Recurrent inactivating RASA2 mutations in melanoma

Arafeh, Rand; Qutob, Nouar; Emmanuel, Rafi; Keren-Paz, Alona; Madore, Jason; Elkahloun, Abdel G.; Wilmott, James S.; Gartner, Jared J.; Pizio, Antonella Di; Winograd‐Katz, Sabina; Sindiri, Sivasish; Rotkopf, Ron; Dutton‐Regester, Ken; Johansson, Peter; Pritchard, Antonia L.; Waddell, Nicola; Hill, Victoria; Lin, Jimmy C.; Hevroni, Yael; Rosenberg, Steven A.; Khan, Javed; Ben‐Dor, Shifra; Niv, Masha Y.; Ulitsky, Igor; Mann, Graham J.; Scolyer, Richard A.; Hayward, Nicholas K.; Samuels, Yardena

doi:10.1038/ng.3427

Cited by 96 publications

(83 citation statements)

References 24 publications

(35 reference statements)

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“…We have shown recently that PDX derived from BRAF inhibitor relapsed patients and expanded on chronic therapy could be used to identify effective second line combination therapies based on genomic and proteomic profiling (Krepler et al, 2016). While these studies demonstrate the feasibility of the PDX approach, the melanoma TCGA and other studies (Arafeh et al, 2015; Cancer Genome Atlas, 2015; Krauthammer et al, 2015) highlight the pronounced heterogeneity of this cancer type. Both concepts are combined here in an unparalleled collection of 459 mutationally and clinically diverse melanoma PDX and live frozen tissues, providing an exhaustive and testable resource for the melanoma research field.…”

Section: Introductionmentioning

confidence: 72%

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

et al. 2017

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Summary Therapy of advanced melanoma has been changing dramatically. Following mutational and biological sub-classification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays, and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.

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Section: Introductionmentioning

confidence: 72%

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

et al. 2017

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“…Using the most stringent approaches to distinguish driver versus passenger mutations by the InVEx procedure [29], TCGA analysis identified 13 core genes (BRAF, NRAS, TP53, NF1, CDKN2A, ARID2, PTEN, PPP6C, RAC1, IDH1, DDX3X, MAP2K1, and RB1) of which IDH1 and DDX3X were the only novel significant genes identified by this study. Two subsequent whole-exome studies in melanoma identified loss of function mutations in RASA2, encoding a GTPase activating protein for RAS, in 4% of cutaneous melanomas, suggesting its role as a key driver gene in melanoma and particularly in NF1-mutated tumors [32,44]. RASA2 mutations result in RAS activation, leading to increased proliferation and migration of melanoma cells and poorer overall survival of stage III melanoma patients [44].…”

Section: Novel Driver Genes Revealed By Genomic Approachesmentioning

confidence: 98%

“…Two subsequent whole-exome studies in melanoma identified loss of function mutations in RASA2, encoding a GTPase activating protein for RAS, in 4% of cutaneous melanomas, suggesting its role as a key driver gene in melanoma and particularly in NF1-mutated tumors [32,44]. RASA2 mutations result in RAS activation, leading to increased proliferation and migration of melanoma cells and poorer overall survival of stage III melanoma patients [44]. The prognostic significance of most of these newly identified driver genes in cutaneous melanoma is still largely unknown, and need to be explored.…”

Section: Novel Driver Genes Revealed By Genomic Approachesmentioning

confidence: 99%

Contemporary and potential future molecular diagnosis of melanoma

Gandolfi¹,

Dallaglio²,

Longo

et al. 2016

Expert Review of Molecular Diagnostics

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We reviewed the most recent publications about the biology of cutaneous melanoma, to provide an overview of the most recent insights into the complexity of this tumor and their potential impact in the clinical settings. Expert commentary: Starting from the first attempts to provide a molecular classification of melanoma, it has been evident that this tumor represents a widely heterogeneous disease. This complexity and the multivariate nature of melanoma represent a major obstacle in developing the best management strategies for patients.

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“…NF1 encodes Neurofibromin 1, a Ras-GAP, that switches the Ras protein from its active GTP-bound state into its inactive GDPbound state, thereby turning off MAPK signalling promoted proliferation 45 . Inactivating NF1 mutations are found at high frequency not only in Neurofibromatosis 1 46 but also in a variety of cancers like melanoma 47,48 , glioblastoma 49,50 and ovarian cancer 51 . We first confirmed by qRT-PCR that SPRED2 mRNA levels following CRISPRa mediated gene activation were almost identical in K562 cells with or without NF1 (Fig.…”

Section: Spred2 Sensitises Cells Through Nf1mentioning

confidence: 99%

Decoding directional genetic dependencies through orthogonal CRISPR/Cas screens

Boettcher

Tian

Blau

et al. 2017

Preprint

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SummaryGenetic interaction studies are a powerful approach to identify functional interactions between genes. This approach can reveal networks of regulatory hubs and connect uncharacterised genes to well-studied pathways. However, this approach has previously been limited to simple gene inactivation studies. Here, we present an orthogonal CRISPR/Cas-mediated genetic interaction approach that allows the systematic activation of one gene while simultaneously knocking out a second gene in the same cell. We have developed this concept into a quantitative and scalable combinatorial screening platform that allows the parallel interrogation of hundreds of thousands of genetic interactions. We demonstrate that the established platform works robustly to uncover genetic interactions in human cancer cells and to interpret the direction of the flow of genetic information.peer-reviewed)

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Recurrent inactivating RASA2 mutations in melanoma

Cited by 96 publications

References 24 publications

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

Contemporary and potential future molecular diagnosis of melanoma

Decoding directional genetic dependencies through orthogonal CRISPR/Cas screens

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