Identification of an ERCC2 mutation associated mutational signature of nucleotide excision repair deficiency in...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Next-generation sequencing (NGS) mutational signatures identify tumors with DNA repair deficiencies for targeted therapies.
• Current methods often rely on whole exome (WES) or whole genome sequencing (WGS), but limited targeted panels are increasingly used.
• New approaches are needed to derive mutational signatures from limited targeted sequencing data.

Purpose of the Study:

• To derive and validate a panel sequencing-based mutational signature for nucleotide excision repair (NER) deficiency.
• To associate this signature with ERCC2 mutations in bladder cancer.
• To explore the clinical utility of this signature in predicting response to platinum therapy.

Main Methods:

• Utilized publicly available targeted panel sequencing data.
• Developed a composite mutational signature associated with NER deficiency.
• Analyzed the association between the signature, ERCC2 status, and clinical outcomes in bladder cancer.
• Examined the signature in other solid tumor types with ERCC2 mutations.

Main Results:

• A novel panel sequencing-based mutational signature for NER deficiency induced by ERCC2 mutations was derived and validated.
• ERCC2 wild-type (WT) bladder cancers with high signature levels showed better response to neoadjuvant platinum therapy and improved overall survival.
• The characteristic signature was also observed in other solid tumors with ERCC2 mutations.

Conclusions:

• Targeted panel sequencing can identify clinically relevant mutational signatures, such as one associated with NER deficiency.
• This signature predicts improved outcomes with platinum therapy in ERCC2 WT bladder cancer.
• The findings suggest a potential therapeutic strategy for ERCC2-mutant solid tumors beyond bladder cancer.