Genetic susceptibility in differentiated thyroid cancer

*Erich M. Sturgis, M.D. Anderson Cancer Center 

Keywords: differentiated thyroid cancer, papillary thyroid cancer, genetic susceptibility, polymorphisms, association studies

Erich M. Sturgis, M.D., M.P.H. Department of Head and Neck Surgery and Department of Epidemiology The University of Texas M.D. Anderson Cancer Center

Differentiated thyroid cancer (DTC) (i.e., papillary, follicular, and Hurthle cell), arising from thyroid follicular epithelial cells, occurs in sporadic and familial forms. The familial form accounts for approximately 5% of cases with some having a more aggressive behavior than its sporadic counterpart. The genetic predisposition to familial DTC is not well defined; the 6 potential regions for harboring a familial NMTC gene are MNG1 (14q31), TCO (19p13.2), fPTC/PRN (1q21), NMTC1 (2q21), FTEN (8p23.1-p22), and the telomere-telomerase complex, however such findings have not been uniformly replicated and thus far no high-penetrance gene has been identified [1]. The genetic risks for the sporadic form of DTC are even less well understood, in which disease susceptibility is determined by common variants in low-penetrance genes, and more likely by the interactions of multiple genetic variations with environmental factors. Recent advances in genetic epidemiology of thyroid cancer have elucidated multiple genes (and genetic polymorphisms) that affect individual predisposition to sporadic DTC.

In identifying the genetic susceptibility factors for sporadic DTC, the candidate gene and pathway-directed approaches, based on a priori hypothesis that certain genes/pathways are implicated in DTC development, have been widely applied in the large majority of genetic association studies. The most commonly studied candidate genes/pathways are the DNA repair genes/pathways because of the strong relationship between ionizing radiation exposure and DTC. Using a hospital-based case-control study design, our group assessed the DTC risk and found significant associations with functional single nucleotide polymorphisms (SNPs) of XRCC1 (rs25487-Arg399Gln) [2], XRCC3 (rs861539-Thr241Met) [3], BRCA1 (rs799917-Pro871Leu, rs16942-Lys1183Arg) [4], and ATM (rs1800057-Pro1054Arg, rs189037) [5] genes. Some of these associations have been verified in other case-control populations and additional SNPs in DNA repair genes including RAD51, RAD52, XRCC2 and NBS1 have also been reported (for review, see [6,7]). Another group of radiation-related genes that have been frequently studied are those in maintaining of genome integrity and cell cycle control. In particular, p53-rs1042522 (Arg72Pro) has been reported to be associated with DTC risk in more than one study [8,9]. Our preliminary data of the p53 regulating genes MDM2 and p14ARF found two promoter SNPs MDM2-rs2279744 and p14ARF-rs3731217 were associated with a significantly increased risk of DTC [Zhang et al, unpublished results]. Additionally, polymorphisms in RET gene, which is frequently rearranged in radiation-related PTC, have been studied, and 2 SNPs (rs1800860 and rs1800861) were associated with susceptibility to DTC [10,11]. Of note, a recent study screening a large number of tagSNPs identified 7 gene regions that are related to maintenance of genomic integrity, including 2 in DNA repair (HUS1, ALKBH3), 2 in apoptosis (BAK1, FAF1_CDKN2C), 2 in Wnt/beta-catenin-signaling (FZD6, DACT3) and 1 in the epigenetic (HDAC4) pathways [12]. Although the biological effects remain unclear, several genes in xenobiotic metabolism pathways have been linked to alteration of DTC risk, including GSTM1, GSTT1, NAT2, CYP1A1 and CYP2D6. Our previous study found that individuals with both null genotypes of GSTM1 and GSTT1 was associated with a significantly increased risk for DTC, and the significant association was verified among women, smokers and non-whites [13]. A large screening study of metabolism and detoxification pathways in PTC, however, found no significant association between PTC risk and phase I and II pathways and the detoxification pathway as a whole [14]. In addition to the genes/pathways described above, recent exploratory studies revealed significant associations between DTC susceptibility and several genes involved in various aspects of tumor development, including, but not limited to, WWOX tumor suppressor (rs3764340-Pro282Ala) [15], WDR3 (haplotype) [16], and the thyroglobulin gene (rs180223-Ser734Ala, rs853326-Met1028Val) [17], supporting that the DTC susceptibility is determined by a wide range of genes.

Complementary to the deductive candidate gene and pathway-oriented approaches, thus far, 2 genome wide association studies (GWAS) have been reported and identified new susceptibility genes without making a priori biological assumptions. The first GWAS on thyroid cancer is a multi-center case-control study in individuals of European descent, in which two common variants on 9q22.33 and 14q13.3, rs965513 and rs944289, respectively, together were associated with 5.7-fold increase of risk for DTC [18]. The authors demonstrated that the tagSNP rs965513 on 9q22.33 was associated with early onset age at diagnosis of DTC and alternations in thyroid-related hormone levels, and suggested the association may reflect altered function of the nearest gene FOXE1(TTF2). A later GWAS in radiation-related PTC from the Chernobyl region verified the significant association of PTC with rs965513 (OR=1.65, 95% CI: 1.43–1.91) and additionally reported a significant association for SNP rs1867277 in the 5’-UTR of FOXE1 (OR=1.48, 95%CI: 1.27–1.71) [19]. The latter is in line with the result of a candidate gene association study in European population, in which rs1867277 was the most significant SNP in the FOXE1 gene that was associated with PTC risk (OR=1.49, 95%CI: 1.30–1.70) and the risk allele (A) of rs1867277 was demonstrated to affect FOXE1 transcription through the recruitment of USF1/USF2 transcription factors [20].

In general, different approaches have been employed to determine the role of genetic susceptibility in DTC development and the current evidence supports that an increase in DTC risk is affected by individual predisposition associated with multiple variants in low-penetrance genes. Functional studies are warranted to elucidate the underlying mechanisms of these polymorphisms. Moreover, future effects will need to not only verify these results in more populations but also greater study of potential gene-gene and gene-environment interactions. Such association studies are extremely demanding and require large sample sizes and validation in different populations and with specific DTC subtypes, phenotypes and/or genotypes. These demands highlight the need for international consortia to study thyroid cancer susceptibility.

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