Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Nature medicine (Impact Factor: 27.36). 07/2010; 16(7):793-8. DOI: 10.1038/nm.2166
Source: PubMed


Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers, suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement-negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.

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    • "Several high-risk tumors expressed unique, but potentially functional, non-ETS fusions. Non-ETS fusion transcripts have been previously identified in prostate tumors [39–41], but have been understudied due to their non-recurrence, and the predicted loss-of-function of the vast majority. Their clinical relevance requires further elucidation, and much will be revealed through transcriptome sequencing of advanced prostate tumors underway as part of the SU2C Dream Team efforts. "
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    ABSTRACT: Background Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly at the individual tumor level. We selected a cohort of 25 high-risk prostate tumors, representing the lethal phenotype, and applied deep RNA-sequencing and matched whole genome sequencing, followed by detailed molecular characterization.ResultsTen tumors were exposed to neo-adjuvant hormone therapy and expressed marked evidence of therapy response in all except one extreme case, which demonstrated early resistance via apparent neuroendocrine transdifferentiation. We observe high inter-tumor heterogeneity, including unique sets of outlier transcripts in each tumor. Interestingly, outlier expression converged on druggable cellular pathways associated with cell cycle progression, translational control or immune regulation, suggesting distinct contemporary pathway affinity and a mechanism of tumor stratification. We characterize hundreds of novel fusion transcripts, including a high frequency of ETS fusions associated with complex genome rearrangements and the disruption of tumor suppressors. Remarkably, several tumors express unique but potentially-oncogenic non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression. Finally, one ETS-negative tumor has a striking tandem duplication genotype which appears to be highly aggressive and present at low recurrence in ETS-negative prostate cancer, suggestive of a novel molecular subtype.Conclusions The multitude of rare genomic and transcriptomic events detected in a high-risk tumor cohort offer novel opportunities for personalized oncology and their convergence on key pathways and functions has broad implications for precision medicine.
    Full-text · Article · Aug 2014 · Genome Biology
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    • "It was also reported that rearrangements in the rapidly accelerated fibrosarcoma (RAF) pathway also occur in advanced prostate cancer (SLC45A3-BRAF, ESRP1-RAF1), which can be targeted by RAF kinase inhibitors.59 Moreover, a recent study was able to identify a median of 90 rearrangements in seven prostate cancer tumor samples.60 "
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    ABSTRACT: In recent years, facilitated by rapid technological advances, we are becoming more adept at probing the molecular processes, which take place in the nucleus, that are crucial for the hierarchical regulation and organization of chromatin architecture. With an unprecedented level of resolution, a detailed atlas of chromosomal structures (histone displacement, variants, modifications, chromosome territories, and DNA looping) and mechanisms underlying their establishment, provides invaluable insight into physiological as well as pathological phenomena. In this review, we will focus on prostate cancer, a prevalent malignancy in men worldwide, and for which a curative treatment strategy is yet to be attained. We aim to catalog the most frequently observed oncogenic alterations associated with chromatin conformation, while emphasizing the TMPRSS2-ERG fusion, which is found in more than one-half of prostate cancer patients and its functions in compromising the chromatin landscape in prostate cancer.
    Full-text · Article · May 2014 · The Application of Clinical Genetics
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    • "Among ETS fusion-negative tumors, mutations in the speckle-type POZ protein (SPOP) are found in 6%–13%,32 mutations in the chromodomain helicase deoxyribonucleic acid binding protein 1 (CHD1) in 5%–10%33 and overexpression of the serine peptidase inhibitor, Kazal type 1 (SPINK1) in ~10%.34 Relatively rare fusions involving RAF kinases are found in ~1% of ETS-negative prostate tumors and are hypothesized to constitute yet another molecular subclass.35 These alterations provide valuable insights into the molecular basis of PCa heterogeneity, and in some cases may provide diagnostic and prognostic benefit.36 "
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    ABSTRACT: Alternative splicing (AS) is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer (PCa) AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa: androgen receptor (AR) and phosphoinositide 3-kinase (PI3K). These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.
    Full-text · Article · May 2014 · Asian Journal of Andrology
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