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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Available from: Charles Even Land, Jul 07, 2015
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    ABSTRACT: Several reports have been published associating some SNPs in DNA repair genes with breast and thyroid cancer disease. Although relevant, the modifying effect of the majority of these SNPs in cell phenotype is still not understood and association studies are contradictory. This inconsistency might be due to different populations used, sample sizes, sample selection bias, genetic background and life style. Retrospective studies like these have to be interpreted with care and are difficult to draw meaningful practical conclusions from that can help directly patients with breast and thyroid cancer. In order to acquire more powerful and accurate results several meta-analysis also have been published reviewing all studies made till publication date about a particular SNP and disease. Again, these reports need to be interpreted with caution, since many authors have study selection bias, including all cases of breast cancer, even the ones with BRCA1 and BRCA2 mutations carriers. Prospective studies and adequately selected meta-analysis should give further insight about the relevance of SNPs in breast and thyroid cancerigenesis. Although the real role of SNPs in cancerigenesis is not well established by the authors, the new era in cancer treatment and prevention lies in the ability to treat patients individually according their genetic constitution and the DNA repair status of their tumours. For that, is crucial to have specific knowledge about the polymorphisms carried by each patient and how these polymorphisms influences response to therapy. In fact, the existence of inter-individual variation influences response and survival rate following chemotherapy and radiation treatment of cancer. Standard cancer therapy involves the use of agents that themselves damage DNA with the ultimate goal of killing the cell. However, damaging the DNA does not always kill the cell, which is avoided by DNA repair pathways that remove the damage from DNA. Recent studies have suggested that the targeting of repair pathways by specific agents can result in effective killing of tumour cells (Li et al., 2010). DNA damage acquired from these treatments can initiate a number of cellular pathways involved in DNA repair, cell cycle control, metabolism and apoptosis (Bewick et al., 2011). If so, SNPs in genes of DNA repair may significantly affect its efficiency, clinical outcome and thus may help identify patients that can benefit from various treatments. Accordingly, new strategies for individualization of treatment in cancer patients are becoming an emerging issue. Due to a phenomenon known as linkage disequilibrium, the value of a SNP in the same chromosome could be associated with specific values in other SNPs nearby. Indeed, specific SNPs associations (tagSNPs) related with the toxicity/efficacy of DNA damaging chemotherapy, improve our ability to map SNPs in specific genes associated with chemotherapy resistance and assure a better clinical outcome for cancer patients. This approach seems to be of importance since it can associate haplotype blocks with cancer therapy with lesser resources (Anunciação et al., 2010; Frazer et al., 2007). Some SNPs in DNA repair genes have been reported as potential markers for individual susceptibility to breast (e.g. XRCC1; XRCC2 and XRCC3 genes polymorphisms) and thyroid (e.g. XRCC1; XRCC3 and RAD51 genes polymorphisms) cancers. However, the incoherent results don’t have enough strength to demonstrate the real role of those SNPs, at least with regards to breast and thyroid carcinomas. We think that genetic polymorphisms, particularly SNPs, may have low influence in breast and thyroid cancerigenesis, however, SNPs may be much more relevant in acquired resistance to chemotherapeutic agents. In fact, new strategies for individualization of treatment in cancer patients are becoming an emerging issue. This approach must be the best way to find a practical result and clinical use for association studies. The emergence of SNPs with important roles in cancer therapy is now the focus of our work. 4.
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