A comprehensive catalogue of somatic mutations from a human cancer genome

Abstract

All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic. 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. Here, the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person are sequenced, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The data provide insight into the causes of tumour formation and the development of the cancer genome, with the dominant mutational signature reflecting DNA damage due to ultraviolet light exposure.