Brandalize Ana Paula Carneiro, Schüler-Faccini Lavínia, Hoffmann Jean-Sébastien, Caleffi Maira, Cazaux Christophe, Ashton-Prolla Patricia
Laboratory of Medical Genomics, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
BMC Cancer. 2014 Nov 19;14:850. doi: 10.1186/1471-2407-14-850.
One of the hallmarks of cancer is the occurrence of high levels of chromosomal rearrangements as a result of inaccurate repair of double-strand breaks (DSB). Germline mutations in BRCA and RAD51 genes, involved in DSB repair, are strongly associated with hereditary breast cancer. Pol θ, a translesional DNA polymerase specialized in the replication of damaged DNA, has been also shown to contribute to DNA synthesis associated to DSB repair. It is noteworthy that POLQ is highly expressed in breast tumors and this expression is able to predict patient outcome. The objective of this study was to analyze genetic variants related to POLQ as new population biomarkers of risk in hereditary (HBC) and sporadic (SBC) breast cancer.
We analyzed through case-control study nine SNPs of POLQ in hereditary (HBC) and sporadic (SBC) breast cancer patients using Taqman Real Time PCR assays. Polymorphisms were systematically identified through the NCBI database and are located within exons or promoter regions. We recruited 204 breast cancer patients (101 SBC and 103 HBC) and 212 unaffected controls residing in Southern Brazil.
The rs581553 SNP located in the promoter region was strongly associated with HBC (c.-1060A > G; HBC GG = 15, Control TT = 8; OR = 5.67, CI95% = 2.26-14.20; p < 0.0001). Interestingly, 11 of 15 homozygotes for this polymorphism fulfilled criteria for Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Furthermore, 12 of them developed bilateral breast cancer and one had a familial history of bilateral breast cancer. This polymorphism was also associated with bilateral breast cancer in 67 patients (OR = 9.86, CI95% = 3.81-25.54). There was no statistically significant difference of age at breast cancer diagnosis between SNP carriers and non-carriers.
Considering that Pol θ is involved in DBS repair, our results suggest that this polymorphism may contribute to the etiology of HBC, particularly in patients with bilateral breast cancer.
癌症的一个标志是由于双链断裂（DSB）修复不准确而出现高水平的染色体重排。参与DSB修复的BRCA和RAD51基因的种系突变与遗传性乳腺癌密切相关。Pol θ是一种专门负责复制受损DNA的跨损伤DNA聚合酶，也已被证明有助于与DSB修复相关的DNA合成。值得注意的是，POLQ在乳腺肿瘤中高表达，这种表达能够预测患者的预后。本研究的目的是分析与POLQ相关的基因变异，作为遗传性（HBC）和散发性（SBC）乳腺癌新的人群风险生物标志物。
我们通过病例对照研究，使用Taqman实时PCR检测法分析了遗传性（HBC）和散发性（SBC）乳腺癌患者中POLQ的9个单核苷酸多态性（SNP）。通过NCBI数据库系统地鉴定多态性，它们位于外显子或启动子区域内。我们招募了204名乳腺癌患者（101名SBC和103名HBC）以及212名居住在巴西南部的未受影响对照者。
位于启动子区域的rs581553 SNP与HBC密切相关（c.-1060A>G；HBC中GG = 15，对照组中TT = 8；OR = 5.67，95%CI = 2.26 - 14.20；p < 0.0001）。有趣的是，该多态性的15名纯合子中有11名符合遗传性乳腺癌和卵巢癌（HBOC）综合征的标准。此外，其中12人患双侧乳腺癌，1人有双侧乳腺癌家族史。该多态性在67名患者中也与双侧乳腺癌相关（OR = 9.86，95%CI = 3.81 - 25.54）。SNP携带者和非携带者在乳腺癌诊断年龄上没有统计学显著差异。
鉴于Pol θ参与DBS修复，我们的结果表明这种多态性可能有助于HBC的病因学研究，特别是在双侧乳腺癌患者中。
