Uveal Melanoma Metastatic Rate is Relative to Stochastic Mutation Rate and Type of Mutation

Abstract

Purpose : We have previously hypothesized that the metastatic rate of uveal melanoma is due to stochastic properties of the primary uveal melanoma and the host response. The purpose of this study was to examine the stochastic properties of primary uveal melanoma including the mutation rate as a function of tumor size and metastatic rate relative to type of mutation.

Methods : We computed the mutation rates in different sized uveal melanomas. Two methods were used to estimate tumor volume: constant aspect ratio and constant base area. We also calculated the metastatic rate using the Rotterdam Ocular Melanoma Study Group dataset of uveal melanoma patients with mutational analysis for BAP1, SF3B1 and EIF1AX.

Results : Based on the 5-year metastatic rates, mutation rates ranged from 1.71 X 10^-11 to 4.19 X 10^-9 and from 4.99 X 10^-11 to 1.02 X 10^-9 per cell divisions using the constant aspect ratio and constant base area methods, respectively, to calculate the tumor size. A higher mutation rate was found for tumors with smaller thicknesses using both methods. EIF1AX mutations were not mutually exclusive, two cases with metastasis harbored BAP1 mutations as well. None of the tumors with an exclusive EIF1AX mutation metastasized. After plotting yearly metastatic rate versus the time after treatment for BAP1 and SF3B1 mutant groups, we observed a small peak at 1 year after treatment and a large peak at 3.5 years for BAP1 mutation, a peak between 2 and 3 years and a late peak at 7 years for SF3B1 mutation.

Conclusions : Our results indicate that tumor size correlating with metastatic rate can largely be explained by a constant mutation rate for each tumor cell. However, we observed a higher metastatic rate for smaller tumors, possibly due to greater numbers of cell divisions occurring during the expansion phases of smaller uveal melanomas. Regarding time to clinically detected metastasis, the first peak appears to coincide with BAP1-mutated tumors and the late peaks appear to coincide with the SF3B1 mutation.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.