• Written By:
    Ocular Pathology/Oncology

    This retrospective study offers new understanding to the genetics and evolution of uveal melanoma.

    Study design

    Researchers performed multi-region DNA sequencing of primary uveal melanoma, corresponding liver metastases and non-tumor reference material from 35 patients with metastatic disease. The distribution of somatic mutations and copy number changes among samples were used to delineate the sequential order in which mutations arose during tumor evolution. Phylogenic trees were created for each case.


    Consistent with a prior investigation, activation of the Gαq signaling cascade (with mutations affecting GNA11, GNAQ, CYSLTR2 or PLCB4 in a mutually exclusive pattern) was common and these mutations underwent relatively early selection in metastasizing uveal melanoma. A subset of cases had loss of wild-type GNAQ occurring later in the evolutionary process. Loss of heterozygosity was unique to GNAQ; it was not observed in GNA11.

    Another finding that was consistent with prior publications: mutually exclusive mutations affecting BAP1, SF3B1 and EIF1AX.  The new findings included loss of function mutations affecting CDKN2A, PBRM1, PIK3R2 and PTEN, and loss of heterozygosity over the GNAQ locus and gain of function mutations affecting EZH2, PIK3CA and MED12. For example, one SF3B1- and EIF1AX-driven tumor acquired a MED12NV40del mutation that has not been previously described in uveal melanoma. The sequential order in which somatic alterations underwent selection during metastatic evolution was calculated by how often a given alteration resided on the trunk versus the branch of each phylogenic tree.

    q mutations were the earliest to undergo selection, followed by gain of 8q, as well as mutations in BAP1, SF3B1 or EIF1AX. Most somatic alterations were enriched in metastases, but only copy number changes of 6q, 1q and high-level gains of 8q were statistically significant. Gains in 1q were more common in this series, compared to prior studies of primary uveal melanoma, consistent with their emergence later in the evolutionary process.


    This study provides new insight into the genetic evolution of uveal melanoma but may be limited by its relatively small sample size of 35 patients.

    Clinical significance

    This work confirms that uveal melanoma continues to genetically evolve as it progresses from primary to metastatic disease, as evidenced by the fact that metastases tend to develop more oncogenic mutations than their primary tumor counterparts. The identification of early driver mutations and a better understanding of the selection they undergo could provide a biomarker strategy for detection of early metastatic disease, as well as a potential means to develop and measure tumor responses to adjuvant therapies.