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Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers
  1. K A Schrader1,
  2. S Masciari2,
  3. N Boyd1,
  4. C Salamanca1,
  5. J Senz1,
  6. D N Saunders1,
  7. E Yorida1,
  8. S Maines-Bandiera1,
  9. P Kaurah3,
  10. N Tung4,
  11. M E Robson5,
  12. P D Ryan6,
  13. O I Olopade7,
  14. S M Domchek8,
  15. J Ford9,
  16. C Isaacs10,
  17. P Brown11,
  18. J Balmana12,
  19. A R Razzak2,
  20. P Miron13,
  21. K Coffey4,
  22. M B Terry14,
  23. E M John15,9,
  24. I L Andrulis16,
  25. J A Knight17,
  26. F P O'Malley18,
  27. M Daly19,
  28. P Bender20,
  29. kConFab21,
  30. R Moore22,
  31. M C Southey23,
  32. J L Hopper24,
  33. J E Garber2,
  34. D G Huntsman1
  1. 1Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  2. 2Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
  3. 3Hereditary Cancer Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
  4. 4Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
  5. 5Memorial Sloan–Kettering Cancer Center, New York, New York, USA
  6. 6Massachusetts General Hospital, Boston, Massachusetts, USA
  7. 7University of Chicago Medical Center, Chicago, Illinois, USA
  8. 8Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  9. 9Stanford University School of Medicine, Stanford, California, USA
  10. 10Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, Washington, USA
  11. 11Breast Center, Baylor College of Medicine, Houston, Texas, USA
  12. 12Hospital Vall d'Hebron, Barcelona, Spain
  13. 13Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
  14. 14Columbia University, New York, New York, USA
  15. 15Northern California Cancer Center Prevention, Institute of California, Fremont, California, USA
  16. 16Ontario Cancer Genetics Network, Cancer Care Ontario, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  17. 17Division of Epidemiology and Biostatistics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  18. 18University of Toronto and St Michael's Hospital, Toronto, Ontario, Canada
  19. 19Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
  20. 20National Institutes of Health, Bethesda, Maryland, USA
  21. 21The Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  22. 22Genome Sciences Centre, Vancouver, British Columbia, Canada
  23. 23Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
  24. 24Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia
  1. Correspondence to Professor David G Huntsman, British Columbia Cancer Agency, Room 3427, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada; dhuntsma{at}bccancer.bc.ca

Abstract

Background Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition.

Method To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions.

Results No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis.

Conclusion Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

  • Hereditary lobular breast cancer
  • CDH1
  • E-cadherin
  • hereditary breast cancer
  • hereditary diffuse gastric cancer
  • genetic screening/counselling
  • oncology
  • cancer: breast

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

https://doi.org/10.1136/jmg.2010.079814

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    Footnotes

    • Funding The collection of resources from the Breast CFR was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (CFR) and principal investigators including those from Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), the Northern California Cancer Center (U01 CA69417), the University of Melbourne (U01 CA69638) and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). kConFab is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. The Breast Cancer Genetics Consortium was funded by a Breast Cancer Research Foundation grant to JG and the consortium (Dana Farber Cancer Institute, Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, University of Chicago, University of Pennsylvania, Stanford University, Georgetown University, Baylor College of Medicine and Hospital Vall d'Hebron). DNA and mutation analysis was performed at the Huntsman Laboratory, British Columbia Cancer Agency and the Genome Sciences Centre, and was supported by the Canadian Cancer Society (principal investigator: David Huntsman; grant No. 18381). This research was supported in part by the Dana Farber/Harvard Cancer Center Breast SPORE (grant number: NIH/NCI (P50-CA89393)). KAS is supported by the University of British Columbia's Clinician Investigator Program. DNS is supported by a Cancer Institute NSW fellowship. SM was supported by Charles A. King Trust, Bank of America Fellowship, Co-Trustee (Boston, MA) and The Humane Society of the Commonwealth of Massachusetts Postdoctoral Research Fellowship. This work was conducted with support from the Scholars in Clinical Science Program of Harvard Catalyst, The Harvard Clinical and Translational Science Center (award No. UL1 RR 025758) and with financial contributions from Harvard University and its affiliated academic healthcare centres.

    • Competing interests None declared.

    • Ethics approval This study was conducted with the approval of the British Columbia Cancer Agency.

    • Provenance and peer review Not commissioned; externally peer reviewed.