Bouras Ahmed, Guidara Souhir, Leone Mélanie, Buisson Adrien, Martin-Denavit Tanguy, Dussart Sophie, Lasset Christine, Giraud Sophie, Bonnet-Dupeyron Marie-Noëlle, Kherraf Zine-Eddine, Sanlaville Damien, Fert-Ferrer Sandra, Lebrun Marine, Bonadona Valerie, Calender Alain, Boutry-Kryza Nadia
Laboratory of Constitutional Genetics for Frequent Cancer HCL-CLB, Centre Léon Bérard, 69008 Lyon, France.
Team 'Endocrine Resistance, Methylation and Breast Cancer' Research Center of Lyon-CRCL, UMR Inserm 1052 CNRS 5286, 69008 Lyon, France.
Cancers (Basel). 2023 Jun 29;15(13):3420. doi: 10.3390/cancers15133420.
The use of multigene panel testing for patients with a predisposition to Hereditary Breast and Ovarian Cancer syndrome (HBOC) is increasing as the identification of mutations is useful for diagnosis and disease management. Here, we conducted a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in 4630 French HBOC suspected patients. Patients were investigated using a germline cancer panel including the 13 genes defined by The French Genetic and Cancer Group (GGC)-Unicancer. In the patients analyzed, 528 pathogenic and likely pathogenic variants (P/LP) were identified, including (n = 203, 38%), (n = 198, 37%), (n = 46, 9%), (n = 36, 7%), (n = 16, 3%), and (n = 13, 2%). In addition, 35 novel (P/LP) variants, according to our knowledge, were identified, and double mutations in two distinct genes were found in five patients. Interestingly, retesting a subset of BRCA1/2-negative individuals with an expanded panel produced clinically relevant results in 5% of cases. Additionally, combining in silico (splicing impact prediction tools) and in vitro analyses (RT-PCR and Sanger sequencing) highlighted the deleterious impact of four candidate variants on splicing and translation. Our results present an overview of pathogenic variations of HBOC genes in the southeast of France, emphasizing the clinical relevance of cDNA analysis and the importance of retesting BRCA-negative individuals with an expanded panel.
对于有遗传性乳腺癌和卵巢癌综合征（HBOC）倾向的患者，多基因检测的应用正在增加，因为突变的鉴定对诊断和疾病管理很有用。在此，我们对4630名法国疑似HBOC患者的BRCA1/2和非BRCA基因测序进行了回顾性分析。使用包括法国遗传与癌症小组（GGC）-Unicancer定义的13个基因的种系癌症检测板对患者进行调查。在分析的患者中，鉴定出528个致病和可能致病的变异（P/LP），包括（n = 203，38%），（n = 198，37%），（n = 46，9%），（n = 36，7%），（n = 16，3%），以及（n = 13，2%）。此外，据我们所知，鉴定出35个新的（P/LP）变异，并且在5名患者中发现了两个不同基因的双突变。有趣的是，对一部分BRCA1/2阴性个体使用扩展检测板进行重新检测，在5%的病例中产生了临床相关结果。此外，将计算机分析（剪接影响预测工具）和体外分析（RT-PCR和桑格测序）相结合，突出了四个候选变异对剪接和翻译的有害影响。我们的结果概述了法国东南部HBOC基因的致病变异，强调了cDNA分析的临床相关性以及用扩展检测板对BRCA阴性个体进行重新检测的重要性。
