Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters

Abstract

Background: Papillary thyroid cancer (PTC) is reported to be highly heritable in epidemiological studies. Genome-wide association studies (GWAS) have uncovered several variants associated with PTC predisposition. It remains unknown whether these variants might contribute to better clinical stratification of PTC patients. Methods: In order to assess the usefulness of germline genetic analyses in the management of PTC patients, the genotypes of five variants (rs965513, rs944289, rs116909374, rs2439302, and rs966423) were determined in 1216 PTC patients and 1416 controls. Additionally, the expression of seven genes located close to GWAS variants (PTCSC3, MBIP, NKX2-1, FOXE1, DIRC3, PTCSC2, and NRG1) were measured in 73 PTC paired tumor/normal tissues, respectively. Next, the association was analyzed between the genotypes of the germline variants and the levels of gene expression with clinical/pathological features such as age, sex, TNM staging, multifocality status, extrathyroidal expansion, and MACIS score. Results: The risk allele of rs965513 was associated with larger tumor size ( p = 0.025) and extrathyroidal expansion (odd ratio [OR] = 1.29, p = 0.045). The variant rs2439302 showed association with lymph node metastasis (OR = 1.24, p = 0.016), and multifocality status of the tumor (OR = 1.24, p = 0.012). The expression of MBIP was associated with T stage ( p = 0.010). MBIP and PTCSC3 displayed lower expression in PTC tissue in males than in females ( p = 0.025 and p = 0.036, respectively). NKX2-1 displayed lower expression in patients with N1 stage ( p = 0.040). Conclusions: The studied germline risk alleles predisposing to PTC were associated with a more aggressive course of the disease reflected by larger tumor diameter, higher multifocality rate, and more advanced N stage at the time of diagnosis. These results show that germline variants not only predispose to PTC but also might impact its clinical course. However, these associations were only moderate, and further large multi-ethnic studies are required to evaluate the usefulness of these germline variants in the clinical stratification of PTC patients.

Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer

“…Our clinical results also showed that the variants of NRG1 are associated with lymph node metastasis in thyroid cancer, especially in BRAF V600E -mutated PTC. A recent report supported this association, showing an association between a variant of NRG1 (rs2439302) and lymph node metastasis in PTC26. Although we did not demonstrate the direct effects of the increased expression of NRG1 on tumour aggressiveness, we could postulate a possibility that the increased expression of NRG1 in the thyroid tissue, which is associated with identified variants, might influence the development or progression of thyroid cancer.…”

Long noncoding RNAs: emerging players in thyroid cancer pathogenesis

“…It was found that larger tumor size and extrathyroidal expansion were associated with risk allele of the variant rs965513. Association with LNM and tumor multifocality was found with the rs2439302 suggesting an important function in clinical course, a role beyond predisposition to PTC (Jendrzejewski et al 2016).…”

“…Moreover, downregulated NONHSAT037832 has been significantly associated with LNM and tumor size (larger tumor) suggesting that NONHSAT037832 and rs2439302 of PTCSC3 could serve as a potential prognostic marker of PTC, as it clearly showed a high value to differentiate between PTCs and noncancerous tissues . The rs2439302 of PTCSC3 has also been associated with LNM and tumor multifocality reflecting a pivotal role in clinical course (Jendrzejewski et al 2016). Besides, LOC100507661 has been frequently detected as a highly expressed lncRNA in PTC and ATC cases, and significantly associated with LNM and the classical BRAF mutation .…”

Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk

“…Familial non-medullary thyroid carcinoma (FNMTC) represents roughly 5% of thyroid malignancies, and no reproducible susceptibility genes have been consistently associated with the diagnosis (93)(94)(95). Given the role of NXX2-1 role in thyrocyte differentiation, proliferation, and survival (96), germline mutations in NKX2-1 have been postulated to play a role in predisposition to thyroid malignancies (97)(98)(99). A single case series demonstrated a recurrent loss-of-function variant of NKX2-1 (p.A339V) in four of 20 independent kindreds affected by both papillary thyroid carcinoma (PTC) and multinodular goiter (MNG; ref.…”