Next-Generation Sequencing of Uveal Melanoma for Detection of Genetic Alterations Predicting Metastasis - PubMed (original) (raw)
Next-Generation Sequencing of Uveal Melanoma for Detection of Genetic Alterations Predicting Metastasis
Armin R Afshar et al. Transl Vis Sci Technol. 2019.
Abstract
Purpose: To clinically use the UCSF500, a pancancer, next-generation sequencing assay in uveal melanoma (UM) and to correlate results with gene expression profiling (GEP) and predictive factors for metastasis.
Methods: Cohort study. Tumor samples of adult UM patients were analyzed with the UCSF500 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, and extraocular extension), and histology (presence of epithelioid cells, closed loops, and mitotic count).
Results: The 62 patients had a mean age of 59 years (range, 24-89 years). Chromosome 3 loss was detected in 30 patients and was associated with larger basal tumor diameter (Wilcoxon rank sum test, P = 0.015), greater thickness (Wilcoxon rank sum test, P = 0.016) and tumor, node, metastasis stage (Fisher test, P = 0.006), epithelioid cytology (Fisher test, P < 0.001), BAP1 mutation (Fisher test, P < 0.001), and chromosome 8q gain (Fisher test, P < 0.001). Class 2 tumors were much more likely to have chromosome 3 loss than class 1 (odds ratio, 121; P < 0.001). 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: UCSF500 detects chromosomal copy number changes and missense mutations that correlate strongly with metastasis predictors, including GEP.
Translational relevance: Next-generation sequencing of UM should enhance survival prognostication.
Keywords: choroidal melanoma; next generation sequencing; prognostication; uveal melanoma.
Figures
Figure 1
Tiling plot including clinical, histopathologic, and genetic features for all patients.
Figure 2
Genome-wide copy number profiles for two representative cases. Shown are the raw log2 ratios of the normalized bin counts from CNVKit (y-axis) along genomic coordinates (x-axis) with segments obtained by circular binary segmentation (black lines) Top: Copy number alterations include losses of chromosomes 3, 8p, and 16q and gain of 8q in a UM that also carried a GNAQ p.Q209P and a truncating BAP1 p.Q4* mutation. Bottom: Copy number gains of 6p and 21 in a tumor with an GNAQ p.Q209L mutation.
Figure 3
Kaplan-Meier curves demonstrating time to metastasis. Top: Time to metastasis in patients according to chromosome 3 loss, detected with the UCSF500 assay. Middle: Time to metastasis in patients with combination of chromosome 3 loss, 8 gain and BAP1 mutation, and time to metastasis with at least one of these three genetic features absent. Bottom: Time to metastasis in patients according to GEP class (class 1 vs. class 2).
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