Uveal Melanoma — QIMR 2016

Overview

Whole-genome (n=14 primary tumors) and whole-exome (n=14: 9 tumors + 5 primary tumor-derived cell lines) sequencing of 28 untreated uveal melanoma (UM) samples with matched germline (blood or saliva) from QIMR Berghofer Medical Research Institute. The study focused on identifying novel driver mutations beyond the canonical GNAQ, GNA11, EIF1AX, SF3B1, and BAP1. Reference genome GRCh37 (hg19); alignment with BWA + GATK; annotation with ANNOVAR.

Composition

  • 28 untreated UM samples with matched germline:
  • Cancer type: UM (uveal melanoma).
  • Low mutation burden: mean 10.6 protein-changing mutations/sample (0.50/Mb).

Assays / panels (linked)

Papers using this cohort

  • PMID:26683228 — Johansson et al. 2016, “Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4,” Oncotarget.

Notable findings derived from this cohort

  • Recurrent PLCB4 p.D630Y (c.G1888T) hotspot identified in 2/28 samples, mutually exclusive with GNAQ/GNA11 mutations; proposed gain-of-function driver in the Gαq signaling pathway PMID:26683228.
  • Canonical UM drivers confirmed: GNA11 p.Q209P (14 samples), GNAQ p.Q209P/p.G48L (8 samples), BAP1 truncating/splice/missense mutations (11 samples), SF3B1 mutations (3 samples), EIF1AX mutations (4 samples, mutually exclusive with BAP1) PMID:26683228.
  • 79% of samples carry COSMIC signature 3 (BRCA/defective DSB repair); no UV signature (COSMIC signature 7) detected in any sample PMID:26683228.
  • Monosomy 3 or copy-neutral LOH of chromosome 3 in 8/14 WGS samples (57%); all 6 BAP1-mutant samples were hemizygous for chromosome 3 PMID:26683228.
  • 8q gain is a late event: 93% of mutations on gained 8q arose before the duplication (bimodal VAF analysis) PMID:26683228.

Sources

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