Identification of an ERCC2 Mutation-Associated Mutational Signature of Nucleotide Excision Repair Deficiency in Targeted Panel Sequencing Data.

Abstract

Purpose: Next-generation sequencing-based mutational signatures are frequently used to identify tumors with specific DNA repair deficiencies for targeted therapeutic strategies. Although mutational signatures are commonly derived from whole-exome or whole-genome sequencing data, patients often undergo tumor sequencing using more limited targeted panels that typically encompass several hundred cancer-associated genes. Identifying clinically relevant mutational signatures from targeted panel data requires new approaches capable of deriving signatures from the more limited sequencing data.

Methods: Using publicly available panel sequencing data, we derived and validated a panel sequencing-based composite mutational signature associated with nucleotide excision repair (NER) deficiency induced by inactivating ERCC2 mutations in bladder cancer.

Results: We found that ERCC2 wild-type (WT) bladder cancer cases that have high levels of this mutational signature respond better to neoadjuvant platinum therapy and have improved overall survival compared with ERCC2 WT cases with low levels of the signature. We also found that other solid tumor types with ERCC2 mutations also show the characteristic mutational signature seen in NER-deficient ERCC2-mutant bladder cancers, suggesting a novel approach to therapeutically target these ERCC2-mutant solid tumors beyond bladder cancer.

Conclusion: Mutational signature-based NER deficiency status can be determined in panel sequencing data of tumor biopsies. This could be used to investigate the connection between NER deficiency and response to neoadjuvant platinum-based chemotherapy.