Clustered Mutations in Human Cancer

Mutations are the frequent cause of cancer. They are mostly viewed as independent events distributed randomly across chromosomes. However, mutation distribution can be affected by permanent or transient features of genome structure and function. The extreme form of nonrandom distributions is a mutation cluster with multiple mutations concentrated in a tiny fraction of the genome. Multiple lesions in abnormally long regions of transient single-stranded deoxyribonucleic acid (DNA) can cause mutation clusters, which have been found in a majority of human cancer types. Mutation spectra indicated that many clusters in cancer genomes were caused by a subclass of apolipoprotein B mRNA-editing polypeptide-like (APOBEC) cytidine deaminases. These enzymes function to restrict retroviruses and retrotransposons by converting cytidine to uridine in single-stranded complementary DNAs (cDNAs). The simple mutation spectra in clusters aided in highlighting APOBECs among the complex set of mutagenic mechanisms operating throughout many cancer genomes. Thus, clusters are an analytical tool for deciphering cancer mutation mechanisms. Key Concepts: Mutation clusters are unusually tightly spaced groups of mutations. Error-prone translesion synthesis across multiple lesions in single-stranded DNA is a mechanism of clustered mutagenesis. Mutation clusters have been found across many types of human cancers. Strand-coordinated clusters can be a tool for deciphering mutagenic mechanisms operating in cancer. Mutations in C- or G-coordinated clusters in human cancers are caused by a subclass of APOBEC cytidine deaminases normally serving to restrict viral and endogenous retroelements. APOBEC-induced mutation clusters as well as single mutations are widespread through many types of human cancers. Keywords: APOBEC ; mutation cluster; kataegis; DNA damage; DNA repair; hypermutation