Santos Luís S, Silva Susana N, Gil Octávia M, Ferreira Teresa C, Limbert Edward, Rueff José
Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
Centre for Interdisciplinary Research in Health (CIIS), Health Sciences Institute (ICS), Universidade Católica Portuguesa, 3504-505 Viseu, Portugal.
Oncol Lett. 2018 May;15(5):6715-6726. doi: 10.3892/ol.2018.8103. Epub 2018 Feb 21.
Thyroid cancer (TC) is the most common endocrine malignancy and its incidence continues to rise worldwide. Ionizing radiation exposure is the best established etiological factor. Heritability is high; however, despite valuable contribution from recent genome-wide association studies, the current understanding of genetic susceptibility to TC remains limited. Several studies suggest that altered function or expression of the DNA mismatch repair (MMR) system may contribute to TC pathogenesis. Therefore, the present study aimed to evaluate the potential role of a panel of MMR single nucleotide polymorphisms (SNPs) on the individual susceptibility to well-differentiated TC (DTC). A case-control study was performed involving 106 DTC patients and 212 age- and gender-matched controls, who were all Caucasian Portuguese. Six SNPs present in distinct MMR genes ( rs1799977, rs26279, rs5745325, rs5742933, rs175080 and rs1042821) were genotyped through TaqMan assays and genotype-associated risk estimates were calculated. An increased risk was observed in rs1042821 variant homozygotes [adjusted odds ratio (OR)=3.42, 95% CI: 1.04-11.24, P=0.04, under the co-dominant model; adjusted OR=3.84, 95% CI: 1.18-12.44, P=0.03, under the recessive model]. The association was especially evident for the follicular histotype and female sex. The association was also apparent when was analysed in combination with other MMR SNPs such as rs26279. Interestingly, two other SNP combinations, both containing the heterozygous genotype, were associated with a risk reduction, suggesting a protective effect for these genotype combinations. These data support the idea that MMR SNPs such as rs1042821, alone or in combination, may contribute to DTC susceptibility. This is coherent with the limited evidence available. Nevertheless, further studies are needed to validate these findings and to establish the usefulness of these SNPs as genetic susceptibility biomarkers for DTC so that, in the near future, cancer prevention policies may be optimized under a personalized medicine perspective.
甲状腺癌（TC）是最常见的内分泌恶性肿瘤，其在全球范围内的发病率持续上升。电离辐射暴露是已明确的最佳病因因素。遗传度较高；然而，尽管近期全基因组关联研究有重要贡献，但目前对TC遗传易感性的认识仍然有限。多项研究表明，DNA错配修复（MMR）系统功能或表达的改变可能与TC发病机制有关。因此，本研究旨在评估一组MMR单核苷酸多态性（SNP）对分化型甲状腺癌（DTC）个体易感性的潜在作用。进行了一项病例对照研究，纳入106例DTC患者和212例年龄及性别匹配的对照，他们均为葡萄牙白种人。通过TaqMan分析对不同MMR基因中存在的6个SNP（rs1799977、rs26279、rs5745325、rs5742933、rs175080和rs1042821）进行基因分型，并计算与基因型相关的风险估计值。在rs1042821变异纯合子中观察到风险增加[共显性模型下调整后的优势比（OR）=3.42，95%置信区间（CI）：1.04 - 11.24，P = 0.04；隐性模型下调整后的OR = 3.84，95% CI：1.18 - 12.44，P = 0.03]。这种关联在滤泡组织学类型和女性中尤为明显。当与其他MMR SNP如rs26279联合分析时，这种关联也很明显。有趣的是，另外两个均包含rs1042821杂合基因型的SNP组合与风险降低相关，表明这些基因型组合具有保护作用。这些数据支持这样的观点，即诸如rs1042821这样的MMR SNP单独或联合起来可能与DTC易感性有关。这与现有有限证据是一致的。然而，需要进一步研究来验证这些发现，并确定这些SNP作为DTC遗传易感性生物标志物的实用性，以便在不久的将来，能够从个性化医疗的角度优化癌症预防政策。
