Cavaco Branca M, Batista Pedro F, Martins Carmo, Banito Ana, do Rosário Francisco, Limbert Edward, Sobrinho Luís G, Leite Valeriano
Centro de Investigação de Patobiologia Molecular (CIPM) and Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.
Endocr Relat Cancer. 2008 Mar;15(1):207-15. doi: 10.1677/ERC-07-0214.
Linkage analysis has identified four familial non-medullary thyroid carcinoma (FNMTC) susceptibility loci: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32) and TCO (19p13.2). To date, there is no evidence for the involvement of genes from the RAS/RAF signalling pathway in FNMTC. The aim of our study was to evaluate the role of the four susceptibility loci, and RAS/RAF signalling pathway genes, in FNMTC. In total, 8 FNMTC families, and 27 thyroid lesions from family members (22 papillary thyroid carcinomas (PTCs): 11 classic, 10 of the follicular variant and 1 of the mixed variant; 4 follicular thyroid adenomas (FTAs) and 1 nodular goitre (NG)), were evaluated for the involvement of the four susceptibility regions, using linkage and loss of heterozygosity (LOH) analyses. BRAF and H-, N- and K-RAS mutations were also screened in the 27 lesions and patients. Linkage analysis in seven informative families showed no evidence for the involvement of any of the four candidate regions, supporting a genetic heterogeneity for FNMTC. Twenty tumours (74%), of which 18 were PTCs, showed no LOH at the four susceptibility loci. The remaining seven tumours (four PTCs, two FTAs and one NG) showed variable patterns of LOH. Fourteen tumours (52%) had somatic mutations: BRAF-V600E mutation was observed in 9 out of the 22 PTCs (41%); and H-RAS and N-RAS mutations were detected in 5 out of the 22 PTCs (23%). Our data suggest that the four candidate regions are not frequently involved in FNMTC and that the somatic activation of BRAF and RAS plays a role in FNMTC tumourigenesis.
连锁分析已确定了四个家族性非髓样甲状腺癌（FNMTC）易感基因座：fPTC/PRN（1p13.2 - 1q22）、NMTC1（2q21）、MNG1（14q32）和TCO（19p13.2）。迄今为止，尚无证据表明RAS/RAF信号通路基因参与FNMTC。我们研究的目的是评估这四个易感基因座以及RAS/RAF信号通路基因在FNMTC中的作用。总共对8个FNMTC家族以及家族成员的27个甲状腺病变（22个甲状腺乳头状癌（PTC）：11个经典型、10个滤泡变体型和1个混合型；4个滤泡性腺瘤（FTA）和1个结节性甲状腺肿（NG））进行评估，采用连锁分析和杂合性缺失（LOH）分析来确定这四个易感区域是否受累。同时也对这27个病变和患者进行了BRAF以及H -、N - 和K - RAS突变的筛查。对7个信息丰富的家族进行连锁分析，未发现四个候选区域中任何一个区域受累的证据，这支持了FNMTC存在遗传异质性。20个肿瘤（74%），其中18个为PTC，在四个易感基因座未显示杂合性缺失。其余7个肿瘤（4个PTC、2个FTA和1个NG）显示出不同的杂合性缺失模式。14个肿瘤（52%）存在体细胞突变：在22个PTC中有9个（41%）观察到BRAF - V600E突变；在22个PTC中有5个（23%）检测到H - RAS和N - RAS突变。我们的数据表明，这四个候选区域并不经常参与FNMTC，并且BRAF和RAS的体细胞激活在FNMTC肿瘤发生中起作用。
