Short communication CDH1 germ-line missense mutation identified by multigene sequencing in a family with no history of diffuse gastric cancer Tirzah Braz Petta Lajus ⁎, Roberto Magnus Duarte Sales Liga Norte-Riograndense Contra o Cancer, CECAN, Av Miguel Castro, 1355, Dix-Sept Rosado, CEP 59062-000 Natal, RN, Brazil abstract article info Article history: Received 24 March 2015 Received in revised form 6 May 2015 Accepted 12 May 2015 Available online 15 May 2015 Keywords: Infiltrative ductal carcinoma Next generation sequencing Multiplex genetic testing Molecular diagnosis CDH1 Germ-line mutation Germ-line mutation in CDH1 gene is associated with high risk for Hereditary Diffuse Gastric Cancer (HDGC) and Infiltrative Lobular Carcinoma (ILC). Although somatic CDH1 mutations were also detected in ILC with a frequen- cy ranging from 10 to 56%, CDH1 alterations in more frequent infiltrative ductal carcinoma (IDC) appear to be rare, and no association with germ-line CDH1 mutation and IDC has been established. Here we report the case of a woman diagnosed with IDC at 39 years of age, presenting extensive familial history of cancer at multiple sites with early-age onset and with no case of HDGC. Deep sequencing have revealed CDH1 missense mutation c.1849GNA (p.Ala617Thr) in heterozygous and four BRCA2 single nucleotide polymorphism in homozygosis. In this family, the mutation c.1849GNA in the CDH1 gene is not related to HDGC nor ILC. Therefore, here we high- light that multigene analysis is important to detect germ-line mutations and genetic variants in patients with cancers at multiple sites in the family, even if inconclusive genetic counseling can be offered, since hereafter, medical awareness will be held. © 2015 Elsevier B.V. All rights reserved. 1. Introduction CDH1 (GenBank: AB025105.1) germ-line mutation is associated with Hereditary Diffuse Gastric Cancer (HDGC OMIM #192090), which is an autosomal dominant cancer predisposition syndrome (Guilford et al., 1998). Patients carrying CDH1 mutation will have an 80% risk of developing HDGC by 80 years old (Fitzgerald et al., 2010). In addition, female patients carry an additional 60% lifetime risk of developing infiltrative lobular carcinoma (ILC) (Keller et al., 1999). The CDH1 gene is located on the 16q22.1 chromosome and encodes the E-cadherin intercellular adhesion protein. This protein acts as a tumor suppressor and plays an important role in maintenance of the ep- ithelial tissue architecture (van Roy and Berx, 2008; Berx and Van Roy, 2001). Mutations in this gene primarily affect both the intracellular and extracellular domains of the protein and thus affect the integrity of the protein, leading to disturbances in epithelial tissue cell–cell adhe- sion, increased cell motility and an enhanced infiltrative capacity and tumor metastasis (Mateus et al., 2009; Ghaffari et al., 2010). Breast cancer represents a group of diseases, with different histolog- ical, molecular and clinical characteristics with at least 17 different mo- lecular subtypes currently described (Perou et al., 2000). IDC accounts for almost 80% of all breast cancers, whereas ILC accounts for 14%. One of the hallmarks of ILC is the loss or altered expression of CDH1. Although ductal tumors are much more common than lobular breast cancer, CDH1 mutations have been observed in lobular carcinomas at a frequency exceeding 50%, but were not found in ductal tumors in sev- eral studies (Berx et al., 1995; Berx et al., 1996; Becker et al., 1999; Kashiwaba et al., 1995), suggesting a differential role for CDH1 in the development of the 2 malignancies. With the advances in genomic research by the introduction of next- generation sequencing (NGS), DNA from a subject with personal history of cancer can be screened for several tumor suppressor genes simulta- neously in a cost effective manner (Walsh et al., 2011; Ku et al., 2013; Chong et al., 2014). Many clinical diagnostic laboratories offer multi- gene testing ranging from 2 to 50 genes (Walsh et al., 2006, 2011). How- ever, some physicians prefer to only test for those genes in which established surveillance and treatment protocol exists, such as Li Fraumeni syndrome (germ-line mutation in TP53), Cowden syndrome (germ-line mutation in PTEN) and Hereditary Breast and Ovarian cancer syndrome (germ-line mutation in BRCA1 or BRCA2). Here we describe a patient who was refereed to the genetic counsel- ing service for presenting National Comprehensive Cancer Network (NCCN) criteria for Hereditary Breast and Ovarian cancer syndrome Gene 568 (2015) 215–219 Abbreviations: HDGC, Hereditary Diffuse Gastric Cancer; IDC, infiltrative ductal carcinoma; ILC, infiltrative lobular carcinoma; NGS, next-generation sequencing; SNP, single nucleotide polymorphism. ⁎ Corresponding author. E-mail address: pesquisaclinica.tirzah@liga.org.br (T.B.P. Lajus). http://dx.doi.org/10.1016/j.gene.2015.05.035 0378-1119/© 2015 Elsevier B.V. All rights reserved. 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