目的:本研究的主要目的是确定是否有种系遗传风险,使用多基因风险评分(PGS)评估与PTC的分子亚型相关,根据肿瘤驱动突变状态定义。
方法:本研究使用癌症基因组图谱(TCGA)甲状腺癌研究的数据进行。计算来自GWAS命中的PTC的先前验证的10-SNPPGS以确定种系遗传风险。感兴趣的主要分子亚型由肿瘤驱动突变状态定义(BRAFV600E突变与RAS突变与“其他”)。我们还探索了PGS和由mRNA表达定义的分子亚型之间的关联,microRNA表达,和DNA甲基化模式。多因素logistic回归分析用于评估PGS和PTC分子亚型之间的关联,有或没有调整临床变量。估计了其95%置信区间的赔率比(ORs)。
结果:本研究共纳入359例患者。PGS与由肿瘤驱动突变状态定义的特定肿瘤分子亚型显著相关。与“其他”类别中无驱动突变的PTC相比,种系风险增加与BRAFV600E突变PTC的奇数更高相关。与BRAFV600E相比,RAS亚型中的PGS肿瘤分类未检测到显着差异。在探索性分析中,PGS也与mRNA相关,microRNA,和DNA甲基化定义的分子亚型,根据TCGAPTC研究的定义。
结论:PGS在PTC中具有分子亚型特异性关联,这对它们在风险预测中的使用有影响。
BACKGROUND: Genome-wide association studies have identified germline variants associated with elevated PTC risk. It is also known that somatic driver mutations contribute to PTC development and as such PTCs can be further categorized into different molecular subtypes based on their somatic alterations. However, it remains unknown whether identified germline variants predictive of PTC risk are associated with specific molecular subtypes.
OBJECTIVE: The primary goal of the present study is to determine whether germline genetic risk, as assessed using a polygenic score (PGS) is associated with molecular subtypes of papillary thyroid carcinoma (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-single-nucleotide variation PGS for PTC derived from genome-wide association study 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 messenger RNA (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% CIs 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.
CONCLUSIONS: PGS has molecular subtype-specific associations in PTC, which has implications for their use in risk prediction.