Next-generation sequencing of uveal melanoma with clinical and histological correlations: Prognostic value of new mutations in the PI3K/AKT/mTOR pathway

Clin Exp Ophthalmol. 2023 Nov;51(8):822-834. doi: 10.1111/ceo.14302. Epub 2023 Oct 6.


Background: Uveal melanoma (UM) is the eye's most common primary malignancy and there are no effective therapies for disseminated disease. It is important to try to know the patient's prognosis. The aim of this study was to reflect genetic variants, studied using NGS, of a series of 69 cases of UM and its correlation with histopathology and clinical progression.

Methods: We performed targeted NGS using a 519-gene panel.

Results: There were selected 28 different mutated genes, showing a total of 231 genetic variants that affected the function of the protein. The most common secondary mutations occurred in SF3B1 (in 26%), followed by BAP1 (in 23%), LRP1B (22%) and FGFR4 (20%). BAP1 mutation was associated with a greater likelihood of metastases and with greater presence of epithelioid cells. LRP1B was also associated with presence of epithelioid cells SF3B1 mutation was significantly associated with a spindle morphology. We found variants in the RAD51B, TOP2A, PTPRD, TSC2, DHX9, PDK1 and MTOR that have not been previously reported in consulted databases. The presence of a mutation in: CHEK2, DHX9 and PDK1 was associated with metastases.

Conclusions: BAP1 is the most solid biomarker of a poor prognosis in UM and mutations can be detected using NGS. SF3B1 is associated with the spindle cell subtype of UM, which gives it probably a favourable prognostic value. Our study suggests that mutations in DHX9 and PDK1 can have prognostic value. These potential biomarkers are related to the PI3K/AKT/mTOR pathway and makes them candidates for developing new directed therapies.

Keywords: BAP1; NGS; SF3b1 and PI3K/AKT/MTOR pathway; mutations; uveal melanoma.

MeSH terms

  • DNA Mutational Analysis
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mutation
  • Phosphatidylinositol 3-Kinases* / genetics
  • Prognosis
  • Proto-Oncogene Proteins c-akt / genetics
  • Tumor Suppressor Proteins / genetics
  • Uveal Neoplasms* / genetics


  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Tumor Suppressor Proteins

Supplementary concepts

  • Uveal melanoma

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