Göhler Stella, Da Silva Filho Miguel Inacio, Johansson Robert, Enquist-Olsson Kerstin, Henriksson Roger, Hemminki Kari, Lenner Per, Försti Asta
Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69121, Heidelberg, Germany.
Department of Radiation Science, Oncology, Umeå University, 90187, Umeå, Sweden.
Cancer Causes Control. 2017 Apr;28(4):259-271. doi: 10.1007/s10552-017-0849-3. Epub 2017 Feb 25.
Germline mutations in tumour suppressor genes cause various cancers. These genes are also somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic breast tumours.
After excluding the well-characterized breast cancer (BC) genes, we screened 15 novel genes consistently classified as BC driver genes in next-generation sequencing approaches for single nucleotide polymorphisms (SNPs). Altogether 40 SNPs located in the core promoter, 5'- and 3'-UTR or which were nonsynonymous SNPs were genotyped in 782 Swedish incident BC cases and 1,559 matched controls. After statistical analyses, further evaluations related to functional prediction and signatures of selection were performed.
TBX3 was associated with BC risk (rs2242442: OR = 0.76, 95% CI 0.64-0.92, dominant model) and with less aggressive tumour characteristics. An association with BC survival and aggressive tumour characteristics was detected for the genes ATR (rs2227928: HR = 1.63; 95% CI 1.00-2.64, dominant model), RUNX1 (rs17227210: HR = 3.50, 95% CI 1.42-8.61, recessive model) and TTN (rs2303838: HR = 2.36; 95% CI 1.04-5.39; rs2042996: HR = 2.28; 95% CI 1.19-4.37, recessive model). According to the experimental ENCODE data all these SNPs themselves or SNPs in high linkage disequilibrium with them (r ≥ 0.80) were located in regulatory regions. RUNX1 and TTN showed also several signatures of positive selection.
The study gave evidence that germline variants in BC driver genes may have impact on BC risk and/or survival. Future studies could discover further germline variants in known or so far unknown driver genes which contribute to cancer development.
肿瘤抑制基因中的种系突变会引发各种癌症。这些基因在散发性肿瘤中也会发生体细胞突变。我们推测，在散发性乳腺肿瘤中常见突变的基因中可能也存在与癌症相关的种系变异。
在排除已明确的乳腺癌（BC）基因后，我们在新一代测序方法中筛选了15个一直被归类为BC驱动基因的新基因，以寻找单核苷酸多态性（SNP）。总共对782例瑞典新发BC病例和1559例匹配对照中的40个位于核心启动子、5'和3'非翻译区或非同义SNP进行了基因分型。经过统计分析后，进行了与功能预测和选择特征相关的进一步评估。
TBX3与BC风险相关（rs2242442：优势模型下，OR = 0.76，95%CI 0.64 - 0.92），且与侵袭性较低的肿瘤特征相关。对于基因ATR（rs2227928：优势模型下，HR = 1.63；95%CI 1.00 - 2.64）、RUNX1（rs17227210：隐性模型下，HR = 3.50，95%CI 1.42 - 8.61）和TTN（rs2303838：隐性模型下，HR = 2.36；95%CI 1.04 - 5.39；rs2042996：隐性模型下，HR = 2.28；95%CI 1.19 - 4.37），检测到与BC生存和侵袭性肿瘤特征相关。根据实验性ENCODE数据，所有这些SNP本身或与其处于高连锁不平衡（r≥0.80）的SNP都位于调控区域。RUNX1和TTN也显示出一些正选择特征。
该研究证明BC驱动基因中的种系变异可能会影响BC风险和/或生存。未来的研究可能会在已知或迄今未知的驱动基因中发现更多有助于癌症发展的种系变异。
