Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers

摘要: Objective Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and base excision gene MUTYH underlie hereditary colorectal cancer (CRC) polyposis syndromes. We evaluated robustness discriminatory potential of tumour mutational signatures CRCs for identifying germline PV carriers. Design Whole-exome sequencing formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR carriers, 12 biallelic 25 sporadic MLH1 methylated MMR-deficient (MMRd controls) 160 MMR-proficient (MMRp included 498 TCGA tumours. COSMIC V3 single substitution (SBS) indel (ID) were assessed their ability to differentiate that developed carriers from non-carriers. Results The combination SBS18 SBS36 contributing >30% a CRC’s signature profile able discriminate all other non-carrier control with 100% accuracy (area under curve (AUC) 1.0). associated specific p.Gly396Asp (p=0.025) p.Tyr179Cys (p=5×10-5), respectively. ID2 ID7 could carrier MMRp (AUC 0.99); however, SBS ID signatures, alone or combination, not provide complete discrimination 0.79) between MMRd controls. Conclusion Assessment can non-carriers high accuracy, demonstrating utility as diagnostic variant classification tool.