Association of polygenic score with tumor molecular subtypes in papillary thyroid carcinoma

PURPOSE: The primary goal of the present study is to determine whether germline genetic risk, as assessed using a polygenic risk score (PGS) is associated with molecular subtypes of PTC, defined based on tumor driver mutation status.

METHODS: This study was carried out using data from The Cancer Genome Atlas (TCGA) thyroid cancer study. A previously validated 10-SNP PGS for PTC derived from GWAS hits was calculated to ascertain germline genetic risk. The primary molecular subtypes of interest were defined by tumor driver mutation status (BRAFV600E-mutated vs. RAS-mutated vs "other"). We also explored associations between PGS and molecular subtypes defined by mRNA expression, microRNA expression, and DNA methylation patterns. Polytomous logistic regression analysis was used to assess the association between PGS and PTC molecular subtype with and without adjustment for clinical variables. Odds ratios (ORs) with their 95% confidence intervals were estimated.

RESULTS: A total of 359 patients were included in the study. PGS was significantly associated specific tumor molecular subtypes defined by tumor driver mutation status. Increasing germline risk was associated with having a higher odd of BRAFV600E-mutated PTC compared to PTCs without driver mutations in the "other" category. No significant difference was detected in terms of PGS tumor categorization in the RAS subtype compared to BRAFV600E. In exploratory analyses, PGS was also associated with mRNA, microRNA, and DNA methylation defined molecular subtypes, as defined by the TCGA PTC study.

CONCLUSION: PGS has molecular subtype-specific associations in PTC, which has implications for their use in risk prediction.