Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

Abstract

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.

Micronuclei Formation upon Radioiodine Therapy for Well-Differentiated Thyroid Cancer: The Influence of DNA Repair Genes Variants

“…The same was observed in the only two other association studies that we found focusing on this SNP [121,122]. Interestingly, in three out of these four studies, significant associations were detected when interactions with other SNPs-MSH6 rs1042821 [21], MLH3 rs175080 [120], and CHRNA5 rs16969968 [121]-were considered. Besides the important role that MSH4 plays in recombinational repair during meiosis [123], it is also suggested to participate, through interaction with a vast array of binding partners, in DSB-triggered damage response and repair [85,123,124].…”

“…Likewise, in our study, MN frequency was also significantly increased (absolute and change from baseline values) in TC patients carrying the A allele of MSH4 rs5745325, one month after 131 I administration. MSH4 rs5745325 (c.289G>A; Ala97Thr) has only seldom been evaluated: on single SNP analysis, two prior studies by our team failed to detect an association with either thyroid [21] or breast cancer risk [120]. The same was observed in the only two other association studies that we found focusing on this SNP [121,122].…”

“…SNPs were selected from those already analyzed by our team in a cohort of 106 DTC patients, according to selection criteria published elsewhere [18][19][20][21]. Due to sample size limitations, only SNPs presenting a minor allele frequency (MAF) > 0.15 in the original pool of patients were considered.…”

“…Single nucleotide polymorphisms (SNPs) in DNA repair enzymes across these three pathways have been identified and some have been demonstrated to affect the DNA repair capacity [14,15]. Such DNA repair SNPs may therefore modulate sensitivity to IR and many have indeed been associated with TC or, more specifically, DTC susceptibility (for which IR exposure is the best-established risk factor) [16][17][18][19][20][21]. It is likely that such functional DNA repair SNPs, through interference with the extent of IR-induced DSBs on thyrocytes, could influence the cytotoxic potential of RAI therapy, hence its efficacy on DTC treatment.…”

DNA Mismatch Repair Gene Variants in Sporadic Solid Cancers

“…A recent case–control study comprising 106 thyroid cancer patients and 212 age- and gender-matched controls revealed that MSH6 rs1042821 variant homozygotes exhibited higher risk of this cancer (OR = 3.42, CI = 1.04–11.24, p = 0.04). Despite the fact that this association was especially evident for the follicular histotype and female sex, the outcomes need to be replicated [ 126 ]. Homozygous carriers had a higher risk of CpG island methylated phenotype (CIMP+) in colon cancer (OR = 2.20, 95% CI = 1.10–4.20) than those with WT genotype [ 76 , 124 , 127 , 128 ].…”