Germline E-cadherin mutations in familial lobular breast cancer

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 hereditary diffuse gastric cancer (HDGC) syndrome, and an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in patients with LBC in non-HDGC families. This study aimed to investigate the frequency of germline CDH1 mutations in patients with LBC with early onset disease or family histories of breast cancer without DGC. Methods: Germline DNA was analysed 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 the age of 45 years, 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 amplified using PCR 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 woman who had LBC at the age of 42 years and a first degree relative with invasive LBC. Conclusions: Germline CDH1 mutations can be associated with invasive LBC 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. Clarification of the cancer risks in the syndrome is essential.

Low penetrance breast cancer predisposition SNPs are site specific

“…However, the CGEMS prostate cancer study showed no evidence of an association with rs9929218 and prostate cancer. Loss of E-cadherin expression is characteristic of invasive lobular breast cancers [34] and germline mutations have been found in some familial lobular carcinomas [35]. There was no evidence of an association between rs9929218 and lobular cancer in the BIGGS cohort, however the study does not have the power to detect such an association if it existed with only 106 invasive lobular cancers in this series.…”

Breast cancer susceptibility: current knowledge and implications for genetic counselling

“…21,22 Disease-causing 16 Even in families without diffuse gastric cancer in their medical history, CDH1 mutations could be found in women with lobular breast cancer. 24 In view of the increased cancer risk, intensified surveillance programmes are indicated. 22,25 For women with neurofibromatosis type I (NF1) (MIM no.…”

Comprehensive genetic and functional characterization of IPH‐926: a novel CDH1‐null tumour cell line from human lobular breast cancer

“…Germline CDH1 mutation is the genetic defect underlying some rare cases of hereditary ILBCs [3,8]. Profiling approaches focusing on genomic imbalances established that nearly all ILBCs harbour a loss of 16q22, the locus of CDH1 [9].…”