Thyroid Nodules, Polymorphic Variants in DNA Repair andRET-Related Genes, and Interaction with Ionizing Radiation Exposure from Nuclear Tests in Kazakhstan

Abstract

Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-62). Cases with thyroid nodules (n=907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender, and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history, and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, p = 0.03) and GFRA1 -193C>G (rs not assigned, p = 0.05) and decreased risk with XRCC1 R194W (rs1799782, p-trend = 0.03) and TGFB1 T263I (rs1800472, p = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n=25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% confidence interval 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT p value = 0.02). Polymorphisms in RET signaling, DNA repair, and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways, such as genes in double strand break repair, apoptosis, and genes related to proliferation should also be pursued.

Associations Between XRCC1 Arg399Gln, Arg194Trp, and Arg280His Polymorphisms and Risk of Differentiated Thyroid Carcinoma: A Meta-analysis

“…Figure 1 illustrates the study selection process and the detailed characteristics of the included studies are shown in Table 1. A total of 10 published studies (1,606 DTC patients and 3,577 controls) were included in the Arg399Gln analysis (Zhu et al, 2004;Siraj et al, 2008;Chiang et al, 2008;Ho et al, 2009;Akulevich et al, 2009;Sigurdson et al, 2009;Ryu et al, 2011;Garcia-Quispes et al, 2011;Fard-Esfahani et al, 2011;Santos et al, 2012) Santos et al, 2012). The genotypic distribution of the controls was consistent with HWE, with the exception of two studies (Sigurdson et al, 2009;Ryu et al, 2011).…”

“…A total of 10 published studies (1,606 DTC patients and 3,577 controls) were included in the Arg399Gln analysis (Zhu et al, 2004;Siraj et al, 2008;Chiang et al, 2008;Ho et al, 2009;Akulevich et al, 2009;Sigurdson et al, 2009;Ryu et al, 2011;Garcia-Quispes et al, 2011;Fard-Esfahani et al, 2011;Santos et al, 2012) Santos et al, 2012). The genotypic distribution of the controls was consistent with HWE, with the exception of two studies (Sigurdson et al, 2009;Ryu et al, 2011). Six relevant studies with a total number of 1,015 cases and 1,581 controls were included in the Arg194Trp analysis (Zhu et al, 2004;Chiang et al, 2008;Ho et al, 2009;Fard-Esfahani et al, 2011;Ryu et al, 2011;Santos et al, 2012).…”

X-Ray Repair Cross-Complementing Group 1(XRCC1) Genetic Polymorphisms and Thyroid Carcinoma Risk: a Meta-Analysis

“…There are also some case-control studies conducted to explore the association of SNPs of XRCC1 and thyroid cancer risk (Zhu et al, 2004;Chiang et al, 2008;Siraj et al, 2008;Akulevich et al, 2009;Ho et al, 2009;Sigurdson et al, 2009;Fard-Esfahani et al, 2011;García-Quispes et al, 2011;Ryu et al, 2011). However, the results were not consistent.…”

DNA Repair Perspectives in Thyroid and Breast Cancer: The Role of DNA Repair Polymorphisms

“…However, Sigurdson and colleagues (Sigurdson et al, 2009) reported that, among residents near Semipalatinsk, Kazakhstan XRCC1 Arg194Trp is associated with decreased thyroid nodule risks for increasing minor alleles, and a similar patterns of association were observed for a small number of papillary thyroid cancers. The results in our study do not reveal an association between XRCC1 Arg194Trp genotypes and thyroid cancer risk, and these differences might be due a different risk factors for thyroid tumours (exposure to ionizing radiation (Sigurdson et al, 2009) versus sporadic tumours), and genetic background of different populations. Concerning XRCC1 Arg280His polymorphism only a positive association was described in Caucasian populations (Garcia-Quispes et al, 2011).…”

“…Concerning XRCC1 Arg280His polymorphism only a positive association was described in Caucasian populations (Garcia-Quispes et al, 2011). Interestingly, in white non-Hispanics, the XRCC1 399Gln variant allele may be associated with decreased risk of DTC, and in Caucasians, who lived in the areas of the Russian Federation and Belarus contaminated with radionuclides from Chernobyl fallout, it was observed that the XRCC1 Arg399Gln polymorphism, regardless of radiation exposure, was associated with a decreased risk of Papillary Thyroid Carcinoma (PTC) according to the multiplicative and dominant models of inheritance (Sigurdson et al, 2009). However, we cannot exclude that other XRCC1 gene polymorphisms may interact, alone or when combined, with other genes such as the ADPRT (Chiang et al, 2008).…”