Germline variants in DNA repair genes, diagnostic radiation and risk of thyroid cancer

Jason E Sandler, Huang Huang, Nan Zhao, Weiwei Wu, Fangfang Liu, Shuangge Ma, Robert Udelsman, Yawei Zhang

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. Using data and DNA samples from a Connecticut population-based case-control study performed in 2010-2011, we genotyped 440 cases of incident thyroid cancer and 465 population-based controls for 296 single-nucleotide polymorphisms (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. 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 (>10mm) in the additive-model. The gene-environment interaction analysis yielded 24 SNPs with P-interaction<0.05 for all thyroid cancer, 12 SNPs with P-interaction<0.05 for thyroid microcarcinoma, and 5 SNPs with P-interaction<0.05 for larger tumor. 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. Thyroid microcarcinoma may represent a distinct subset of thyroid cancer. The effect of diagnostic radiation on thyroid cancer risk varies by germline polymorphism.