Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
PLoS One. 2007 May 9;2(5):e426. doi: 10.1371/journal.pone.0000426.
Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.
METHODOLOGY/PRINCIPAL FINDINGS: We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4 (Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line.
CONCLUSIONS/SIGNIFICANCE: This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.
百分之五十的肺腺癌存在编码 EGFR 信号通路蛋白的六个基因中的体细胞突变，即 EGFR、HER2/ERBB2、HER4/ERBB4、PIK3CA、BRAF 和 KRAS。我们对一大群肺腺癌进行了突变分析，以揭示该信号通路中可能导致肺肿瘤发生的其他潜在体细胞突变。
方法/主要发现：我们分析了总共 261 例切除的、临床注释的非小细胞肺癌（NSCLC）标本的基因组 DNA。通过对 PCR 扩增基因产物的高通量双脱氧核苷酸测序，筛选了 39 个基因的编码序列中的体细胞突变。只有在独立的肿瘤衍生 PCR 产物中发现而在匹配的正常组织中未发现的突变才被认为是体细胞突变。对 9MB 的肿瘤序列进行测序，确定了 239 个假定的遗传变异。我们进一步检查了 RAS 家族基因中的 22 个变异和各自蛋白激酶结构域编码外显子中的 135 个变异。我们总共鉴定了 37 个非同义体细胞突变；其中 36 个突变共同发生在 EGFR、KRAS、BRAF 和 PIK3CA 中。一个体细胞突变是 FGFR4（Glu681Lys）激酶结构域（外显子 16）中的一个先前未报道的突变，在 158 个肿瘤中的 1 个中发现。FGFR4 突变类似于 ERBB2 中报道的肿瘤特异性体细胞突变，并且位于与肺腺癌细胞系中报道的 FGFR4（Pro712Thr）激酶结构域突变相同的外显子中。
结论/意义：这项研究是对相当数量肺腺癌中特定信号通路的主要基因进行的全面突变分析之一。我们的结果表明，EGFR 信号通路中激酶基因的大多数功能获得性突变已经被发现。我们的研究结果还表明 FGFR4 参与了一部分肺腺癌的发病机制。
