Clinical implications of GWAS variants associated with differentiated thyroid cancer

Abstract

The genetic risk of differentiated thyroid cancer (DTC) probably consists of multiple low-penetrance, single-nucleotide polymorphisms (SNP). Such markers are difficult to uncover by linkage analysis but can be revealed by association studies. Genome-wide association studies (GWASs) have uncovered 31 SNPs associated with DTC. These markers carry a low to moderate risk for DTC, but their cumulative effect increases with each successive risk allele. These data support the important contribution of low penetrance variants in the pathogenesis of DTC. Contrary to somatic mutations such as BRAFV600E, germline variants can be ascertained prior to surgical treatment. Therefore, we hypothesise that GWAS SNPs might impact the clinical course of DTC and we can benefit from this knowledge in choosing a treatment strategy. Several associations between clinical factors and GWAS markers have been reported so far. The most important are associations between rs966423 and mortality (HR = 1.60, p = 0.038), extrathyroidal extension (ETE) (OR = 1.57, p = 0.019); rs965513 and tumour diameter (slope of regression 0.14, p = 0.025), lymph node metastasis (OR = 1.59, p = 0.030) and ETE (OR = 1.29, p = 0.045); rs944289 and distant metastasis (OR = 0.58, p = 0.042); and rs116909374 and lymph node metastasis (OR = 0.61, p = 0.016). These findings show that GWAS SNPs are not only the ignition factors (together with environmental factors) for malignant transformation of thyrocytes but might also impact the clinical course of DTC. Surprisingly, it is not always the risk allele for DTC that is associated with worse clinical outcome. The second interesting observation is that GWAS SNPs show different associations with DTC clinical features depending on their histological subtypes. These point to the complexity of DTC with putatively different roles of genes at different stages of DTC development.

Genetic Susceptibility to Differentiated Thyroid Cancer

“…may help stratify individuals according to their risk of developing DTC, which can be useful for elaborating screening policies. Moreover, inherited genetic factors can also impact the final outcome of the disease such as histological subtypes, localization of metastases, or molecular profiling of the tumor, and their characterization can help to predict effectiveness of the initial treatment [120].…”

Thyroid cancer polygenic risk score combined with deep learning analysis of ultrasound images improves the classification of thyroid nodules as benign or malignant

“…Integration of the PRS with clinical factors was shown to improve the prediction of subsequent thyroid cancer in childhood cancer survivors 49 . Individual variants were tested for their association with tumor size, locoregional and distant metastases, extrathyroidal extension, and multifocality (reviewed in 50 ). We demonstrated that incorporating PRS into the thyroid nodule risk stratification results in an improved ability to discriminate between benign and malignant nodules as measured by the classifier AUROC (Table 2).…”

FOXE1 polymorphism rs965513 predisposes to thyroid cancer in a European cohort

“…Our data suggests that rs965513 is associated with tumours >10mm and multifocality. A recent review identifies rs965513 as being associated with increased DTC tumour size and extra-thyroidal extension ( Jendrzejewski et al 2019 ). Other germline mutations have also been linked to additional pathological characteristics including nodal disease burden, metastatic disease and disease-specific mortality ( Jendrzejewski et al 2019 ).…”