Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Abstract

SUMMARY Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1 -mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low-versus intermediate-risk clinical mutation subtypes.

A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases

“…WGS profiling and SV calling was carried for individual TCGA projects as previously described (Cancer Genome Atlas Network, 2012, 2015a, 2015b; Cancer Genome Atlas Research Network, 2014a, 2014b, 2015a, 2015b, 2017a, 2017b; Cancer Genome Atlas Research Network et al, 2013a; Chen et al, 2016; Davis et al, 2014; Robertson et al, 2017), as well as detailed in the Supplemental Experimental Procedures. Previous studies show that on the order of 96%–98% of high-confidence SVs from high-pass WGS data detected by the Meerkat algorithm are able to be validated by PCR (Davis et al, 2014; Yang et al, 2013).…”

“…With TCGA gene expression data, large-scale integration between WGS and expression data is possible. TCGA WGS data were generated with either low-depth-of-coverage (low pass) or high-depth-of-coverage (high pass), with both types of WGS being used effectively to identify SVs in previous TCGA consortium-led studies focusing on a specific cancer type (Cancer Genome Atlas Network, 2012, 2015a, 2015b; Cancer Genome Atlas Research Network, 2013, 2014a, 2014b, 2015b, 2017a, 2017b; Davis et al, 2014; Robertson et al, 2017). While low-pass WGS may involve decreased sensitivity of detection, >1,200 cases in TCGA have low-pass data, representing a rich resource, with no pan-cancer study to date using these data.…”

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

“…UM is characterized by distinct gross chromosomal abnormalities that are associated with patient outcome, the most common being monosomy 3 (M3), which corresponds with a significantly worse prognosis 8, 9, 10, 11, 12. M3 is frequently accompanied by polysomy 8q, and increasing copies of 8q significantly correlate with reduced survival, in a dose‐dependent fashion 8, 10, 13, 14.…”

“…Further abnormalities described in UM include loss of 1p, which is associated with poor prognosis in the context of M3 15, and gains on 6p, which, in the absence of additional chromosomal abnormalities, correspond with a good prognosis 16, 17. More recently, mutations occurring in UM have been identified in several genes, including GNAQ , GNA11 , BAP1 , SF3B1 , EIF1AX , PLCB4 , and CYSLTR2 11, 18, 19, 20, 21, 22. In particular, inactivating BAP1 mutations are associated with a poor outcome, being present in ∼84% of all UMs that went on to produce metastases 19, 23, 24.…”

A pilot study of intrahepatic yttrium‐90 microsphere radioembolization in combination with intravenous cisplatin for uveal melanoma liver‐only metastases

“…Uveal melanoma is the most common primary intraocular malignancy in adults and is both clinically and genomically distinct from cutaneous melanoma. 1 Despite successful local therapy, almost half of all patients develop metastases, with the majority relapsing in the liver. 2 Unlike cutaneous melanoma, there are no effective systemic treatments for metastatic uveal melanoma, and indeed, there is no defined standard of care.…”