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Updated: Dec 23, 2025
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Molecular profiling of driver events in metastatic uveal melanoma
Joakim Karlsson1, Lisa M Nilsson1, Suman Mitra1
1Sahlgrenska Cancer Center, Departments of Surgery, Oncology or Transplantation Surgery, Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital, Box 425, 40530, Gothenburg, Sweden.
Abstract:
Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations are overrepresented and found in 29/32 of cases. Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease. One outlier tumor has a high mutational burden associated with UV-damage. CDKN2A deletions also occur, which are rarely present in primaries. A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains. Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 is also abundant. This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease.
Insights
Metastatic uveal melanoma, a distinct cancer, shows frequent BAP1 alterations. Restoring BAP1 shifts tumor cells to a better prognosis subtype, offering new therapeutic insights.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Metastatic uveal melanoma (MUM) is poorly understood, biologically distinct from cutaneous melanoma, and lacks effective therapies.
- Genomic profiling of MUM is crucial for understanding its progression and identifying therapeutic targets.
Purpose of the Study:
- To perform the largest whole-genome analysis of metastatic uveal melanoma to date.
- To characterize the genomic landscape and transcriptomic subtypes of MUM.
- To investigate the role of BAP1 alterations and tumor-infiltrating lymphocytes in MUM.
Main Methods:
- Whole-genome sequencing of metastatic uveal melanoma tumors and infiltrating lymphocytes.
- Functional reintroduction of BAP1 in patient-derived cell lines.
- Focused knockdown screen for overexpressed genes.
- Analysis of immune checkpoint receptor expression.
Main Results:
- BAP1 alterations were identified in 29/32 (91%) of metastatic uveal melanoma cases.
- Restoring BAP1 function induced a transcriptomic shift towards a subtype associated with better primary disease prognosis.
- One outlier tumor exhibited high mutational burden linked to UV damage.
- CDKN2A deletions were observed, which are rare in primary uveal melanoma.
- Tumor-infiltrating lymphocytes were tumor-reactive, with abundant expression of immune checkpoint receptors (TIM-3, TIGIT, LAG3).
Conclusions:
- BAP1 alterations are a key feature of metastatic uveal melanoma, and their restoration may reverse transcriptomic profiles towards a more favorable subtype.
- The genomic landscape of metastatic uveal melanoma includes UV-damage mutational signatures and CDKN2A deletions.
- Immune checkpoint receptor expression on tumor-infiltrating lymphocytes suggests potential for immunotherapy, despite challenges.
