Araujo Luiz H, Timmers Cynthia, Bell Erica Hlavin, Shilo Konstantin, Lammers Philip E, Zhao Weiqiang, Natarajan Thanemozhi G, Miller Clinton J, Zhang Jianying, Yilmaz Ayse S, Liu Tom, Coombes Kevin, Amann Joseph, Carbone David P
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
J Clin Oncol. 2015 Jun 10;33(17):1966-73. doi: 10.1200/JCO.2014.59.2444. Epub 2015 Apr 27.
Technologic advances have enabled the comprehensive analysis of genetic perturbations in non-small-cell lung cancer (NSCLC); however, African Americans have often been underrepresented in these studies. This ethnic group has higher lung cancer incidence and mortality rates, and some studies have suggested a lower incidence of epidermal growth factor receptor mutations. Herein, we report the most in-depth molecular profile of NSCLC in African Americans to date.
A custom panel was designed to cover the coding regions of 81 NSCLC-related genes and 40 ancestry-informative markers. Clinical samples were sequenced on a massively parallel sequencing instrument, and anaplastic lymphoma kinase translocation was evaluated by fluorescent in situ hybridization.
The study cohort included 99 patients (61% males, 94% smokers) comprising 31 squamous and 68 nonsquamous cell carcinomas. We detected 227 nonsilent variants in the coding sequence, including 24 samples with nonoverlapping, classic driver alterations. The frequency of driver mutations was not significantly different from that of whites, and no association was found between genetic ancestry and the presence of somatic mutations. Copy number alteration analysis disclosed distinguishable amplifications in the 3q chromosome arm in squamous cell carcinomas and pointed toward a handful of targetable alterations. We also found frequent SMARCA4 mutations and protein loss, mostly in driver-negative tumors.
Our data suggest that African American ancestry may not be significantly different from European/white background for the presence of somatic driver mutations in NSCLC. Furthermore, we demonstrated that using a comprehensive genotyping approach could identify numerous targetable alterations, with potential impact on therapeutic decisions.
技术进步使得对非小细胞肺癌（NSCLC）中的基因扰动进行全面分析成为可能；然而，非裔美国人在这些研究中的代表性往往不足。该种族群体的肺癌发病率和死亡率较高，一些研究表明表皮生长因子受体突变的发生率较低。在此，我们报告了迄今为止非裔美国人中最深入的NSCLC分子图谱。
设计了一个定制的检测板，以覆盖81个与NSCLC相关基因的编码区和40个祖先信息标记。临床样本在大规模平行测序仪上进行测序，并通过荧光原位杂交评估间变性淋巴瘤激酶易位。
研究队列包括99名患者（61%为男性，94%为吸烟者），其中包括31例鳞状细胞癌和68例非鳞状细胞癌。我们在编码序列中检测到227个非同义变体，包括24个具有不重叠的经典驱动改变的样本。驱动突变的频率与白人无显著差异，并且在遗传血统与体细胞突变的存在之间未发现关联。拷贝数改变分析揭示了鳞状细胞癌中3号染色体臂上可区分的扩增，并指向少数可靶向的改变。我们还发现频繁的SMARCA4突变和蛋白缺失，主要发生在驱动基因阴性的肿瘤中。
我们的数据表明，在NSCLC中，非裔美国人的血统与欧洲/白人背景在体细胞驱动突变的存在方面可能没有显著差异。此外，我们证明使用全面的基因分型方法可以识别众多可靶向的改变，这可能对治疗决策产生影响。
