Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels. Issue 10 (15th April 2019)

• Record Type: Journal Article
• Authors: Feliubadaló, Lídia; López‐Fernández, Adrià; Pineda, Marta; Díez, Orland; del Valle, Jesús; Gutiérrez‐Enríquez, Sara; Teulé, Alex; González, Sara; Stjepanovic, Neda; Salinas, Mónica; Capellá, Gabriel; Brunet, Joan; Lázaro, Conxi; Balmaña, Judith
• Other Names: Campos Olga investigator.; Carrasco Estela investigator.; Cuesta Raquel investigator.; Darder Esther investigator.; Gadea Neus investigator.; Gómez Carolina investigator.; Grau Elia investigator.; Iglesias Silvia investigator.; Izquierdo Angel investigator.; Llort Gemma investigator.; Menéndez Mireia investigator.; Moles‐Fernández Alejandro investigator.; Montes Eva investigator.; Muñoz Xavier investigator.; Navarro Matilde investigator.; Ramon y Cajal Teresa investigator.; Sanz Judit investigator.; Solanes Ares investigator.; Stradella Agostina investigator.; Tornero Eva investigator.; Torres‐Esquius Sara investigator.; Tuset Noemí investigator.; Urgell Gisela investigator.; Velasco Angela investigator.
• Is Part Of: International journal of cancer. Volume 145:Issue 10(2019)
• Page Start: 2682
• Page End: 2691
• Publication Date: 2019-04-15
• Subjects: germline cancer panel -- cancer susceptibility -- actionability; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32304
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PV) in customized predefined panels according to clinical suspicion by phenotype and compared it to the yield obtained in the analysis of our clinical research gene panel. We also investigated mutational yield of opportunistic testing of BRCA1/2 and mismatch repair (MMR) genes in all patients. A total of 1, 205 unrelated probands with clinical suspicion of hereditary cancer were screened for germline mutations using panel testing. Overall, 1, 048 females and 157 males were analyzed, mean age at cancer diagnosis was 48; 883 had hereditary breast/ovarian cancer‐suspicion, 205 hereditary nonpolyposis colorectal cancer (HNPCC)‐suspicion, 73 adenomatous‐polyposis‐suspicion and 44 with other/multiple clinical criteria. At least one PV was found in 150 probands (12%) analyzed by our customized phenotype‐driven panel. Tumoral MMR deficiency predicted for the presence of germline MMR gene mutations in patients with HNPCC‐suspicion (46/136 vs . 0/56 in patients with and without MMR deficiency, respectively). Opportunistic testing additionally identified five MSH6, one BRCA1 and one BRCA2 carriers (0.6%). The analysis of the extended 24‐gene panel provided 25 additional PVs (2%), including in 4 out of 51 individuals harboring MMR‐proficient colorectal tumors (2 CHEK2 and 2 ATM ). Phenotype‐based panels provide a notable rate of PVs with clinical actionability. Opportunistic testing of MMR and BRCA genes leads to a significant straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers, and endorses the model of opportunistic testing of genes with clinical utility within a standard genetic counseling framework. Abstract : What's new? Multigene panels offer a powerful tool for analyzing several cancer‐related genes with a single test. But which genes are actually useful in guiding medical decisions in the clinic? In this study, the authors analyzed several customized, phenotype‐driven diagnostic gene panels. These yielded a notable rate of pathogenic variants with clear clinical actionability. The study also found that opportunistic testing of MMR and BRCA genes leads to a significant, straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers. This approach could be applied within a standard genetic counseling framework.