Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Pesochny-2, St.-Petersburg, Russia, 197758.
St.-Petersburg Pediatric Medical University, St.-Petersburg, Russia, 194100.
Breast Cancer Res Treat. 2020 Feb;179(3):731-742. doi: 10.1007/s10549-019-05492-6. Epub 2019 Nov 21.
Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC.
Whole exome sequencing (WES) of lymphocyte DNA was performed for 49 Russian patients with clinical signs of genetic BC predisposition, who lacked Slavic founder mutations in BRCA1, BRCA2, CHEK2, and NBS1 genes.
Bioinformatic analysis of WES data was allowed to compile a list of 229 candidate mutations. 79 of these mutations were subjected to a three-stage case-control analysis. The initial two stages, which involved up to 797 high-risk BC patients, 1504 consecutive BC cases, and 1081 healthy women, indicated a potentially BC-predisposing role for 6 candidates, i.e., USP39 c.*208G > C, PZP p.Arg680Ter, LEPREL1 p.Pro636Ser, SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and ING1 p.Pro319Leu. USP39 c.*208G > C was strongly associated with triple-negative breast tumors (p = 0.0001). In the third replication stage, we genotyped the truncating variant of PZP (rs145240281) and the potential splice variant of USP39 (rs112653307) in three independent cohorts of Russian, Byelorussian, and German ancestry, comprising a total of 3216 cases and 2525 controls. The data obtained for USP39 rs112653307 supported the association identified in the initial stages (the combined OR 1.72, p = 0.035).
This study suggests the role of a rare splicing variant in BC susceptibility. USP39 encodes an ubiquitin-specific peptidase that regulates cancer-relevant tumor suppressors including CHEK2. Further epidemiological and functional studies involving these gene variants are warranted.
已知乳腺癌（BC）易感基因中的种系变异解释了不到一半的遗传性 BC 病例。本研究旨在确定 BC 的缺失遗传决定因素。
对 49 名具有遗传 BC 易感性临床迹象的俄罗斯患者进行淋巴细胞 DNA 的全外显子组测序（WES），这些患者在 BRCA1、BRCA2、CHEK2 和 NBS1 基因中缺乏斯拉夫创始突变。
WES 数据的生物信息学分析允许编制 229 个候选突变列表。对其中 79 个突变进行了三阶段病例对照分析。前两个阶段涉及多达 797 名高危 BC 患者、1504 例连续 BC 病例和 1081 名健康女性，表明 6 个候选基因具有潜在的 BC 易感性作用，即 USP39 c.*208G > C、PZP p.Arg680Ter、LEPREL1 p.Pro636Ser、SLIT3 p.Arg154Cys、CREB3 p.Lys157Glu 和 ING1 p.Pro319Leu。USP39 c.*208G > C 与三阴性乳腺癌（p = 0.0001）强烈相关。在第三个复制阶段，我们在俄罗斯、白俄罗斯和德国血统的三个独立队列中对 PZP 的截断变体（rs145240281）和 USP39 的潜在剪接变体（rs112653307）进行了基因分型，总共有 3216 例病例和 2525 例对照。USP39 rs112653307 的数据支持在初始阶段确定的关联（合并 OR 1.72，p = 0.035）。
本研究表明罕见剪接变体在 BC 易感性中的作用。USP39 编码一种泛素特异性肽酶，可调节包括 CHEK2 在内的与癌症相关的肿瘤抑制因子。需要进一步进行涉及这些基因变异的流行病学和功能研究。
