Next-generation sequencing provides a powerful tool to dissect the influences that environmental perturbations exert on the genome. In what became the first catalog of somatic mutations from a human cancer genome, Peter J. Campbell, Ph.D., group leader at the Wellcome Trust Sanger Institute’s Cancer Genome Project, and collaborators recently completed the sequencing of malignant melanoma and lymphoblastoid cell line genomes derived from the same person and, in a companion study, they examined the genomic mutational burden that accumulates in smokers who develop small-cell lung cancer.
“We set out to use next-generation sequencing to examine genomic changes at a detail that was never looked at before, and we wanted to identify the vast majority or all mutations present in those cancers,” explained Dr. Campbell. The causes of these two cancers were relatively well characterized—melanoma is linked to sunlight, while lung cancer is caused by exposure to cigarette smoke.
“We wanted to see if we are able to visualize the records of those exposures in the genome. And indeed that is what we found,” said Dr. Campbell. The investigators identified tens of thousands of mutations in both cancers, and the vast majority provided a hallmark that can be used to establish a direct link between exposure and mutations in the respective cells, in addition to signs of DNA repair processes that were functional in the respective cells.
For example, over 22,000 somatic mutations, of which 134 were located within coding exons, were identified in small-cell lung cancer, providing a powerful signature that cigarette smoke leaves on the genome. In addition, the authors showed that over the lifetime of a cell clone that eventually becomes cancerous, one mutation would accumulate for approximately every 15 cigarettes smoked.
Next-generation platforms allow genetic variation to be characterized in a high-throughput way, at a fraction of the cost that we were previously used to. “In the future, patients with cancer and other disorders can have their entire genome sequenced with the aim of understanding what is going on in that individual patient to cause that disease, and hopefully that will lead us to much better targeted therapeutic approaches,” added Dr. Campbell.