This study identifies 21 distinct mutational signatures in human cancers, revealing the diversity of mutational processes underlying cancer development. By analyzing 4,938,362 mutations from 7,042 cancers, the researchers found that some mutational signatures are common across multiple cancer types, while others are specific to individual cancer classes. These signatures are associated with factors such as patient age, mutagenic exposures, and DNA repair defects. Additionally, localized hypermutation, termed 'kataegis', is found in many cancer types and is often linked to genomic rearrangements. The study highlights that mutational signatures can be influenced by various factors, including intrinsic DNA replication errors, exogenous mutagenic exposures, and defects in DNA repair mechanisms. Some signatures, such as those attributed to the APOBEC family of cytidine deaminases, are associated with specific cancer types. Others, like those linked to tobacco smoking or ultraviolet light exposure, are associated with particular mutational patterns. The research also explores the role of transcriptional strand bias in mutational signatures, showing that certain mutations are more prevalent on one strand of DNA than the other. This bias is linked to processes such as transcription-coupled nucleotide excision repair. Additionally, the study identifies mutational signatures associated with insertions and deletions, which are often linked to defects in DNA repair mechanisms such as mismatch repair and homologous recombination. The study further associates mutational signatures with cancer aetiology, showing that some signatures are linked to specific environmental factors or genetic defects. For example, signature 7 is associated with malignant melanoma and is linked to ultraviolet light-induced mutations. Signature 4 is associated with tobacco smoking and is linked to mutations caused by tobacco carcinogens. The study also identifies localized hypermutation, termed 'kataegis', which is characterized by clusters of mutations in specific genomic regions. These clusters are often found near genomic rearrangements and are associated with certain cancer types, such as breast and lung cancers. Overall, the study provides a comprehensive understanding of the mutational processes underlying cancer development, highlighting the diversity of mutational signatures and their potential implications for cancer aetiology, prevention, and therapy. The findings suggest that further research is needed to fully understand the underlying mechanisms of these mutational processes and their role in cancer development.This study identifies 21 distinct mutational signatures in human cancers, revealing the diversity of mutational processes underlying cancer development. By analyzing 4,938,362 mutations from 7,042 cancers, the researchers found that some mutational signatures are common across multiple cancer types, while others are specific to individual cancer classes. These signatures are associated with factors such as patient age, mutagenic exposures, and DNA repair defects. Additionally, localized hypermutation, termed 'kataegis', is found in many cancer types and is often linked to genomic rearrangements. The study highlights that mutational signatures can be influenced by various factors, including intrinsic DNA replication errors, exogenous mutagenic exposures, and defects in DNA repair mechanisms. Some signatures, such as those attributed to the APOBEC family of cytidine deaminases, are associated with specific cancer types. Others, like those linked to tobacco smoking or ultraviolet light exposure, are associated with particular mutational patterns. The research also explores the role of transcriptional strand bias in mutational signatures, showing that certain mutations are more prevalent on one strand of DNA than the other. This bias is linked to processes such as transcription-coupled nucleotide excision repair. Additionally, the study identifies mutational signatures associated with insertions and deletions, which are often linked to defects in DNA repair mechanisms such as mismatch repair and homologous recombination. The study further associates mutational signatures with cancer aetiology, showing that some signatures are linked to specific environmental factors or genetic defects. For example, signature 7 is associated with malignant melanoma and is linked to ultraviolet light-induced mutations. Signature 4 is associated with tobacco smoking and is linked to mutations caused by tobacco carcinogens. The study also identifies localized hypermutation, termed 'kataegis', which is characterized by clusters of mutations in specific genomic regions. These clusters are often found near genomic rearrangements and are associated with certain cancer types, such as breast and lung cancers. Overall, the study provides a comprehensive understanding of the mutational processes underlying cancer development, highlighting the diversity of mutational signatures and their potential implications for cancer aetiology, prevention, and therapy. The findings suggest that further research is needed to fully understand the underlying mechanisms of these mutational processes and their role in cancer development.