Abstract 2202: Identification of CDH1 mutations in patients with lobular carcinoma with and without a family history of gastric cancer

Abstract

Abstract Background: The E-cadherin (CDH1) gene is involved in cell adhesion and maintenance of tissue architecture. Loss of expression of CDH1 has been found in both invasive lobular carcinoma (ILCA) of the breast as well as hereditary diffuse gastric cancer (HDGC). While mutations in CDH1 have been found in patients with hereditary diffuse gastric cancer, less is known about the role of CDH1 mutations in patients with breast cancer, thus mutation status was determined in a breast cancer cohort with and without family histories of gastric cancer. Methods: The Clinical Breast Care Project database was queried to identify all patients with ILCA with or without a family history of gastric or stomach cancer as well as those with non-lobular invasive cancer with a family history of gastric or stomach cancer. Genomic DNA was isolated from peripheral blood samples. DNA variants were detected for each exon using high-resolution melting technology and the underlying change identified by direct sequencing. Results: Of the 72 patients with ILCA, five had a first degree relative with stomach cancer; 14 patients with non-lobular invasive cancer (12 IDCA, one mixed lobular and ductal, and one tubular) had first degree relatives with stomach or gastric cancer. Three mutations previously associated with gastric cancer were identified: A617T and V832M were identified in a patient with ILCA with no history of gastric cancer and in a patient with IDCA with a family history of gastric cancer, respectively, while one patient with ILCA and no family history harbored the splice site mutation 1137G-T. Three novel variants were also identified: G879S, in a patient with ILCA and no family history, P825Q in a patient with mixed lobular and ductal features with a family history of stomach cancer and L230F in a patient with IDCA and a family history of stomach cancer. Conclusions: The frequency of CDH1 mutations in this patient population was low (∼7%) and were split between patients with ILCA and no family history of gastric cancer and those with non-lobular cancers and at least one family member with gastric or stomach cancer. Identification of known mutations in patients with non-lobular carcinomas suggests that while these specific CDH1 mutations are associated with increased risk of hereditary diffuse gastric cancer, they do not confer increased risk for lobular cancer. In those patients with ILCA, the low frequency of germline mutations in CDH1 suggests alternate methods, such as epigenetic modification or miRNA silencing, may be driving the suppression of expression of E-cadherin and the development of ILCA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2202. doi:10.1158/1538-7445.AM2011-2202