Non-B DNA-Informed Mutation Burden as a Marker of Treatment Response and Outcome in Cancer

Abstract

AbstractBackgroundGenomic instability plays a key role in tumorigenesis and cancer research, with Tumor Mutation Burden (TMB) being a crucial biomarker quantifying total mutation to indicate therapeutic effectiveness, particularly in immunotherapy. However, TMB is not always a reliable predictor of treatment response and displays heterogeneity. Non-B DNA, alternative DNA forms have the potential to increase susceptibility to mutations that lead to the development of cancer. The tendency of these structures to induce mutations highlights their critical role in cancer onset and advancement, indicating their potential merit when combined with mutation information for enhanced markers in cancer with potential novel insights.Methods and findingsWe introduce two novel markers, “nbTMB” (non-B-informed tumor mutation burden) and “mlTNB” (mutation-localized-informed tumor non-B burden). We show in three separate case studies applying these markers the following findings: 1) nbTMB informs on survival heterogeneity among TMB-High patients undergoing immunotherapy whereas TMB is unable to further differentiate; 2) nbTMB informs on altered cisplatin sensitivity among ovarian cancer patient-derived cell lines whereas TMB is unable to differentiate; and 3) mlTNB informs on survival heterogeneity among early stage pancreatic cancer progressors in whom other markers of genomic instability fail to differentiate.ConclusionsThese novel markers offer a nuanced approach in which to enhance our current understanding of treatment responses and outcomes in cancer, underscoring the need for a more comprehensive exploration of the interplay between non-B and B-DNA features.