细胞周期调控基因的多态性影响散发性甲状腺髓样癌的发生发展。

Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma.

作者信息

Barbieri R B, Bufalo N E, Secolin R, Assumpção L V M, Maciel R M B, Cerutti J M, Ward L S

机构信息

University of Campinas (FCM - Unicamp)126, Tessalia Vieira de Camargo, Street. Cidade Universitaria Zeferino Vaz, Campinas - São Paulo, 13083-887 BrazilFederal University of Sao Paulo (Unifesp)669, Pedro Toledo Street, São Paulo-SP 04039-032, Brazil.

出版信息

Eur J Endocrinol. 2014 Dec;171(6):761-7. doi: 10.1530/EJE-14-0461.

DOI:10.1530/EJE-14-0461

PMID:25565272

Abstract

BACKGROUND

The role of key cell cycle regulation genes such as, CDKN1B, CDKN2A, CDKN2B, and CDKN2C in sporadic medullary thyroid carcinoma (s-MTC) is still largely unknown.

METHODS

In order to evaluate the influence of inherited polymorphisms of these genes on the pathogenesis of s-MTC, we used TaqMan SNP genotyping to examine 45 s-MTC patients carefully matched with 98 controls.

RESULTS

A multivariate logistic regression analysis demonstrated that CDKN1B and CDKN2A genes were related to s-MTC susceptibility. The rs2066827GT+GG CDKN1B genotype was more frequent in s-MTC patients (62.22%) than in controls (40.21%), increasing the susceptibility to s-MTC (OR=2.47; 95% CI=1.048-5.833; P=0.038). By contrast, the rs11515CG+GG of CDKN2A gene was more frequent in the controls (32.65%) than in patients (15.56%), reducing the risk for s-MTC (OR=0.174; 95% CI=0.048-0.627; P=0.0075). A stepwise regression analysis indicated that two genotypes together could explain 11% of the total s-MTC risk. In addition, a relationship was found between disease progression and the presence of alterations in the CDKN1A (rs1801270), CDKN2C (rs12885), and CDKN2B (rs1063192) genes. WT rs1801270 CDKN1A patients presented extrathyroidal tumor extension more frequently (92%) than polymorphic CDKN1A rs1801270 patients (50%; P=0.0376). Patients with the WT CDKN2C gene (rs12885) presented larger tumors (2.9±1.8 cm) than polymorphic patients (1.5±0.7 cm; P=0.0324). On the other hand, patients with the polymorphic CDKN2B gene (rs1063192) presented distant metastases (36.3%; P=0.0261).

CONCLUSION

In summary, we demonstrated that CDKN1B and CDKN2A genes are associated with susceptibility, whereas the inherited genetic profile of CDKN1A, CDKN2B, and CDKN2C is associated with aggressive features of tumors. This study suggests that profiling cell cycle genes may help define the risk and characterize s-MTC aggressiveness.

摘要

背景

关键细胞周期调控基因如CDKN1B、CDKN2A、CDKN2B和CDKN2C在散发性甲状腺髓样癌（s-MTC）中的作用仍 largely unknown。

方法

为了评估这些基因的遗传多态性对s-MTC发病机制的影响，我们使用TaqMan SNP基因分型技术对45例s-MTC患者和98例对照进行了仔细匹配的检测。

结果

多因素逻辑回归分析表明，CDKN1B和CDKN2A基因与s-MTC易感性相关。rs2066827GT+GG CDKN1B基因型在s-MTC患者中（62.22%）比在对照中（40.21%）更常见，增加了s-MTC的易感性（OR=2.47；95%CI=1.048-5.833；P=0.038）。相比之下，CDKN2A基因的rs11515CG+GG在对照中（32.65%）比在患者中（15.56%）更常见，降低了s-MTC的风险（OR=0.174；95%CI=0.048-0.627；P=0.0075）。逐步回归分析表明，这两种基因型共同可解释s-MTC总风险的11%。此外，还发现疾病进展与CDKN1A（rs1801270）、CDKN2C（rs12885）和CDKN2B（rs1063192）基因改变的存在之间存在关联。WT rs1801270 CDKN1A患者甲状腺外肿瘤扩展的频率（92%）高于多态性CDKN1A rs1801270患者（50%；P=0.0376）。WT CDKN2C基因（rs12885）的患者肿瘤较大（2.9±1.8 cm），而多态性患者的肿瘤较小（1.5±0.7 cm；P=0.0324）。另一方面，多态性CDKN2B基因（rs1063192）的患者出现远处转移（36.3%；P=0.0261）。