Recurrent mutations in topoisomerase IIα cause a previously undescribed mutator phenotype in human cancers

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Topoisomerases (Top2) manage DNA topology crucial for cellular processes.
• While Top2 stabilization is mutagenic in yeast, its role in higher eukaryotes and cancer is less understood.
• Chemotherapeutic agents targeting Top2 can induce mutagenesis.

Purpose of the Study:

• To investigate the mutagenic potential of specific mutations in human topoisomerase II alpha (hTOP2α).
• To characterize a novel mutator phenotype associated with hTOP2α mutations in human cancers.
• To explore the link between this phenotype and the mutation patterns in cancer driver genes.

Main Methods:

• Analysis of p.K743N mutations in human hTOP2α.
• Overexpression of orthologous mutant protein in yeast to study mutagenesis.
• Genetic analysis using mutant yeast strains.
• Biochemical assays to understand cleavage complex trapping.
• Examination of tumor genomes for the ID_TOP2α signature and indels in cancer genes.

Main Results:

• hTOP2α p.K743N mutations were linked to a novel mutator phenotype, ID_TOP2α, in human cancers.
• The ID_TOP2α signature, comprising 2- to 4-bp duplications and deletions, was found in all tumors with hTOP2α p.K743N.
• This signature was absent in a large cohort of other tumors (n=12,269).
• Tumors with ID_TOP2α showed indels in cancer genes like PTEN, TP53, and BRAF.
• Sequence motifs at ID_TOP2α sites were prevalent at indels in cancer-driver genes.

Conclusions:

• The hTOP2α p.K743N mutation drives a distinct mutator phenotype (ID_TOP2α) in cancer.
• ID_TOP2α mutagenesis, involving specific duplication and deletion patterns, may contribute to tumorigenesis by mutating cancer-driver genes.
• Topoisomerase II plays a significant role in maintaining genome stability and its dysfunction can lead to cancer development.