家族性非髓样甲状腺癌患者中易感基因座的等位基因丢失与 BRAF 和 RAS 突变的发生。

Allelic loss of susceptibility loci and the occurrence of BRAF and RAS mutations in patients with familial non-medullary thyroid cancer.

机构信息

Department of Surgery, Ajou University School of Medicine, Suwon, Korea.

出版信息

J Surg Oncol. 2012 Jan;105(1):10-4. doi: 10.1002/jso.22064. Epub 2011 Aug 8.

DOI:10.1002/jso.22064

PMID:21826673

Abstract

OBJECTIVES

Approximately 5% of non-medullary thyroid cancer (NMTC) diagnoses are made against a background of familial predisposition and, in such instances, the disease is termed familial non-medullary thyroid cancer (FNMTC). To date, neither genetic alterations causing FNMTC nor genes predisposing to the condition have been described. The objective of the present study was to evaluate loss of heterozygosity (LOH) at the four known susceptibility loci (fPTC/PRN, NMTC1, MNG1, and TCO1) and to compare the mutation rates of RAS/RAF genes in patients with FNMTC and sporadic NMTC.

METHODS

Fourteen FNMTCs in patients from seven families were analyzed in terms of involvement of the four susceptibility loci, and 63 thyroid cancer tumors [FNMTC (29) and NMTC (34)] were evaluated for the occurrence of mutations in BRAF, and H-, N-, and K-RAS, using polymerase chain reaction, single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing.

RESULTS

Only five (35.7%) tumors showed loss of LOH at the three susceptibility loci (NMTC1, MNG1, or TCO1). These allelic losses did not show a specific pattern. Four (13.8%) FNMTCs and one (2.9%) NMTC had H-RAS (codon 12) mutations. Further, mutation of BRAF V600E was observed in 12 (41.4%) FNMTCs and 29 (85.3%) NMTCs.

CONCLUSION

Four known susceptibility loci are infrequently involved in FNMTC. Although further studies are needed, the present findings additionally suggest that somatic activation of oncogenes via BRAF and RAS mutation plays a role in FNMTC tumorigenesis.

摘要

目的

约 5%的非髓样甲状腺癌（NMTC）诊断是在家族易感性的背景下做出的，在这种情况下，该疾病被称为家族性非髓样甲状腺癌（FNMTC）。迄今为止，尚未描述导致 FNMTC 的遗传改变或导致该疾病的基因。本研究的目的是评估四个已知易感性位点（fPTC/PRN、NMTC1、MNG1 和 TCO1）的杂合性缺失（LOH），并比较 FNMTC 和散发性 NMTC 患者中 RAS/RAF 基因的突变率。

方法

分析了来自七个家族的 14 例 FNMTC 患者的四个易感性位点受累情况，并对 63 例甲状腺癌肿瘤[FNMTC（29 例）和 NMTC（34 例）]进行了 BRAF 和 H、N、K-RAS 基因突变的检测，使用聚合酶链反应、单链构象多态性（PCR-SSCP）分析和直接测序。

结果

只有 5 例（35.7%）肿瘤在三个易感性位点（NMTC1、MNG1 或 TCO1）显示杂合性缺失。这些等位基因丢失没有特定的模式。4 例（13.8%）FNMTC 和 1 例（2.9%）NMTC 存在 H-RAS（密码子 12）突变。此外，在 12 例（41.4%）FNMTC 和 29 例（85.3%）NMTC 中观察到 BRAF V600E 突变。