 3. Expression Regulation in Cancer Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal. 4. Hereditary Cancer Program, BC Cancer Agency, Vancouver, British Columbia, Canada. 5. Division of Anatomical Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada. 6. Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada. 7. The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada9Rosalind and Morris Goodman Cancer Research Centre, Montreal, Quebec, Canada. 8. Human Reproduction Service, University Hospitals of Coimbra, Coimbra, Portugal11Faculty of Medicine, University of Coimbra, Coimbra, Portugal. 9. Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisbon Portugal. 10. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada7Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada. 11. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. 12. Frauenshuh Cancer Center, Park Nicollet Clinic, St Louis Park, Minnesota. 13. Cancer Research UK Cambridge Institute, Cambridge, England. 14. Provincial Medical Genetics Program, St John's, Newfoundland, Canada. 15. Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona. 16. Cancer Care Program, Dr. H. Bliss Murphy Cancer Centre Eastern Health, St John's, Newfoundland, Canada. 17. Institute of Pathology, Technische Universität München, München, Germany. 18. Creighton's Hereditary Cancer Center, Omaha, Nebraska. 19. Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand. 20. Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada22Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto, Ontario, Canada. 21. Department of Experimental Oncology, European Institute of Oncology, Milano, Italy24Department of Medical Surgical Sciences and Neurosciences, Section of General Surgery and Surgical Oncology, University of Siena, Siena, Italy. 22. Department of Medical Surgical Sciences and Neurosciences, Section of General Surgery and Surgical Oncology, University of Siena, Siena, Italy25Istituto Toscano Tumori (ITT), University Hospital of Siena, Siena, Italy. 23. Expression Regulation in Cancer Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal26Faculty of Medicine, University of Porto, Porto, Portugal. 24. Department of Oncology, University of Cambridge, Strangeway's Research Laboratory, Wort's Causeway, Cambridge, England28Department of Public Health and Primary Care, University of Cambridge, Strangeway's Research Laboratory, Wort's Causeway, Cambridge, En. 25. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada7Department of Molecular.
Abstract
IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.
IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.
Authors: Winifred Lo; Bin Zhu; Arvind Sabesan; Ho-Hsiang Wu; Astin Powers; Rebecca A Sorber; Sarangan Ravichandran; Ina Chen; Lucas A McDuffie; Humair S Quadri; Joal D Beane; Kathleen Calzone; Markku M Miettinen; Stephen M Hewitt; Christopher Koh; Theo Heller; Sholom Wacholder; Udo Rudloff Journal: J Med Genet Date: 2019-02-11 Impact factor: 6.318
Authors: Joris van de Haar; Sander Canisius; Michael K Yu; Emile E Voest; Lodewyk F A Wessels; Trey Ideker Journal: Cell Date: 2019-05-30 Impact factor: 41.582