Date of Award
Medical Doctor (MD)
Radiation exposure is a well-documented risk factor for thyroid cancer. Recent studies have demonstrated that diagnostic radiation is particularly associated with increased risk of thyroid microcarcinoma (tumors ≤ 10mm). DNA repair proteins help protect cells from the effects of ionizing radiation; germline variations in DNA repair gene might render some individuals more susceptible than others to the sequelae of diagnostic imaging. So far, few studies have investigated the germline molecular biology of thyroid cancer; none 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, I genotyped 438 cases of incident thyroid cancer and 465 controls for a total of 299 single-nucleotide polymorphisms (SNPs) in 52 genes involved in DNA damage repair. I used multivariate unconditional logistic regression models to estimate associations between each SNP and risk of thyroid cancer, as well as to directly estimate the genotype-environment interaction between each SNP and ionizing radiation. Three SNPs were associated with increased risk of papillary thyroid cancer and with PTC microcarcinoma: rs2708896 (Ptrend = 0.0057) and rs10951937 (Ptrend = 0.0070), both linked to HUS1, and rs12769288 (Ptrend=0.0023), linked to MGMT. No SNPs were associated with increased risk of PTC large tumor size (>10mm). The gene-environment 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 large tumor size. My study provides the first direct evidence that germline genetic variations interact with diagnostic radiation to put certain individuals at even greater risk of thyroid cancer after undergoing diagnostic imaging studies.
Sandler, Jason Elliott, "Germline Variants In Dna Repair Genes Are Associated With Increased Risk Of Thyroid Cancer" (2016). Yale Medicine Thesis Digital Library. 2076.