Association of Uveal Melanoma Metastatic Rate With Stochastic Mutation Rate and Type of Mutation

Abstract

Importance: To understand the mechanisms of metastasis of uveal melanoma in order to advise patients and develop treatments for this tumor. Objective: 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 the type of mutation. Data sources, Study Selection, Main Outcome and Measures: We computed the mutation rate in different sized uveal melanomas using previously published large datasets. Tumor volume was estimated using the spherical cap method. We also calculated the metastatic rate using an updated dataset of uveal melanoma patients with known mutations in BAP1, SF3B1 and EIF1AX provided by the Rotterdam Ocular Melanoma Study Group. Results: Based on the 5-year metastatic rates, mutation rates ranged from 1.09 X 10−8 to 7.86 X 10−7 per cell division, using our calculation algorithm. A higher mutation rate was found for tumors with smaller thicknesses. EIF1AX mutations were not exclusive of other mutations as two cases with EIF1AX mutations and metastasis also had BAP1 mutations. None of the tumors with only an EIF1AX mutation metastasized. After plotting the yearly metastatic rate versus time after treatment, we observed a small peak at 1 year and a large peak at 3.5 years after treatment for BAP1 mutations, with peaks between 2 and 3 years and at 7 years for SF3B1 mutations. Conclusions and Relevance: We observed a higher mutation rate for smaller tumors, which may be explained by a greater number of cell divisions occurring during the expansion phase of smaller uveal melanomas. Regarding time to clinically detected metastases, the first two peaks appear to relate to BAP1-mutated tumors and the late peak to SF3B1-mutated tumors.

Understanding Uveal Melanoma Metastasis to the Liver: The Zimmerman Effect and the Zimmerman Hypothesis

“…Specific type of mutation and the Zimmerman effect. Our study of the time of metastatic uveal melanoma versus type of mutation 15 based on a large dataset 18 showed that uveal melanomas harboring BAP1 mutations account for metastases detected at 2 to 3 years, and that those with SF3B1 mutations account for metastases detected at 4 to 8 years after the primary tumor is diagnosed and treated. This helps explain the Zimmerman effect.…”

“…This can be explained by the expansion phase in tumor growth: When a precursor lesion, such as a nevus, undergoes a mutational event in which it becomes a malignant neoplasm (melanoma), the mutation rate is higher than after the neoplasm is established and grows. 15 To summarize, as a melanoma initially forms, the proportion of metastasis-related mutant versus nonmutant cells in the tumor is slightly higher than when the melanoma further enlarges, although the larger the tumor, the greater the absolute number of metastasis-related mutant tumor cells.…”

“…Recent investigations have emphasized that tumor size, when coupled with mutational analysis of the primary uveal melanoma, results in a more robust prediction of metastasis and outcome than either individual metric, 12,13 although this has been well documented in the past. 14 Our laboratory was able to calculate the mutation rate on different-sized uveal melanomas 15 based on a study from the Wills Eye Hospital. 16 We calculated that spontaneous mutation rates were similar in all uveal melanomas, with the exception that the spontaneous rate was slightly higher in small compared with medium and large melanomas (Fig 1).…”

“…Our meta-analysis showed that the peak incidence of death at approximately 3 years after diagnosis of the primary tumor was associated with BAP1 mutations, whereas later deaths were associated with SF3B1 mutations (Fig 2). 15 Thus, there is something more than random mutational events that is predictive of survival time in patients with uveal melanoma. That something is the specific type of mutation.…”

“…Spontaneous mutation rates in different-sized uveal melanomas. We calculated the spontaneous mutation rates in uveal melanoma 15 on the basis of previously published Collaborative Ocular Melanoma Study (COMS) data. 4 There is a slightly higher rate in small versus medium and large melanomas because of the expansion phase in tumor development.…”