Article

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

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD 20892-7238, USA.
Radiation Research (Impact Factor: 2.45). 02/2009; 171(1):77-88. DOI: 10.1667/RR1327.1
Source: PubMed

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 (1949-1962). 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% CI 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.

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    • "Many studies have reported the association of XRCC1 polymorphisms at 194, 280, and 399 (Arg194Trp, Arg280His, and Arg399Gln) with thyroid cancer risk [16]–[25], but the results were inconclusive, some original studies thought that these polymorphisms were associated with thyroid cancer risk, but others had different opinions. In addition, attention has been mainly drawn at a meta-analytical level upon the association of XRCC1 polymorphisms at 194, 280, and 399 with thyroid cancer risk [8], [9]. "
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    ABSTRACT: Background The previous published data on the association between the X-ray repair cross-conplementation group 1 (XRCC1) polymorphisms and thyroid cancer risk remained controversial. Hence, we performed a meta-analysis on all available studies that provided 1729 cases and 3774 controls (from 11 studies) for XRCC1 Arg399Gln, 1040 cases and 2487 controls for Arg194Trp (from 7 studies), and 1432 cases and 3356 controls for Arg280His (from 8 studies). Methodology/Principal Findings PubMed, CNKI, and EMBASE database were searched to identify relevant studies. Overall, no significant association was found between XRCC1 Arg399Gln (recessive model: OR = 0.95, 95% CI = 0.77–1.15; dominant model: OR = 0.89, 95% CI = 0.75–1.05; homozygote model: OR = 0.92, 95% CI = 0.69–1.23; Heterozygote model: OR = 0.91, 95% CI = 0.80–1.03; additive model: OR = 0.93, 95% CI = 0.81–1.07), Arg194Trp (recessive model: OR = 1.41, 95% CI = 0.62–3.23; dominant model: OR = 1.01, 95% CI = 0.77–1.34; homozygote model: OR = 1.42, 95% CI = 0.55–3.67; Heterozygote model: OR = 1.03, 95% CI = 0.85–1.26; additive model: OR = 1.08, 95% CI = 0.81–1.42), and Arg280His (recessive model: OR = 1.08, 95% CI = 0.56–2.10; dominant model: OR = 1.01, 95% CI = 0.84–1.22; homozygote model: OR = 1.00, 95% CI = 0.51–1.96; Heterozygote model: OR = 1.04, 95% CI = 0.75–1.42; additive model: OR = 1.03, 95% CI = 0.86–1.23) and thyroid cancer risk when all the eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significant association was still not found in these three genetic polymorphisms. Conclusions/Significance In summary, this meta-analysis indicates that XRCC1 Arg399Gln, Arg280His, and Arg194Trp are not associated with thyroid cancer.
    PLoS ONE 09/2014; 9(9):e87764. DOI:10.1371/journal.pone.0087764 · 3.23 Impact Factor
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    • "DNA Repair Perspectives in Thyroid and Breast Cancer: The Role of DNA Repair Polymorphisms 465 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). "
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    • "DNA Repair Perspectives in Thyroid and Breast Cancer: The Role of DNA Repair Polymorphisms 465 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). "
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