Cell：肺癌全基因组测序研究有助个体化治疗

肺癌是世界范围内癌症死亡的主要原因，其伴随的是相应的低生存率。两项新型的全基因组测序研究解开了致死性肺癌中所涉及的新基因，而且结果也揭示了在抽烟者和不抽烟者中机体突变的巨大差异。相关研究成果刊登在了近日的国际杂志Cell上。研究结果为提高个体生存率的个体化治疗铺平了道路。

来自华盛顿大学医学院的研究者Ramaswamy Govindan指出，我们付出了很多努力，旨在完全理解肺癌的基因组蓝图，尤其是那些有抽烟历史的人。这项研究帮助我们开发出新型的靶向疗法来改善癌症病人的治疗结果。

每年肺癌能够夺取130万人的生命，而且肺癌患者5年的生存率仅仅有15%。尽管抽烟是该疾病的主要风险因子，但是有很大一部分肺癌患者并没有吸烟史。过去的研究揭示了不同类型的肺癌病人，包括吸烟者和非吸烟者，其机体中或许存在不同类型的遗传突变，这或许影响其对药物疗法的反应。

在这项新型研究中，由研究者Richard Wilson领导的研究团队对非小细胞肺癌患者（NSCLC）的肿瘤进行了基因组测序，NSCLC是肺癌的主要类型。研究者在NSCLC患者中发现，吸烟者所发生的突变比率是不吸烟者的10倍以上，而且这两组研究对象中均有不同类型的突变。研究者同时也揭示了突变可以引起疾病的发生，在54个基因中发现这些改变或为当前的药物提供新的靶点。

刊登在Cell上的第二篇研究中，来自布洛德研究所研究所的研究者重点研究了一种称为肺腺癌的非小细胞肺癌亚型，通过研究发现，相比非吸烟者，吸烟人群的肿瘤细胞中存在不同类型的突变。研究者Alice Berger表示，这是截止到目前关于肺腺癌的一项重大的基因组学研究，我们的结果对于运用强大的第二代测序技术来研究理解肿瘤生物学带来了一定的帮助。

编译自：Two Studies Could Lead to New Personalized Therapies for Lung Cancer Patients

doi:10.1016/j.cell.2012.08.024
PMC:
PMID:

Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers

Ramaswamy Govindan, Li Ding, Malachi Griffith, Janakiraman Subramanian, Nathan D. Dees, Krishna L. Kanchi, Christopher A. Maher, Robert Fulton, Lucinda Fulton, John Wallis, Ken Chen, Jason Walker, Sandra McDonald, Ron Bose, David Ornitz, Donghai Xiong, Ming You, David J. Dooling, Mark Watson, Elaine R. Mardis, Richard K. Wilson

We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.

doi:10.1016/j.cell.2012.08.029
PMC:
PMID:

Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing

Marcin Imielinski, Alice H. Berger, Peter S. Hammerman, Bryan Hernandez, Trevor J. Pugh, Eran Hodis, Jeonghee Cho, James Suh, Marzia Capelletti, Andrey Sivachenko, Carrie Sougnez, Daniel Auclair, Michael S. Lawrence, Petar Stojanov, Kristian Cibulskis, Kyusam Choi, Luc de Waal, Tanaz Sharifnia, Angela Brooks, Heidi Greulich, Shantanu Banerji, Thomas Zander, Danila Seidel, Frauke Leenders, Sascha Ansén, Corinna Ludwig, Walburga Engel-Riedel, Erich Stoelben, Jürgen Wolf, Chandra Goparju, Kristin Thompson, Wendy Winckler, David Kwiatkowski, Bruce E. Johnson, Pasi A. Jänne, Vincent A. Miller, William Pao, William D. Travis, Harvey I. Pass, Stacey B. Gabriel, Eric S. Lander, Roman K. Thomas, Levi A. Garraway, Gad Getz, Matthew Meyerson

Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.