Evidence for APOBEC3B mutagenesis in multiple human cancers

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Somatic mutations are common in human cancers, but their origins are often unclear.
• The DNA cytidine deaminase APOBEC3B was previously identified as a major contributor to mutations in breast cancer.
• Understanding the broader role of APOBEC3B in mutagenesis across various cancer types is crucial.

Purpose of the Study:

• To investigate the extent to which APOBEC3B contributes to mutagenesis in a wide range of human cancers.
• To analyze mutation patterns, distributions, and loads in relation to APOBEC3B expression across 19 cancer types.
• To determine if APOBEC3B is a general driver of genomic instability in human malignancies.

Main Methods:

• Analysis of gene expression data from over 4,800 exomes across 19 cancer types.
• Examination of mutation patterns, distributions, and loads, totaling over 1,000,000 somatic mutations.
• Correlation of APOBEC3B upregulation with mutation signatures and clustered mutations in specific cancer genomes.

Main Results:

• APOBEC3B is significantly upregulated in at least six cancer types, including bladder, cervix, lung, head and neck, and breast cancers.
• The APOBEC3B preferred target sequence is frequently mutated and shows clustered mutation patterns in these cancers.
• A substantial proportion of both dispersed and clustered mutations across multiple cancers are linked to APOBEC3B activity.

Conclusions:

• APOBEC3B is a major mutagenic factor implicated in a significant fraction of somatic mutations in several human cancer types.
• APOBEC3B-catalyzed genomic uracil lesions are a likely cause of widespread and localized mutations observed in these cancers.
• These findings highlight APOBEC3B as a potential therapeutic target for reducing mutational burden in diverse cancers.