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

Nikolai Klebanov,Mark J Daly,Mykyta Artomov,William B Goggins,Hensin Tsao,Emma Daly

doi:10.1038/s41598-019-41015-5

Abstract

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.

Highlights

Tumor mutational burden has been described as a predictor of tumor behavior and immunological response[1,2,3]
Total missense mutational burden across all cohorts ranged from a low of 8 missense mutations among acute myeloid leukemia (LAML) and thymoma (THYM), to 256 median mutations among the skin cutaneous melanoma (SKCM) cohort (Fig. S1). 10 individuals were removed as tumor exonic missense mutational burden (TEMMB) outliers (Fig. S2)
Total (TEMB) and missense (TEMMB) tumor exonic mutational burden were found to be closely correlated among all cohorts: Pearson’s r ranged from 0.95–1.00 for all cohorts other than uveal melanoma (UVM) which revealed a strong positive correlation with r = 0.88 likely due to a small (N = 79) sample size (p < 2.2 × 10−16 for all cohorts) (Fig. S3)

Summary

Introduction

Tumor mutational burden has been described as a predictor of tumor behavior and immunological response[1,2,3]. High mutational burden may in some cases represent a high underlying number of drivers, and indicate a higher-risk tumor: for example patients with high mutational burden lung adenocarcinoma tumors showed a 14-month survival decrease[4], supporting that high mutation burden may be a harbinger of poor clinical outcomes. Patients with melanomas with a high mutational load showed improved survival with ipilimumab[6] and improved overall survival[7]; patients with highly mutated ovarian cancer had improved postoperative chemotherapy response and higher overall survival[2]. We hypothesized that tumor exonic missense mutational burden (TEMMB) is predictive of underlying total exonic mutational burden (TEMB), and that TEMMB is independent of critical demographic and tumor-specific factors. We hypothesized that TEMMB is a predictive marker of tumor immune surveillance and clinical outcomes. Missense mutational load was found to be highly correlated with predicted www.nature.com/scientificreports/. Missense mutations produce specific amino acid changes in a known pattern, allowing for a systematic way to characterize mutational profiles by defining recurrent and non-recurrent mutations

Methods

Results

Conclusion