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- Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibilityPublication . Santos, Luís S.; Silva, Susana N.; Gil, Octávia M.; Ferreira, Teresa C.; Limbert, Edward; Rueff, JoséThyroid 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 (MLH1 rs1799977, MSH3 rs26279, MSH4 rs5745325, PMS1 rs5742933, MLH3 rs175080 and MSH6 rs1042821) were genotyped through TaqMan® assays and genotype-associated risk estimates were calculated. An increased risk was observed in MSH6 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 MSH6 was analysed in combination with other MMR SNPs such as MSH3 rs26279. Interestingly, two other SNP combinations, both containing the MSH6 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 MSH6 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.
- Micronuclei formation upon radioiodine therapy for well-differentiated thyroid cancer: the influence of dna repair genes variantsPublication . Santos, Luís S.; Gil, Octávia M.; Silva, Susana N.; Gomes, Bruno C.; Ferreira, Teresa C.; Limbert, Edward; Rueff, JoséRadioiodine therapy with131I remains the mainstay of standard treatment for well-differentiated thyroid cancer (DTC). Prognosis is good but concern exists that131I-emitted ionizing radiation may induce double-strand breaks in extra-thyroidal tissues, increasing the risk of secondary malignancies. We, therefore, sought to evaluate the induction and 2-year persistence of micronuclei (MN) in lymphocytes from 26131I-treated DTC patients and the potential impact of nine homologous recombination (HR), non-homologous end-joining (NHEJ), and mismatch repair (MMR) polymorphisms on MN levels. MN frequency was determined by the cytokinesis-blocked micronucleus assay while genotyping was performed through pre-designed TaqMan® Assays or conventional PCR-restriction fragment length polymorphism (RFLP). MN levels increased significantly one month after therapy and remained persistently higher than baseline for 2 years. A marked reduction in lymphocyte proliferation capacity was also apparent 2 years after therapy. MLH1 rs1799977 was associated with MN frequency (absolute or net variation) one month after therapy, in two independent groups. Significant associations were also observed for MSH3 rs26279, MSH4 rs5745325, NBN rs1805794, and tumor histotype. Overall, our results suggest that131I therapy may pose a long-term challenge to cells other than thyrocytes and that the individual genetic profile may influence131I sensitivity, hence its risk-benefit ratio. Further studies are warranted to confirm the potential utility of these single nucleotide polymorphisms (SNPs) as radiogenomic biomarkers in the personalization of radioiodine therapy.
- Thyroid cancer: the quest for genetic susceptibility involving DNA repair genesPublication . Santos, Luís S.; Gomes, Bruno Costa; Bastos, Hélder N.; Gil, Octávia M.; Azevedo, Ana Paula; Ferreira, Teresa C.; Limbert, Edward; Silva, Susana N.; Rueff, JoséThe incidence of thyroid cancer (TC), particularly well-differentiated forms (DTC), has been rising and remains the highest among endocrine malignancies. Although ionizing radiation (IR) is well established on DTC aetiology, other environmental and genetic factors may also be involved. DNA repair single nucleotide polymorphisms (SNPs) could be among the former, helping in explaining the high incidence. To further clarify the role of DNA repair SNPs in DTC susceptibility, we analyzed 36 SNPs in 27 DNA repair genes in a population of 106 DTCs and corresponding controls with the aim of interpreting joint data from previously studied isolated SNPs in DNA repair genes. Significant associations with DTC susceptibility were observed for XRCC3 rs861539, XPC rs2228001, CCNH rs2230641, MSH6 rs1042821 and ERCC5 rs2227869 and for a haplotype block on chromosome 5q. From 595 SNP-SNP combinations tested and 114 showing relevance, 15 significant SNP combinations (p < 0.01) were detected on paired SNP analysis, most of which involving CCNH rs2230641 and mismatch repair variants. Overall, a gene-dosage effect between the number of risk genotypes and DTC predisposition was observed. In spite of the volume of data presented, new studies are sought to provide an interpretability of the role of SNPs in DNA repair genes and their combinations in DTC susceptibility.