Sarin Lab, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India.
Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400085, India.
Asian Pac J Cancer Prev. 2020 May 1;21(5):1289-1293. doi: 10.31557/APJCP.2020.21.5.1289.
Role of RET proto-oncogene as predisposing gene for Medullary Thyroid Carcinoma is well established which provides the basis for clinical management of patients. However clinical behavior of MTC varies considerably among patients. Several studies have investigated whether SNPs in low penetrance genes could modulate the clinical behavior of MTC but with conflicting or inconclusive results. The present study aimed to investigate the modifier effect of 13 SNPs of three distinct genetic pathways -Detoxification, Cell cycle regulation and RET on the clinico-pathological features of hereditary and sporadic MTC.
SNPs were genotyped using RFLP or TaqMan method. The genotypes were correlated with various clinico-pathological parameters (age and calcitonin levels at MTC diagnosis, tumor volume, nodal and distant metastasis).
Nodal metastasis was the only clinico-pathological parameter showing significant association with any SNP. In the hereditary MTC group (n=77), incidence of nodal metastases was significantly higher in wild type allele for Cyp1A1m1, CDKN2A and CDKN2C (p=0.01 for all three). In sporadic MTC group (n=361) CDKN2C wild type allele had higher nodal metastasis (p=0.03).
In this largest MTC cohort with comprehensive analysis of modulatory role of 13 most frequently studied SNPs with MTC clinical outcome, we observed a statistically significant association of few SNPs with nodal metastasis. However as these SNPs did not show association with any other clinico-pathological parameters like tumor volume or Calcitonin, they may not be true modifier of MTC. Additional large cohort studies with clinico-pathological details and long-term follow-up are needed to identify genetic modifiers of MTC behavior.
RET 原癌基因作为甲状腺髓样癌的易患基因的作用已得到充分确立，为患者的临床管理提供了依据。然而，MTC 的临床行为在患者之间差异很大。有几项研究调查了低外显率基因中的 SNP 是否可以调节 MTC 的临床行为，但结果存在冲突或不一致。本研究旨在探讨三个不同遗传途径——解毒、细胞周期调节和 RET 的 13 个 SNP 对遗传性和散发性 MTC 的临床病理特征的修饰作用。
使用 RFLP 或 TaqMan 方法对 SNP 进行基因分型。将基因型与各种临床病理参数（MTC 诊断时的年龄和降钙素水平、肿瘤体积、淋巴结和远处转移）相关联。
只有淋巴结转移是与任何 SNP 都具有显著关联的临床病理参数。在遗传性 MTC 组（n=77）中，Cyp1A1m1、CDKN2A 和 CDKN2C 的野生型等位基因的淋巴结转移发生率显著更高（p=0.01）。在散发性 MTC 组（n=361）中，CDKN2C 的野生型等位基因的淋巴结转移发生率更高（p=0.03）。
在这项最大的 MTC 队列中，我们对与 MTC 临床结果相关的 13 个最常研究的 SNP 的调节作用进行了全面分析，观察到少数 SNP 与淋巴结转移具有统计学显著关联。然而，由于这些 SNP 与肿瘤体积或降钙素等其他临床病理参数没有关联，它们可能不是 MTC 的真正修饰因子。需要进行更多具有临床病理细节和长期随访的大型队列研究，以确定 MTC 行为的遗传修饰因子。
