中国汉族女性大规模全外显子组关联研究发现三个新的乳腺癌易感基因座

　　编者按：虽然全基因组关联研究已经确定了超过90个乳腺癌易感基因座，但是缺失遗传仍然显而易见，并且编码变异对乳腺癌易感的影响尚未被系统评价。目前发现的乳腺癌易感基因变异，绝大多数位于基因内含子（基因间）且仅能解释小部分疾病变异。与功能最为相关的基因组部分为外显子，85%的功能变异位于外显子。外显子即基因组DNA出现于成熟RNA分子的序列，包含编码蛋白质合成所需要的绝大部分信息，被内含子（无编码意义的间插序列）隔开，转录后经过加工被连接在一起，生成成熟的RNA分子。外显子组指基因组全部外显子区域的集合，人类外显子组只占人类基因组长度的1%左右。全外显子组测序与全基因组测序相比，显然更简便、更经济、更高效，同时由于其对目标区域的覆盖率更高，有利于基因变异的检出。

　　2018年3月23日，美国癌症研究协会《癌症研究》在线发表安徽医科大学第二附属医院、安徽医科大学生命科学学院、芬兰奥卢大学、华中农业大学信息学院、复旦大学附属肿瘤医院余科达、孙孟红、邵志敏等学者的大规模全外显子组关联研究报告，通过2万4162位中国汉族女性个体（1万55位乳腺癌患者和1万4107位无乳腺癌对照者）发现三个新的乳腺癌易感基因座。

　　该研究通过全外显子组测序，除了验证已知的易感基因座（例如ESR1、FGFR2、TOX3），还确定了两个新的错义突变：C21orf58（rs13047478，荟萃P=4.52×10-8）、ZNF526（rs3810151，荟萃P=7.60×10-9）以及一个新的非编码变异：7q21.11（rs13047478，P<5×10-8）。C21orf58和ZNF526对于控制乳腺癌细胞生长具有功能作用，并且发现两种编码变异是几种附近基因的表达定量特征基因座（eQTL）。rs13047478与乳腺组织基因MCM3AP和YBEY的表达显著相关（P<5.00×10-8）。在人类血样中，rs3810151与PAFAH1B3和CNFN基因表达显著相关（P=8.39×10-8、P=3.77×10-4）。乳腺肿瘤与正常乳腺相比，C21orf58和ZNF526与这些表达定量特征基因座基因的表达存在差异。

　　因此，该研究发现了乳腺癌遗传易感性的其他基因座和新基因，揭示了遗传因素对汉族乳腺癌发病机制的影响，凸显了疾病发展的多基因基础，提供了潜在的临床应用。

Cancer Res. 2018 Mar 23. [Epub ahead of print]

A large-scale, exome-wide association study of Han Chinese women identifies three novel loci predisposing to breast cancer.

Zhang B, Chen MY, Sheng YJ, Zhuo XB, Gao P, Zhou FS, Liang B, Zu J, Zhang Q, Suleman S, Xu YH, Xu MG, Xu JK, Liu CC, Giannareas N, Xia JH, Zhao Y, Huang ZL, Yang Z, Cheng H, Li N, Hong YY, Li W, Zhang MJ, Yu KD, Li G, Sun MH, Chen ZD, Wei GH, Shao ZM.

No.2 Hospital, Anhui Medical University, Hefei, Anhui, China; School of Life Sciences, Anhui Medical University, Hefei, Anhui, China; State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, Anhui, China; Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Fudan University Shanghai Cancer Center/Cancer Institute, Shanghai, China; College of Informatics, Huazhong Agricultural University, Wuhan, China.

Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g. ESR1, FGFR2 and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10-8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10-9) and one new non-coding variant at 7q21.11 (P < 5 × 10-8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 x 10-8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 x 10-8) and CNFN (P = 3.77 x 10-4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.

PMID: 29572226

PII: canres.1721.2017

DOI: 10.1158/0008-5472.CAN-17-1721