A small-cell lung cancer genome with complex signatures of tobacco exposure

Abstract

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. The two cancer genome sequences presented in this issue demonstrate how next-generation sequencing technologies can inform us about mutational processes, repair pathways and gene networks associated with cancer development. First, the genome of a cell line derived from a bone marrow metastasis in a patient who had small-cell lung cancer. This cancer is typical of the type induced by smoking, and the sequence contains mutation signatures characteristic of some of the more than 60 carcinogens present in tobacco smoke. The second paper compares the whole genome sequence of a melanoma cell line to a lymphoblastoid cell line from the same individual. This, the first complete mutational analysis of a solid tumour, reveals a dominant mutational signature reflecting DNA damage due to exposure to ultraviolet light. Tobacco smoke contains more than sixty carcinogens that bind and mutate DNA. Here, massively parallel sequencing technology is used to sequence a small-cell lung cancer cell line, exploring the mutational burden associated with tobacco smoking. Multiple mutation signatures from the cocktail of carcinogens in tobacco smoke are found, as well as evidence of transcription-coupled repair and another, more general, expression-linked repair pathway.