Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk

Abstract

A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumulative effect of the SNPs identified so far in the Italian population. The combined analysis of the previous GWAS and the present Italian study provided evidence of association with rs7935113 (GALNTL4, OR = 1.36, 95%CI 1.20–1.53, p-value = 7.41 × 10−7) and rs1203952 (FOXA2, OR = 1.29, 95%CI 1.16–1.44, p-value = 4.42 × 10−6). Experimental ENCODE and eQTL data suggested that both SNPs may influence the closest genes expression through a differential recruitment of transcription factors. The assessment of the cumulative risk of eleven SNPs showed that DTC risk increases with an increasing number of risk alleles (p-trend = 3.13 × 10−47). Nonetheless, only a small fraction (about 4% on the disease liability scale) of DTC is explained by these SNPs. These data are consistent with a polygenic model of DTC predisposition and highlight the importance of association studies in the discovery of the disease hereditability.

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

“…However-since MMR proteins functionally interact within the same pathwayan additive (or even multiplicative) effect with other MMR SNPs is possible. Supporting this hypothesis, several studies have shown that, although individual susceptibility alleles may have only a modest effect, DTC risk may be substantially increased when multiple risk variants are considered together (15,16). Considering the strong genetic component of DTC susceptibility, such a role for gene-gene interactions is likely (16).…”

“…Recently performed GWAS (6-12) have provided valuable contribution but, even so, explain only part of the estimated heritability of DTC (11,15,16). Several reasons may contribute: it is possible that the highly stringent criteria applied to GWAS to prevent false-positive findings result in the exclusion of SNPs truly associated with DTC risk (14).…”

“…Furthermore, evidence from the latest GWAS (10-13) suggests the existence of population-specific DTC risk alleles, raising the possibility that novel cancer susceptibility markers, specific for geographically distinct populations, may remain to be identified. Finally, gene-gene and gene-environment interactions, despite seldom addressed, may also play an important role and explain part of the unresolved heritability of DTC susceptibility (15,16). The identification of additional common variants, gene-environment and gene-gene interactions predisposing to DTC may thus unveil at least part of the unexplained genetic component of DTC susceptibility.…”

“…Additional markers have recently been suggested (8,(10)(11)(12)(13) but still require confirbut still require confirmation and replication. Overall, the number of confirmed GWAS-proposed DTC risk alleles is still very limited (14) and, more importantly, explains only a relatively small proportion of the estimated heritability of DTC (11,15,16).…”

A Comprehensive Meta-analysis of Case–Control Association Studies to Evaluate Polymorphisms Associated with the Risk of Differentiated Thyroid Carcinoma

“…This limitation is solved by genome-wide association studies (GWASs) in which the whole genome is analyzed without formulating any a priori hypothesis. GWASs on DTC allowed discovering novel variants, including those near FOXE1, DIRC3, NKX2-1 (15)(16)(17) and, more recently, those near IMMP2L, RARRES1, SNAPC4/CARD9, ARSB, BATF, DHX35, SPATA13, GALNTL4, and FOXA2 (18)(19)(20). However, to ensure a high quality and to prevent false-positive findings, highly stringent criteria are applied in the GWASs with the disadvantage of excluding SNPs truly associated with the risk.…”