Genetic risk association of CDKN1A and RET gene SNPs with medullary thyroid carcinoma: Results from the largest MTC cohort and meta‐analysis

Abstract

Background Medullary thyroid carcinoma (MTC) is a rare subtype of thyroid cancer. Other than gain‐of‐function RET mutations, no other genetic, lifestyle or environmental risk associations have been established for MTC. Several case‐control studies and meta‐analysis have examined the risk association of different SNPs with MTC in different populations but with contradictory or inconclusive results. Methods In a large cohort of 438 Indian MTC cases and 489 gender and ethnicity matched healthy controls from 1000 genome project, a comprehensive risk association of 13 SNPs of three pathways—detoxification, cell cycle regulation and RET was performed along with meta‐analysis of RET SNPs. Results Multivariate logistic regression analysis identified a protective risk association of CDKN1ASer31Arg SNP with both hereditary (OR 0.26; 95% confidence interval [CI] 0.13‐0.55; P < .001) and sporadic MTC (OR 0.53; 95% CI 0.36‐0.78; P = .001). An increased risk association was identified for NAT2Y94Y SNP (OR 1.62, 95% CI 1.17‐2.25, P = .004) and CDKN2A3′UTR SNP (OR 1.89, 95% CI 1.19‐2.98, P = .006) with sporadic MTC and RET S904S with hereditary MTC (OR 2.82, 95% CI 1.64‐4.86, P < .001). Meta‐analysis of RET SNPs including our cohort identified increased risk association of all four RET SNPs with MTC. Conclusion In this largest SNP risk association study for MTC and the only risk association study of the 13 most commonly studied MTC associated SNPs in a single cohort of this rare cancer, a significant protective risk association of CDKN1ASer31Arg SNP with MTC was shown for the first time. Meta‐analysis identified significant risk association of all four RET SNPs, not observed in previous meta‐analysis.

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China

“…Since 12 patients with concomitant secondary variants R114H, T278N, and D489N presented with a relatively wide range of diagnostic ages, the clinical disease course remains uncertain and inconsistent. A cautious approach might be to remain aware of the possible concomitant presence of compound mutations when faced with an abnormal natural disease course or unusual clinical features; however, appropriate validation is needed to avoid misinterpretation and irreversible clinical consequences [ 25 , 29 , 30 , 37 , 38 , 42 ].…”

“…Previous studies, however, were either mostly limited to RET SNP hotspots, reported controversial conclusions, or had not examined susceptibility [ 33 – 36 ]. These issues suggest the need for analysis of potential modifying factors, including the entire RET coding region, and an individualized strategy for clinical management of MEN2 should be considered [ 1 , 19 , 29 , 34 , 37 , 38 ].…”

Effects of a Long-Term Administration of Aqueous Extract of Prunella vulgaris&nbsp;L. on Survival, Spontaneous Thyroid Carcinoma and Neoplastic&nbsp;C-cell Hyperplasia&nbsp;in Rats

“…Abundant studies have yielded a robust evidence for a causal role of RET proto-oncogene mutation in the development of neoplastic CCH and the subsequent hereditary MTC [24][25][26]. Activating transcription factor 4 (ATF4) is shown to suppress MTC by targeting RET gene in vivo and in vitro [27].…”

The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review

“…Other pathogenic variants commonly observed in HTC lead to enhanced cell proliferation. These include pathogenic variants in the RAS family of oncogenes that are involved in controlling cell division, as well as mutations in the negative regulator of RAS pathway– NF1 (neurofibromatosis type 1) and CDKN1A (cyclin dependent kinase inhibitor 1A), which is involved in cell cycle regulation [ 32 , 35 , 36 , 37 ]. In addition, commonly mutated ATXN1 (antioxidant protein 1 homolog), involved in the regulation of the cell cycle and oxidative stress, may play a role in HTC oncogenesis [ 38 ].…”