Next-generation sequencing of uveal melanoma for detection of genetic alterations predicting metastasis

Abstract

Purpose : To clinically utilize a pan-cancer, targeted next-generation sequencing assay in uveal melanoma, and to correlate results with gene expression profiling and predictive factors for metastasis.

Methods : Cohort study. Tumor samples of adult UM patients were analyzed with the UCSF500 60 and GEP. Main outcomes were copy number changes in chromosomes 1, 3, 6 and 8 and mutations in GNAQ, GNA11, SF3B1, EIF1AX, BAP1, SRSF2, U2AF1 and PLCB4. Chromosome 3 loss (a metastasis predictor) was tested for correlation with GEP class, tumor characteristics (largest basal diameter, thickness, ciliary body involvement, extraocular extension) and histology (presence of epithelioid cells, closed loops, mitotic count).

Results : The 62 patients had a mean age of 58.6 years (range, 24 – 88). Chromosome 3 loss was detected in 30 and was associated with larger basal tumor diameter (Wilcoxon test, p=0.015), higher thickness (Wilcoxon test, p=0.016) and TNM stage (Fisher test, p=0.006), epithelioid cytology (Fisher test, p=4*10-6), BAP1 mutation (Fisher test, p=8*10-12) and chromosome 8q gain (Fisher test, p=10*10-9). Class 2 tumors were much more likely to have chromosome 3 loss compared to Class 1 (odds ratio, 121; p=6*10-10). Eleven patients developed metastatic UM, of which five died during the study. All metastatic cases had chromosome 3 loss, 8 gain, BAP1 mutation and Class 2 GEP. Five Class 1 tumors had chromosome 3 loss.

Conclusions : A targeted, next-generation sequencing assay detected chromosomal copy number changes and missense mutations that correlate strongly with metastasis predictors in uveal melanoma, including gene expression profiling results.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.