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Germline E-Cadherin mutations in familial lobular breast cancer
  1. Serena Masciari (serena_masciari{at}dfci.harvard.edu)
  1. Department of Medical Oncology Dana Farber Cancer Institute, Boston MA, United States
    1. Nina Larsson
    1. Department of Clinical Genetics, University Hospital, Lund, Sweden, Sweden
      1. Janine Senz
      1. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
        1. Niki Boyd
        1. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
          1. Pardeep Kaurah
          1. Hereditary Cancer Program, British Columbia Cancer Agency, Vancouver, Canada
            1. Michaela J Kandel
            1. Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Germany
              1. Lyndsay N Harris
              1. Yale Cancer Center New Haven, CT, United States
                1. Hugo C Pinheiro
                1. Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal
                  1. Armelle Troussard
                  1. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
                    1. Penelope Miron
                    1. Department of Cancer Biology Dana Farber Cancer Institute, Boston MA, United States
                      1. Nadine Tung
                      1. Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA, United States
                        1. Carla Oliveira
                        1. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
                          1. Laura Collins
                          1. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, United States
                            1. Stuart Schnitt
                            1. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, United States
                              1. Judy E Garber (judy_garber{at}dfci.harvard.edu)
                              1. Department of Medical Oncology, Dana Farber Cancer Institute, Boston MA, United States
                                1. David Huntsman (dhuntsma{at}bccancer.bc.ca)
                                1. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

                                  Abstract

                                  Background: The cell surface glycoprotein, E-Cadherin (CDH1) is a key regulator of adhesive properties in epithelial cells. Germline mutations in CDH1 are well-established as the defects underlying the Hereditary Diffuse Gastric Cancer (HDGC)syndrome: an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in LBC patients outside of HDGC families. We sought to investigate the frequency of germline CDH1 mutations in LBC patients with early onset disease or family histories of breast cancer without DGC.

                                  Methods: Germline DNA was analyzed in 23 women with invasive lobular or mixed ductal and lobular breast cancers who had at least one close relative with breast cancer or had themselves been diagnosed before age 45, had tested negative for a germline BRCA1 or BRCA2 mutation, and reported no personal or family history of diffuse gastric cancer. The full coding sequence of CDH1 including splice junctions was PCR amplified and screened for mutations using DHPLC and sequencing.

                                  Results: A novel germline CDH1 truncating mutation in the extracellular portion of the protein (517insA) was identified in one subject who had lobular breast cancer at age 42 and a first degree relative with invasive lobular breast cancer.

                                  Conclusions: Germline CDH1 mutations can be associated with invasive lobular breast cancer in the absence of diffuse gastric cancer. The finding, if confirmed, may have implications for management of individuals at risk for this breast cancer subtype, and compels clarification of the cancer risks in the syndrome.

                                  • CDH1
                                  • Lobular Breast Cancer
                                  • familial breast cancer
                                  • germline mutations

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