Founder Variants and Thyroid Cancer Risk.

Germline pathogenic variants in are associated with a moderate increase in the lifetime risk for breast cancer. Increased risk for other cancers, including non-medullary thyroid cancer (NMTC), has also been suggested. To date, data implicating variants in NMTC predisposition primarily derive from studies within Poland, driven by a splice site variant (c.444 + 1G>A) that is uncommon in other populations. In contrast, the predominant variants in non-Polish populations are c.1100del and c.470T>C/p.I157T, representing 61.1% and 63.8%, respectively, of all pathogenic variants in two large U.S.-based commercial laboratory datasets. To further delineate the impact of common variants on thyroid cancer, we aimed to investigate the association of three founder variants (c.444 + 1G>A, c.1100del, and c.470T>C/p.Ile157Thr) on NMTC susceptibility in three groups of unselected NMTC patients. The presence of three founder variants was assessed within three groups: (1) 1544 NMTC patients (and 1593 controls) from previously published genome-wide association study (GWAS) analyses, (2) 789 NMTC patients with germline exome sequencing (Oncology Research Information Exchange Network [ORIEN] Avatar), and (3) 499 NMTC patients with germline sequence data available in The Cancer Genome Atlas (TCGA). A case-control study design was utilized with odds ratios (ORs) calculated by comparison of all three groups with the Ohio State University GWAS control group. The predominant Polish variant (c.444 + 1G>A) was present in only one case. The proportion of patients with c.1100del was 0.92% in the GWAS group, 1.65% in the ORIEN Avatar group, and 0.80% in the TCGA group. The ORs (with 95% confidence intervals [CIs]) for NMTC associated with c.1100del were 1.71 (0.73-4.29), 2.64 (0.95-7.63), and 2.5 (0.63-8.46), respectively. The proportion of patients with c.470T>C/p.I157T was 0.91% in the GWAS group, 0.76% in the ORIEN Avatar group, and 0.80% in the TCGA group, respectively. The ORs (with CIs) for NMTC associated with c.470T>C/p.I157T were 1.75 (0.74-4.39), 1.52 (0.42-4.96), and 2.31 (0.58-7.90), respectively. Our analyses of unselected patients with NMTC suggest that variants c.1100del and c.470T>C/p.I157T have only a modest impact on thyroid cancer risk. These results provide important information for providers regarding the relatively low magnitude of thyroid cancer risk associated with these variants.