Two clock-like somatic mutational signatures were identified in a variety of human tumors.
Major finding: Two clock-like somatic mutational signatures were identified in a variety of human tumors.
Concept: Clock-like mutations accumulate in normal somatic cells and correlate with age of cancer diagnosis.
Impact: The mutation rate of signature 1 is affected by the rate of cell division.
Over time, normal somatic cells accumulate mutations, and these mutations can contribute to a cancer cell's mutational signature. The underlying mechanisms that give rise to somatic mutations in normal cells are poorly understood. Mutations may occur at a steady rate in a “clock-like” manner, in contrast to episodic accumulations of mutations over a short period of time. In tumors with a clock-like mutational process, the number of mutations would correlate with age at cancer diagnosis. To identify clock-like mutational signatures, Alexandrov and colleagues analyzed 7,329,860 somatic mutations from 10,250 cancer genomes in 36 tumor types. Among thirty-three distinct mutational signatures, two, signatures 1 and 5, showed clock-like behavior. For both of these signatures, the number of mutations increased with age and correlated with age of diagnosis in a broad range of cancer types. Signatures 1 and 5 were poorly correlated with each other across tumor types, suggesting that different biologic processes drive their mutation rates. Signature 1 was primarily characterized by C>T mutations at NpCpG trinucleotides, suggesting that the molecular mechanism leading to signature 1 mutations may be deamination of 5-methylcytosine that results in accumulation of T·G mismatches that are converted to C>T mutations after DNA replication. Of note, the rate of signature 1 mutations was elevated in many epithelial cancers with high turnover, supporting the idea that cells with higher rates of mitosis may display higher mutation rates and that cell proliferation may play an important role in signature 1. Signature 5 was characterized by C>T and T>C mutations; however, the mechanism underlying this mutational process is not understood. Although further studies are needed to better elucidate the biologic processes underlying these mutations, these results provide evidence of two unique clock-like mutational signatures in human somatic cells and will aid in the understanding of cancer development.