Department of Biology, University of Pisa, Pisa, Italy.
Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Cisanello, Pisa, Italy.
Thyroid. 2020 Nov;30(11):1579-1588. doi: 10.1089/thy.2019.0352. Epub 2020 May 5.
Sporadic medullary thyroid carcinoma (sMTC) is an uncommon neoplasia arising from the calcitonin-producing parafollicular cells of the thyroid. Previous studies evaluated whether single nucleotide polymorphisms (SNPs) within (a pivotal proto-oncogene for this disease) are associated with the risk for developing sMTC, but the results are inconclusive. In this work, we evaluated the association of -SNPs c.74-126G>T (rs2565206), p.Gly691Ser (rs1799939, G>A), p.Leu769 = (rs1800861, G>T), p.Ser836 = (rs1800862, C>T), and p.Ser904 = (rs1800863, C>G) (listed in the order of their chromosomal location) with sMTC. This is one of the largest casecontrol association studies carried out on sMTC, including 585 sMTC cases (negative for germline mutations within ), 1529 patients affected by sporadic nonmedullary thyroid carcinoma (sNMTC), and 989 healthy controls, from central and southern Italy and collected in the period 2000-2017. sNMTC patients showed similar genotype and allele frequencies compared with healthy controls. On the other hand, among sMTC patients, the T-allele of p.Leu769 = was less frequent (OR = 0.70 [CI 0.58-0.84], = 1.9 × 10) and rare homozygotes TT showed an OR = 0.32 ([CI 0.17-0.60], = 2.3 × 10). Moreover, a statistically significant excess of the haplotype 2 (characterized by the alleles T-G-G-C-C of the listed SNPs) was observed ( = 3.9 × 10). The SNPs were not associated with the expression of mRNA, that is, they did not exert an effect in as quantitative trait locus (cis-eQTL). However, a strong eQTL association was found for p.Leu769 = and the neighboring gene ( = 9.3 × 10; effect-size = -0.65), whose function in cancer is unknown. This study shows that specific haplotypes, in particular haplotype 2 and the T-allele of p.Leu769 = , are associated with a reduced risk of sMTC in Italians.
散发性甲状腺髓样癌（sMTC）是一种罕见的肿瘤，起源于甲状腺的降钙素产生的滤泡旁细胞。先前的研究评估了 （该疾病的关键原癌基因）内的单核苷酸多态性（SNPs）是否与发生 sMTC 的风险相关，但结果尚无定论。在这项工作中，我们评估了 -SNPs c.74-126G>T（rs2565206）、p.Gly691Ser（rs1799939，G>A）、p.Leu769 = （rs1800861，G>T）、p.Ser836 = （rs1800862，C>T）和 p.Ser904 = （rs1800863，C>G）（按染色体位置顺序列出）与 sMTC 的关联。这是在 sMTC 上进行的最大的病例对照关联研究之一，包括来自意大利中部和南部的 585 例 sMTC 病例（ 种系突变阴性）、1529 例散发性非甲状腺髓样癌（sNMTC）患者和 989 例健康对照者，收集时间为 2000-2017 年。sNMTC 患者与健康对照组的基因型和等位基因频率相似。另一方面，在 sMTC 患者中，p.Leu769 = 的 T 等位基因频率较低（OR = 0.70 [CI 0.58-0.84]， = 1.9 × 10），罕见的纯合子 TT 显示 OR = 0.32 [CI 0.17-0.60]， = 2.3 × 10）。此外，观察到列表中 SNPs 的等位基因 T-G-G-C-C 特征的 2 号单倍型（haplotype 2）显著过量（ = 3.9 × 10）。这些 SNP 与 mRNA 的表达无关，即它们没有作为数量性状基因座（cis-eQTL）发挥作用。然而，发现 p.Leu769 = 和邻近基因 （ = 9.3 × 10；效应大小 = -0.65）之间存在很强的 eQTL 关联，其在癌症中的功能尚不清楚。本研究表明，特定的 单倍型，特别是单倍型 2 和 p.Leu769 = 的 T 等位基因，与意大利人群中 sMTC 风险降低相关。
