Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Nature. 2010 Jan 14;463(7278):184-90. doi: 10.1038/nature08629. Epub 2009 Dec 16.
Cancer is driven by mutation. Worldwide, tobacco smoking is the principal lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in frame, and another two lines carrying PVT1-CHD7 fusion genes, indicating that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.
癌症是由突变驱动的。在全球范围内，吸烟是导致癌症的主要生活方式暴露因素，通过 >60 种与 DNA 结合并使其发生突变的化学物质发挥致癌作用。我们使用大规模平行测序技术对小细胞肺癌细胞系 NCI-H209 进行测序，以探索与吸烟相关的突变负担。共鉴定出 22910 个体细胞替换，包括 134 个编码外显子中的替换。多种突变特征证明了烟草烟雾中致癌混合物及其对特定碱基和周围序列背景的倾向。转录偶联修复和第二种更普遍的表达相关修复途径的影响显而易见。我们鉴定了一个串联重复，将 CHD7 的外显子 3-8 按框架复制，还有另外两条携带 PVT1-CHD7 融合基因的染色体，表明 CHD7 可能在这种疾病中经常发生重排。这些发现说明了下一代测序在提供有关癌症相关突变过程、细胞修复途径和基因网络的前所未有的见解方面的潜力。
