Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma.

By A. G. Robertson, J. Shih, C. Yau, E. Gibb, Junna Oba, K. Mungall, Julian M. Hess, Vladislav Uzunangelov, Vonn Walter, Ludmila V. Danilova and 160 more. Cancer Cell, 2018

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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 intermedi-ate-risk clinical mutation subtypes. revealed by applying standard SNP/indel algorithms to next-generation sequencing data, suggesting that many BAP1 alterations are undetected using current techniques. We show that poor-prognosis UM initially develop monosomy 3 (M3), followed by BAP1 alterations that are associated with a unique global DNA methylation proﬁle. Despite this shared methylation state, poor-prognosis M3-UM separated into two subsets by copy number alterations, RNA (mRNA/lncRNA/miRNA) expression, and cellular pathway activity proﬁles. Our integrated analysis reveals that the somatic copy number and associated gene expression subtypes correlate with differential clinical outcomes. Our ﬁndings reveal four distinct molecular and clinical UM proﬁles, emphasizing the need for stratiﬁed UM patient management. All clinical outcome events were calculated using the time interval in days from the date of the pathologic diagnosis of primary tumor to either the date of documented metastatic disease (UM metastasis), death (UM survival), or last follow-up, censored to 5 years. Kaplan-Meier (KM) analysis for UM-speciﬁc death (n=77), UM-speciﬁc metastasis (n=70), and UM-speciﬁc metastasis or death (n=77) was performed using the survival R package, and log-rank testing was used to compare curves. For genes, sample groups with low vs. high expression were generated by thresholding at the median expression level. orientations consistent with formation of a sense–sense chimera. Junction-spanning reads are detected by constructing a sequence database that holds all possible exon-exon junctions that match the 3 0 end of one gene fused to 5 0 end of a second gene. Unmapped reads aligned to the database of all hypothetical exon junctions created by using the Ensembl transcriptome reference. Only reads for which the mate pair maps to either of the two fusion partner genes are considered as fusion transcripts. In this study, we extracted fusions with (1) at least two discordant read pairs, (2) at least one junction spanning read and (3) without high gene homology between each fusion gene partner (BLAST E-value > 0.001). Next, we applied the concept of mutation allele fraction to RNA sequencing data, and calculated the ratio of junction-spanning reads to the total number of reads crossing over the junction point in the reference transcript. We used the transcript allele fraction (TAF) to exclude artifacts that depend on highly expressed transcripts. We included fusion transcripts showing TAF > 0.01 of both genes in our fusion list. In addition, we ﬁltered out fusions that are found in normal TCGA samples. DNA (1,000 ng) for each sample was treated with sodium bisulﬁte, recovered using the Zymo EZ DNA methylation kit (Zymo Research, Irvine, CA) according to the manufacturer’s speciﬁcations and eluted in 18 ul volume. After passing quality control, bisulﬁte-converted DNA samples were whole-genome ampliﬁed followed by enzymatic fragmentation and hybridized overnight to BeadChips followed by a locus-speciﬁc base extension with labeled nucleotides (cy3 and cy5). BeadArrays are scanned and the raw data are imported into custom R programs for pre-processing and calculation of DNA methylation beta value for each probe and sample. Quality control and probe ex-clusions were done using standard

Subfields: Cancer Research, Cell Biology, Ophthalmology

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Citations in the corpus

Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients (2018, background): “, 2017), uveal melanoma (Robertson et al., 2017), and glioblastoma (Marcelino Meliso et al.”
Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer (2018, background): “…of stemness, attesting to their underlying molecular heterogeneity, as previously reported (Cancer Genome Atlas Network, 2015; Cancer Genome Atlas Research Network, 2011, 2012, 2014a, 2014b, 2015a, 2015b, 2017; Cancer Genome Atlas Research Network et al., 2013a, 2013b; Robertson et al., 2017).”