Burden of unique and low prevalence somatic mutations correlates with cancer survival

Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others. To study the link between mutational burden and survival, we analyzed survival effects of tumor exonic missense mutation burden (TEMMB) across 6947 specimens spanning 31 cancers which have undergone whole exome sequencing as part of TCGA. We adjusted TEMMB for age, sex, stage, and recruitment center, and computed Cox-proportional models of TEMMB survival effects. We assigned a recurrence score (RS) to each cohort, defining RS as the burden of recurrent mutations exceeding 1% population prevalence. High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60–0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59–0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70–0.93], p = 0.003. High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00–1.74], p < 0.05. We identified that TEMMB survival effects were governed by the balance of recurrent and non-recurrent mutations. In cancers with a low RS, high TEMMB was correlated with better survival outcomes (r = 0.49, p = 0.02). In conclusion, TEMMB effects on survival depend on recurrent mutation enrichment; tumor types that are highly enriched in passenger mutations show a survival benefit in the setting of high tumor mutational burden.