Heterogeneity revealed by integrated genomic analysis uncovers a molecular switch in malignant uveal melanoma

Lange, Mark; Pelt, Sake I. van; Versluis, Mieke; Jordanova, Ekaterina S.; Kroes, Wilma G. M.; Ruivenkamp, Claudia; Burg, Sjoerd H. van der; Luyten, Gregorius P M; Hall, Thorbald van; Jager, Martine J.; Velden, Pieter A. van der

doi:10.18632/oncotarget.5637

Cited by 47 publications

(68 citation statements)

References 32 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our cohort, immune infiltrates were highly correlated with upregulation of chemotactic signals (e.g., CXCL9 and CXCL13) and of stimulators and targets (e.g., IFNG and HLA) that are essential in T cell-mediated immune therapies. Also in contrast with other cancers, an increased HLA class I expression has been associated with a worse prognosis in UM (de Lange et al, 2015), and is considered a tumor-escape mechanism from natural killer cell-mediated cytotoxicity in blood (Jager et al, 2002). The increased HLA class I expression in poor-prognosis UM is likely induced by infiltrating cytotoxic T cells (van Essen et al, 2016); however, the molecular immune profile of these tumors is consistent with a chronically inflamed milieu in which either T cells are more immunosuppressive (regulatory T cells) and/or cytotoxic T cells have been rendered dysfunctional (Bronkhorst et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Robertson¹,

Shih²,

Yau³

et al. 2017

Cancer Cell

Self Cite

660

681

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Robertson¹,

Shih²,

Yau³

et al. 2017

Cancer Cell

Self Cite

660

681

View full text Add to dashboard Cite

show abstract

“…Besides chromosome status, gene-expression profiling has become a valuable tool for prognostication in UM. 36,37 As it closely corresponds to chromosome 3 status, it is likely that addition of the AJCC stage could improve the prognostic value of gene-expression profiling as well. The idea that AJCC staging could refine prognostication by gene-expression analysis has already been proposed by Kivelä and Kujala in 2013.…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Value of AJCC Staging in Uveal Melanoma Is Enhanced by Adding Chromosome 3 and 8q Status

Doğrusöz

Bagger

Duinen

et al. 2017

Invest. Ophthalmol. Vis. Sci.

Self Cite

View full text Add to dashboard Cite

Citation: Dogrusöz M, Bagger M, van Duinen SG, et al. The prognostic value of AJCC staging in uveal melanoma is enhanced by adding chromosome 3 and 8q status. Invest Ophthalmol Vis Sci. 2017;58:833-842. DOI:10.1167/ iovs.16-20212 PURPOSE. The American Joint Committee on Cancer (AJCC) staging system has been validated for use as a prognostic parameter in uveal melanoma (UM). We studied whether adding information regarding chromosome 3 and 8q status further enhances the prognostic value of this staging system. METHODS.We retrospectively studied a cohort of 522 patients who had been treated for UM in two different centers between 1999 and 2015. The mean follow-up time was 47.7 months. Cumulative incidence curves were generated and regression analyses were performed for different combinations of AJCC staging and chromosome status. Death due to UM metastases was the primary endpoint.RESULTS. In AJCC stage I cases, only patients with monosomy 3 as well as chromosome 8q gain died due to UM metastases (P < 0.001). Among patients with stage II and III tumors, those with monosomy 3 plus gain of chromosome 8q had the worst prognosis, whereas the clinical outcome of those with only one of these aberrations was intermediate (P < 0.001). Patients without monosomy 3 and 8q gain showed favorable prognosis, independent of their tumor's AJCC stage. In cases with monosomy 3, 8q gain, or both, adding AJCC stage improved the predictive value. Multivariable regression analyses demonstrated that AJCC staging and chromosome 3 and 8q status contain independent information about survival status.CONCLUSIONS. Combining information on AJCC staging and chromosome 3 and 8q status allows a more accurate prognostication in UM. We conclude that the prognostic value of the AJCC staging system can be improved by adding information regarding chromosome 3 and 8q status.

show abstract

“…PRAME RNA expression was measured on the Illumina HT-12v4 chip (Illumina) using probe ILMN_1700031. 21 Expression data for disomy 3 UMs were included in a previous publication. 15 …”

Section: Methodsmentioning

confidence: 99%

PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma

et al. 2017

Self Cite

View full text Add to dashboard Cite

IMPORTANCE Uveal melanoma (UM) is an intraocular primary malignant neoplasm that often gives rise to metastatic disease for which there are no effective therapies. A substantial proportion of UMs express the cancer-testis antigen PRAME (preferentially expressed antigen in melanoma), which can potentially be targeted by adoptive T-cell therapy.OBJECTIVE To determine whether there may be a rationale for PRAME-directed T-cell therapy for metastatic UM.DESIGN, SETTING, AND PARTICIPANTS An experimental study using a retrospective cohort of 64 patients with UM (median follow-up, 62 months) was conducted from January 8, 2015, to November 20, 2016, at the Leiden University Medical Center. Clinical, histopathologic, and genetic parameters were compared between 64 PRAME-positive and PRAME-negative UMs. HLA class I restricted, PRAME-specific T cells were stimulated with UM cell lines to measure their antigen-specific reactivity against these cell lines, which were analyzed for PRAME expression by real-time quantitative polymerase chain reaction. Uveal melanoma metastases from 16 unrelated patients were assessed for PRAME expression by messenger RNA fluorescence in situ hybridization and for HLA class I expression by immunofluorescence staining.MAIN OUTCOMES AND MEASURES Interferon γ production for antigen-specific reactivity and detection of PRAME and HLA class I expression in primary and metastatic UM. RESULTSOf the 64 patients in the study (31 women and 33 men; mean [SD] age at the time of enucleation, 60.6 [15.6] years), PRAME expression was negative in 35 primary UMs and positive in 29 primary UMs. Positive PRAME expression was associated with a high largest basal diameter (15.0 vs 12.0 mm; P = .005), ciliary body involvement (59% vs 26%; P = .008), and amplification of chromosome 8q (66% vs 23%; P = .002). PRAME-specific T cells reacted against 4 of 7 UM cell lines, demonstrating that T-cell reactivity correlated with PRAME expression. Metastatic UM samples were positive for PRAME messenger RNA in 11 of 16 patients and for HLA class I in 10 of 16 patients, with 8 of 16 patients demonstrating coexpression of both PRAME and HLA class I.CONCLUSIONS AND RELEVANCE PRAME is expressed in many primary and metastatic UMs, and about half of the metastatic UMs coexpress PRAME and HLA class I. The finding that PRAME-specific T cells in this study reacted against PRAME-positive UM cell lines suggests a potential role for PRAME-directed immunotherapy for selected patients with metastatic UM.

show abstract

Heterogeneity revealed by integrated genomic analysis uncovers a molecular switch in malignant uveal melanoma

Cited by 47 publications

References 32 publications

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

The Prognostic Value of AJCC Staging in Uveal Melanoma Is Enhanced by Adding Chromosome 3 and 8q Status

PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma

Contact Info

Product

Resources

About