Tumor Mutational Burden Predicts Survival in Merkel Cell Carcinoma

Purpose/Objective(s)In Merkel cell carcinoma (MCC), clinical factors, including advanced age and immunosuppression, are variably prognostic and poorly predictive of treatment response. There is a clear need for robust genetic markers of aggressive disease to inform treatment selection and prognostication. In a cohort of 54 MCC patients, we assessed the impact of tumor mutational burden (TMB), single nucleotide (SNV) and copy number variations (CNV), and Merkel Cell Polyomavirus (MCPyV) integration on MCC-specific survival outcomes.Materials/MethodsGenomic DNA was harvested from paraffin-embedded tissue blocks obtained from patients with biopsy-proven MCC of any anatomic subsite. A total of 54 patients with MCC were included from 2016 – 2019. We performed targeted exome sequencing of a 226-gene panel on a sequencing platform and used our established bioinformatics pipelines for targeted TMB, SNV, CNV, and MCPyV integration site calls. We then assessed the prognostic impact of specific genetic alterations on MCC-specific survival using Kaplan-Meier curves and Cox regression.ResultsDemographic and clinical characteristics of our cohort are shown in the Table. Median (range) follow-up duration after treatment completion was 43 (1 – 78) months. Five-year MCC-specific survival was 75 % (95 % CI: 56.5 – 85.9%). The median (range) targeted TMB was 1 (0 – 69). Frequently altered genes included LRP1B (n = 10, 18.5 %), FAT1 (n = 9, 16.7 %), KMT2D (n = 9, 16.7 %), RB1 (n = 7, 13.0 %), and ABL1 (n = 6, 11.1 %). In 36 of 44 (81.8 %) MCPyV-positive cases, virus was integrated into the host genome with a median (range) of 2 (1 – 30) distinct integration events. In six tumors, MCPyV integrated into COSMIC Tier 1 or Tier 2 cancer-related host genes, thus possibly altering their native function, including ABL2, BLM, HIF1A, KMT2A, MYCL, and TET2. A receiver operating characteristic curve was used to identify a targeted TMB = 13 as a cut-point to maximize differences in MCC-specific survival. Using this cut-point, a higher targeted TMB strongly predicted MCC-specific survival (p = 0.001), even when controlling for clinical nodal status. Tumor MCPyV status, virus state (i.e., integrated vs episomal), and specific SNV/CNVs did not predict MCC-specific survival.ConclusionHigher tumor mutational burden portends worse survival in MCC and may be a clinically useful biomarker of treatment response and for prognostication for this challenging disease.