Investigation of unknown causes of uveal melanoma uncovers seven recurrent genetic mutations

Uveal melanoma (UM) is a rare subtype of melanoma but the most frequent primary cancer of the eye in adults. The goal of this study was to research the genetic causes of UM through a comprehensive frequency analysis of base-pair mismatches in patient genomes. It was hypothesized that chromosomes 15 and 16, due to their role in the expression of eye color, would exhibit UM-associated mutations. The U.S. National Institute of Health (NIH) provided genomic data from surgically resected eye enucleations and liver metastases from 32 UM patients, which we individually analyzed to identify nucleotide base-base mismatches by comparing DNA sequences from cancerous cells to reference DNA sequences. After identifying mismatches we performed a Pareto analysis of cross-patient data to identify chromosomes with recurrent and nonrecurrent genetic mutations across all samples. We then studied the mutated gene functions to evaluate causal links to cancer, such as for genes that encoded known tumor suppressor proteins. We discovered a total of 130 genetic mutations, including seven recurrent mutations, with most mutations occurring in chromosomes 3 and X. Recurrent mutations varied from 8.7% to 17.39% occurrence in the UM patient sample, with all mutations identified as missense. These findings suggest that UM is a recessive heterogeneous disease with selective homozygous mutations. Notably, this study has potential wider significance because the seven genes targeted by recurrent mutations are also involved in other cancers. As a result, immunotherapy is a highly promising treatment for uveal melanoma due to the disease’s heterogeneous nature.