The Identification of Large Rearrangements Involving Intron 2 of the CDH1 Gene in BRCA1/2 Negative and Breast Cancer Susceptibility.

E-cadherin, a gene product, is a calcium-dependent cell-cell adhesion molecule playing a critical role in the establishment of epithelial architecture, maintenance of cell polarity, and differentiation. Germline pathogenic variants in the gene are associated with hereditary diffuse gastric cancer (HDGC), and large rearrangements in the gene are now being reported as well. Because pathogenic variants could be associated with breast cancer (BC) susceptibility, rearrangements could also impact it. The aim of our study is to identify rearrangements in the gene in 148 BC cases with no and pathogenic variants. To do so, a zoom-in CGH array, covering the exonic, intronic, and flanking regions of the gene, was used to screen our cohort. Intron 2 of the gene was specifically targeted because it is largely reported to include several regulatory regions. As results, we detected one large rearrangement causing a premature stop in exon 3 of the gene in a proband with a bilateral lobular breast carcinoma and a gastric carcinoma (GC). Two large rearrangements in the intron 2, a deletion and a duplication, were also reported only with BC cases without any familial history of GC. No germline rearrangements in the coding region were detected in those families without GC and with a broad range of BC susceptibility. This study confirms the diversity of large rearrangements in the gene. The rearrangements identified in intron 2 highlight the putative role of this intron in regulation and alternative transcripts. Recurrent duplication copy number variations (CNV) are found in this region, and the deletion encompasses an alternative transcript. Screening for large rearrangements in the gene could be important for genetic testing of BC.