Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39
Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39
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DOI：
10.1007/s10549-019-05492-6
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发表时间：
2019-11-21
影响因子：
3.8
通讯作者：
Imyanitov, Evgeny N.
中科院分区：
文献类型：
--
作者：
Kuligina, Ekaterina S.;Sokolenko, Anna P.;Imyanitov, Evgeny N.
目的已知的乳腺癌易感基因中的种系变异可解释不到一半的遗传性乳腺癌病例。本研究旨在确定BC缺失的遗传决定因素。方法对49例BRCA1、BRCA2、CHEK2和NBS1基因无斯拉夫方正突变的俄罗斯遗传性BC患者进行淋巴细胞DNA全外显子组测序。结果WES数据的生物信息学分析可以汇编229个候选突变的列表。对其中79个突变进行了三阶段病例对照分析。最初的两个阶段，涉及多达797名高危BC患者、1504例连续BC患者和1081名健康女性，表明6个候选基因具有潜在的BC易感性，即USP39 c.*208g>；C、PZP p.Arg680Ter、LEPREL1 p.Pro636Ser、SLIT3 p.Arg154 Cys、CREB3 p.Lys157Glu和ING1 p.Pro319Leu。USP39c.*208G>；C与三阴性乳腺肿瘤密切相关(p=0.0001)。在第三个复制阶段，我们在俄罗斯、白俄罗斯和德国三个独立的队列中对PZP的截断变异体(Rs145240281)和USP39的潜在剪接变异体(Rs112653307)进行了基因分型，共包括3216例病例和2525名对照。从USP39rs112653307获得的数据支持最初阶段确定的关联(合并OR1.72，p=0.035)。结论本研究提示一种罕见的剪接变异体在BC易感性中的作用。USP39编码一种泛素特异性多肽酶，调节包括CHEK2在内的癌症相关肿瘤抑制因子。涉及这些基因变异的进一步流行病学和功能研究是有必要的。
Purpose 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. Methods 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. Results 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). Conclusions 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.