Defining the mutation signatures of DNA polymerase θ in cancer genomes

Area of Science:

• Molecular Biology
• Cancer Genomics
• DNA Repair Mechanisms

Background:

• DNA polymerase theta (POLQ)-mediated end joining (TMEJ) is a distinct DNA double-strand break (DSB) repair pathway.
• TMEJ is essential for the survival of BRCA-mutated cancer cells, highlighting its therapeutic relevance.

Purpose of the Study:

• To define POLQ-associated mutation signatures in human cancers.
• To identify tumors reliant on POLQ for DSB repair and predict their sensitivity to POLQ inhibition and DSB-producing therapies.

Main Methods:

• Analysis of 82 COSMIC (Catalogue of Somatic Mutations in Cancer) signatures.
• Examination of POLQ expression levels in BRCA-mutated cancers.
• Functional studies using human cancer cells with POLQ disruptions.

Main Results:

• BRCA-mutated cancers with high POLQ expression show enhanced small insertion/deletion signature 6 and single base substitution signature 3.
• TMEJ is the dominant pathway for joining two separated DSBs (distal EJ) in a POLQ-dependent manner.
• Templated insertions with microhomology are enriched in POLQ-dependent distal EJ.

Conclusions:

• POLQ-associated mutation signatures, particularly small insertions/deletions within microhomologies, can identify tumors dependent on POLQ.
• This signature analysis aids in pinpointing cancers with predicted sensitivity to POLQ inhibition and other cancer treatments.