Brose Marcia S, Volpe Patricia, Feldman Michael, Kumar Madhu, Rishi Irum, Gerrero Renee, Einhorn Eugene, Herlyn Meenhard, Minna John, Nicholson Andrew, Roth Jack A, Albelda Steven M, Davies Helen, Cox Charles, Brignell Graham, Stephens Philip, Futreal P Andrew, Wooster Richard, Stratton Michael R, Weber Barbara L
Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia 19104, USA.
Cancer Res. 2002 Dec 1;62(23):6997-7000.
BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15). We identified BRAF mutations in 5 NSCLCs (3%; one V599 and four non-V599) and 22 melanomas (63%; 21 V599 and 1 non-V599). Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption of AKT-induced BRAF inhibition can play a role in malignant transformation. To our knowledge, this is the first report of mutations documenting this interaction in human cancers. Although >90% of BRAF mutations in melanoma involve codon 599 (57 of 60), 8 of 9 BRAF mutations reported to date in NSCLC are non-V599 (89%; P < 10(-7)), strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy.
BRAF编码一种受RAS调节的激酶，该激酶介导细胞生长和恶性转化激酶途径的激活。最近，我们在66%的黑色素瘤以及其他多种人类癌症的较小比例中发现了激活型BRAF突变。为了确定BRAF突变是否导致非小细胞肺癌（NSCLC）中常见的MAP激酶途径激活，并扩展黑色素瘤的初步研究结果，我们对179例NSCLC和35例黑色素瘤的DNA进行了BRAF突变（第11和15外显子）筛查。我们在5例NSCLC（3%；1例V599和4例非V599）和22例黑色素瘤（63%；21例V599和1例非V599）中发现了BRAF突变。本研究中鉴定出三种BRAF突变是新的，它们改变了AKT介导的BRAF磷酸化中重要的残基，表明破坏AKT诱导的BRAF抑制可能在恶性转化中起作用。据我们所知，这是人类癌症中记录这种相互作用的突变的首次报告。尽管黑色素瘤中>90%的BRAF突变涉及599密码子（60例中的57例），但迄今为止在NSCLC中报告的9例BRAF突变中有8例是非V599（89%；P<10-7），强烈提示NSCLC中的BRAF突变在性质上与黑色素瘤中的不同；因此，肺癌和黑色素瘤对RAF抑制剂的反应可能存在治疗差异。尽管不常见，但人类肺癌中的BRAF突变可能识别出对靶向治疗敏感的一部分肿瘤。
