Identification of an ERCC2 mutation associated mutational signature of nucleotide excision repair deficiency in targeted panel sequencing data

Abstract 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 most commonly derived from whole exome (WES) or whole genome sequencing (WGS) data, more patients currently 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. Here, we derive and validate a panel sequencing-based composite mutational signature associated with nucleotide excision repair (NER) deficiency induced by inactivating ERCC2 mutations in bladder cancer. Using publicly available panel sequencing data, we find 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 to ERCC2 WT cases with low levels of the signature. We also find 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. Competing Interest Statement JB, ZsS, MD, KWM, and ZS are listed as coinventors on a pending patent (US-20230128143) regarding a mutational signature-based method to identify nucleotide excision repair deficiency from tumor biopsies.