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Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer.

ABSTRACT: Background: Radiation exposure is a well-documented risk factor for thyroid cancer; diagnostic imaging represents an increasing source of exposure. Germline variations in DNA repair genes could increase risk of developing thyroid cancer following diagnostic radiation exposure. No studies have directly tested for interaction between germline mutations and radiation exposure.Methods: Using data and DNA samples from a Connecticut population-based case-control study performed in 2010 to 2011, we genotyped 440 cases of incident thyroid cancer and 465 population-based controls for 296 SNPs in 52 DNA repair genes. We used multivariate unconditional logistic regression models to estimate associations between each SNP and thyroid cancer risk, as well as to directly estimate the genotype-environment interaction between each SNP and ionizing radiation.Results: Three SNPs were associated with increased risk of thyroid cancer and with thyroid microcarcinoma: HUS rs2708896, HUS rs10951937, and MGMT rs12769288. No SNPs were associated with increased risk of larger tumor (>10 mm) in the additive model. The gene-environment interaction analysis yielded 24 SNPs with Pinteraction < 0.05 for all thyroid cancer, 12 SNPs with Pinteraction < 0.05 for thyroid microcarcinoma, and 5 SNPs with Pinteraction < 0.05 for larger tumors.Conclusions: Germline variants in DNA repair genes are associated with thyroid cancer risk and are differentially associated with thyroid microcarcinoma and large tumor size. Our study provides the first evidence that germline genetic variations modify the association between diagnostic radiation and thyroid cancer risk.Impact: Thyroid microcarcinoma may represent a distinct subset of thyroid cancer. The effect of diagnostic radiation on thyroid cancer risk varies by germline polymorphism. Cancer Epidemiol Biomarkers Prev; 27(3); 285-94. ©2017 AACR.

SUBMITTER: Sandler JE

PROVIDER: S-EPMC6426634 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer.

Sandler Jason E JE Huang Huang H Zhao Nan N Wu Weiwei W Liu Fangfang F Ma Shuangge S Udelsman Robert R Zhang Yawei Y

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20171220 3

<b>Background:</b> Radiation exposure is a well-documented risk factor for thyroid cancer; diagnostic imaging represents an increasing source of exposure. Germline variations in DNA repair genes could increase risk of developing thyroid cancer following diagnostic radiation exposure. No studies have directly tested for interaction between germline mutations and radiation exposure.<b>Methods:</b> Using data and DNA samples from a Connecticut population-based case-control study performed in 2010 t ...[more]

PMID: 29263185

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Project description: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.

Dataset Information

Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer.

Publications

Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer.

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