Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Robertson, A. Gordon; Shih, J.L.; Yau, Christina; Gibb, Ewan A.; Oba, Junna; Mungall, Karen; Heß, Julia; Uzunangelov, Vladislav; Walter, Vonn; Danilova, Ludmila; Lichtenberg, Tara M.; Kucherlapati, Melanie; Kimes, Patrick K.; Tang, Michael C Y; Penson, A.; Babur, Özgün; Akbani, Rehan; Bristow, C.A.; Hoadley, Katherine A.; Iype, Lisa; Chang, Matthew T.; Cherniack, Andrew D.; Benz, Christopher C.; Mills, Gordon B.; Verhaak, Roel G.W.; Griewank, Klaus G.; Felau, Ina; Zenklusen, Jean C.; Gershenwald, Jeffrey E.; Schoenfield, Lynn; Lazar, Alexander J.; Abdel‐Rahman, Mohamed H.; Roman‐Roman, Sergio; Stern, Marc-Henri; Cebulla, Colleen M.; Williams, Michelle D.; Jager, Martine J.; Coupland, Sarah E.; Esmaeli, Bita; Kandoth, Cyriac; Woodman, Scott E.

doi:10.1016/j.ccell.2017.12.013

Cited by 252 publications

(524 citation statements)

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“…Chang and colleagues reported that class 2 UM is strongly associated with genes upregulated in primitive neuroectodermal cells (Chang et al 2008). In support of this, nestin mRNA expression was identified in a panel of genes associated with time to metastasis both from the data generated by The Cancer Genome Atlas (TCGA) and also from their analysis of gene expression data previously generated by Laurent et al, although this association was not found to be significant when examining the hazard ratio and 95% CI (Laurent et al 2011;Robertson et al 2017). Of interest in our current study was the absence of nestin positivity in normal choroidal melanocytes as compared to its presence in UM cells, which may suggest reversion to a more primitive phenotype following UM cell transformation.…”

Section: Discussionmentioning

confidence: 90%

Nestin expression in primary and metastatic uveal melanoma – possible biomarker for high‐risk uveal melanoma

Djirackor

Shakir

Kalirai

et al. 2018

Acta Ophthalmologica

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Section: Discussionmentioning

confidence: 90%

Nestin expression in primary and metastatic uveal melanoma – possible biomarker for high‐risk uveal melanoma

Djirackor

Shakir

Kalirai

et al. 2018

Acta Ophthalmologica

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“…KDM6A (also known as UTX) is a core component of the ‘complex of proteins associated with SET1’ (COMPASS) and it has been shown to require BAP1 for its recruitment at chromatin enhancers . Inactivation of those genes has been reported to occur through different mechanisms, ranging from DNA methylation to complex DNA rearrangements , which can be missed by targeted DNA sequencing. IHC is a reliable method to assess the status of BAP1 , while IHC for KDM6A has been recently used to assess the status of KDM6A in PDAC .…”

Section: Resultsmentioning

confidence: 99%

“…BAP1 and KDM6A have been shown to interact at chromatin enhancers and disruption of this functional interaction in cancers drives malignancy through a mechanism that can be pharmacologically targeted . Inactivation of those genes has been reported to occur through different genetic and epigenetic mechanisms , which can be missed by targeted DNA sequencing approaches and often lead to the loss of functional proteins. In our cohort of SPNs, we found that a lack of or reduced expression of both KDM6A and BAP1 is enriched in metastatic cases, suggesting that their function is a barrier to the development of metastatic disease at least in a subset of SPNs.…”

Section: Discussionmentioning

confidence: 99%

Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas

Amato¹,

Mafficini²,

Hirabayashi

et al. 2018

The Journal of Pathology

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Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low‐grade malignant neoplasms that metastasise to the liver or peritoneum in 10–15% of cases. They almost invariably present somatic activating mutations of CTNNB1 . No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole‐exome sequencing and copy‐number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high‐coverage targeted sequencing of 409 genes. In addition to CTNNB1‐ activating mutations, we found inactivating mutations of epigenetic regulators ( KDM6A , TET1 , BAP1 ) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro‐proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α‐regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…in uterine carcinosarcoma) or variant morphology (e.g. squamous or neuroendocrine differentiation in urothelial bladder carcinoma) . These facets are of undoubted importance, both for quality control of the analysed data, and to provide morphological correlates to molecular findings that might assist in translating molecular findings to clinical diagnostics.…”

Section: Limitations Of Tcga and Pancancer Analysis Projectsmentioning

confidence: 99%

PanCancer insights from The Cancer Genome Atlas: the pathologist's perspective

Cooper

Demicco

Saltz

et al. 2018

The Journal of Pathology

183

140

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The Cancer Genome Atlas (TCGA) represents one of several international consortia dedicated to performing comprehensive genomic and epigenomic analyses of selected tumour types to advance our understanding of disease and provide an open-access resource for worldwide cancer research. Thirty-three tumour types (selected by histology or tissue of origin, to include both common and rare diseases), comprising >11 000 specimens, were subjected to DNA sequencing, copy number and methylation analysis, and transcriptomic, proteomic and histological evaluation. Each cancer type was analysed individually to identify tissue-specific alterations, and make correlations across different molecular platforms. The final dataset was then normalized and combined for the PanCancer Initiative, which seeks to identify commonalities across different cancer types or cells of origin/lineage, or within anatomically or morphologically related groups. An important resource generated along with the rich molecular studies is an extensive digital pathology slide archive, composed of frozen section tissue directly related to the tissues analysed as part of TCGA, and representative formalin-fixed paraffin-embedded, haematoxylin and eosin (H&E)-stained diagnostic slides. These H&E image resources have primarily been used to verify diagnoses and histological subtypes with some limited extraction of standard pathological variables such as mitotic activity, grade, and lymphocytic infiltrates. Largely overlooked is the richness of these scanned images for more sophisticated feature extraction approaches coupled with machine learning, and ultimately correlation with molecular features and clinical endpoints. Here, we document initial attempts to exploit TCGA imaging archives, and describe some of the tools, and the rapidly evolving image analysis/feature extraction landscape. Our hope is to inform, and ultimately inspire and challenge, the pathology and cancer research communities to exploit these imaging resources so that the full potential of this integral platform of TCGA can be used to complement and enhance the insightful integrated analyses from the genomic and epigenomic platforms.

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Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Cited by 252 publications

References 1 publication

Nestin expression in primary and metastatic uveal melanoma – possible biomarker for high‐risk uveal melanoma

Nestin expression in primary and metastatic uveal melanoma – possible biomarker for high‐risk uveal melanoma

Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas

PanCancer insights from The Cancer Genome Atlas: the pathologist's perspective

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