Non-B DNA-informed mutation burden as a marker of treatment response and outcome in cancer

Abstract

Genomic instability is crucial in tumorigenesis, with Tumour Mutation Burden (TMB) being a biomarker to indicate therapeutic effectiveness, particularly in immunotherapy. However, TMB is not always a reliable predictor and displays heterogeneity. Non-B DNA, susceptible to mutations, play a significant role in cancer development, indicating their potential merit when combined with mutation for enhanced markers in cancer. We assessed mutations and non-B DNA interplay as biomarkers. Our methodology quantifies tumour mutations and their co-localization with non-B DNA, using survival and drug sensitivity assessments for clinical relevance. We introduce two novel markers, ‘nbTMB’ (non-B-informed tumour mutation burden) and ‘mlTNB’ (mutation-localised tumour non-B burden). In case studies: (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 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. These novel markers offer a nuanced approach to enhance our understanding of treatment responses and outcomes in cancer, underscoring the need for a comprehensive exploration of the interplay between non-B and B-DNA features.