非小细胞肺癌分子病理学的研究

Study on molecular pathology in non-small cell lung cancer in Shanghai

目的 探讨上海地区人肺癌发生及发展过程中的分子病理学模式。方法 采用DNAslotblot、PCR、PCR SSCP等方法 ,先后检测 2 0 0例NSCLC组织DNA标本中C erbB2、C myc、EGFR癌基因扩增 ,抑癌基因中p5 3基因外显子 5～ 8点突变、p15基因的纯合性丢失 ,以及某些与肺癌相关的染色体 3p及 17p13 .3位点的杂合性丢失 (LOH)。结果 多种癌基因共扩增率与肺癌TNM分期呈正相关 (P <0 .0 0 1)。p5 3基因外显子 5～8点突变率为 49.2 % ( 3 1/63 ) ,其中以外显子 8为主。肺癌组织中p15基因出现高频率纯合性丢失 ,并与肺癌TNM分期密切相关 (P <0 .0 0 5 )。 17p13 .3杂合性丢失率为 40 % ( 8/2 0 ) ,并与p5 3基因的点突变相关联。 3p14及 3p2 5位点处的杂合性总丢失率可高达 66.7% ( 10 8/162 ) ,其中肺腺癌中 3p14及 3p2 5二位点的共丢失率明显高于鳞癌 (P <0 .0 5 )。结论 根据上述结果 ,提出上海市区居民的非小细胞肺癌分子病理学的初步模式 :癌前期病变时已可出现 3p丢失 ,原位癌时以p5 3基因突变及 17p13 .3丢失为主 ,浸润癌及向转移性癌过渡时有多种癌基因C myc、C erbB2及EGFR癌基因共扩增 ,并出现p15基因纯合性丢失。

Objective To investigate the molecular pathogenesis of non small cell lung cancer (NSCLC) in Shanghai. Methods About 200 patients with NSCLC from Shanghai urban residents entered in this study. Oncogenes (C myc, C erbB2 and EGFR), tumor suppressor genes (p53 and p15) and some chromosomes instability (3p14, 3p25 and 17p13.3 ) were determined respectively by DNA slot blot, PCR, PCR SSCP, and DNA sequences. Results The rate of co amplification of oncogenes from 174 cases of NSCLC was significantly higher in stage Ⅲ(50.6%, 40/79) and Ⅱ (31.1% , 14/45) than that in stage Ⅰ (16%, 8/50). Total rate of mutations in p53 gene exons was 49.2%(31/63), while the rate of exon 8 point mutation was the highest. The rate of loss of homozygosity of p15 gene was higher in stage Ⅲ (61.4%, 43/70) than that in stage Ⅰ (34.6%, 18/52) (P<0.05). 40%(8/20) of loss of heterozygosity at 17p13.3 and 66.7%(108/162) at 3p14 or 3p25 were observed. The rate of co deletion on 3p14 and 3p25 of adenocarcinoma was higher than that of squamous cell carcinoma. Conclusion The results suggest that the features of molecular pathogenesis in this series include: (a) 3p deletion in precancerous lesion; (b) p53 mutation and 17p13.3 deletion in carcinoma in situ; (c) amplification of oncogenes for C myc, c erbB2, EGFR and deletion of p15 gene in invasion and metastasis carcinoma of the lung.