Characterization of pancreatic cancer with ultra-low tumor mutational burden

In pancreatic cancer (PC), Tumor mutation burden (TMB) has been reported to be lower than in other cancers, with its clinical significance remaining unclear. We analyzed the dataset of whole-exome sequencing and gene expression profiling of 93 resected PC cases. The median TMB was 0.24. The TMB was classified as High (≥ 5.0), Low (< 5.0, ≥ 1.0), or Ultra-low (< 1.0). Nineteen samples (20%) were classified as TMB-low, and 74 (80%) were classified as TMB-ultra-low; no samples were TMB-high. TMB-ultra-low PC had significantly fewer borderline resectable lesions (P = 0.028) and fewer adenosquamous carcinomas (P = 0.003) than TBM-low PC. Furthermore, the TMB-ultra-low PC showed significantly lower detection rates of driver mutations and copy number variations. Microsatellite instability was not significantly correlated with the TMB status. The TMB-ultra-low PC had a significantly better prognosis than TBM-low PC (P = 0.023). A multivariate analysis identified TMB-ultra-low PC as an independent favorable prognostic factor (hazard ratio, 2.11; P = 0.019). A gene expression analysis showed that TMB-ultra-low PC was associated with reduced TP53 inactivation (P = 0.003) and reduced chromosomal instability (P = 0.001) compared to TBM-low PC. TMB-ultra-low PC had specific gene expression signatures and a better prognosis than TMB-low PC.