Developing gene expression signatures of pathway deregulation in tumors

Watters, James; Roberts, Christopher J.

doi:10.1158/1535-7163.mct-06-0340

Cited by 29 publications

(23 citation statements)

References 53 publications

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“…It also confirms that assessing entire signaling pathways, rather than individual genes, is highly informative with respect to cancer outcome prediction (Bild et al, 2006;Watters and Roberts, 2006;Liu and Ringner, 2007). For neuroblastoma in particular, combined analysis of multiple signaling networks has been successful and might benefit from the addition of other pathways, such as integrin signaling, to further increase prediction sensitivity (Fredlund et al, 2008).…”

Section: Discussionmentioning

confidence: 55%

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

et al. 2009

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Increased activity of MYC protein-family members is a common feature in many cancers. Using neuroblastoma as a tumor model, we established a microRNA (miRNA) signature for activated MYCN/c-MYC signaling in two independent primary neuroblastoma tumor cohorts and provide evidence that c-MYC and MYCN have overlapping functions. On the basis of an integrated approach including miRNA and messenger RNA (mRNA) gene expression data we show that miRNA activation contributes to widespread mRNA repression, both in c-MYCand MYCN-activated tumors. c-MYC/MYCN-induced miRNA activation was shown to be dependent on c-MYC/ MYCN promoter binding as evidenced by chromatin immunoprecipitation. Finally, we show that pathways, repressed through c-MYC/MYCN miRNA activation, are highly correlated to tumor aggressiveness and are conserved across different tumor entities suggesting that c-MYC/ MYCN activate a core set of miRNAs for cooperative repression of common transcriptional programs related to disease aggressiveness. Our results uncover a widespread correlation between miRNA activation and c-MYC/ MYCN-mediated coding gene expression modulation and further substantiate the overlapping functions of c-MYC and MYCN in the process of tumorigenesis.

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Section: Discussionmentioning

confidence: 55%

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

et al. 2009

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“…Recently several studies investigating deregulation of signaling pathways, rather than the importance of expression of individual genes, as central to cancer aggressiveness have been published (40)(41)(42)(43). These observations are particularly interesting in light of the development of small inhibitory molecules able to inhibit individual pathways, and it has been shown that pathway analysis can be used to identify appropriate targets for therapeutic intervention (40).…”

Section: Discussionmentioning

confidence: 99%

High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma

Fredlund

Ringnér

Maris

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

152

158

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The childhood cancer neuroblastoma arises in the developing sympathetic nervous system and is a genotypically and phenotypically heterogeneous disease. Prognostic markers of poor survival probability include amplification of the MYCN oncogene and an undifferentiated morphology. Whereas these features discriminate high-from low-risk patients with precision, identification of poor outcome low-and intermediate-risk patients is more challenging. In this study, we analyze two large neuroblastoma microarray datasets using a priori-defined gene expression signatures. We show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predicts relapse and death from disease. This was evident not only for high-risk patients but was also robust in identifying groups of poor prognosis patients who were otherwise judged to be at low-or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma.neuroblastoma ͉ pathway analysis ͉ MYCN ͉ Myc ͉ differentiation

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“…12 It is therefore plausible that RAS signaling deregulation is an important target of tipifarnib in AML regardless of RAS mutational status. 41 In support of this, Feldkamp et al demonstrated that isotype-specific RAS.GTP levels in brain tumors correlates with response to the FTI SCH66336 irrespective of RAS-activating mutations. 42 In addition, Bild et al recently showed that a gene-expression signature based on RAS overexpression could predict response to another FTI in vitro.…”

Section: Discussionmentioning

confidence: 92%

A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia

Raponi

Lancet

Fan³

et al. 2008

Blood

113

100

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At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib. IntroductionTipifarnib (R115777; ZARNESTRA, Janssen Ortho, Gurabo, Puerto Rico) was one of the first farnesyltransferase inhibitors (FTIs) to be tested in the clinic. 1 It has demonstrated significant activity in hematologic disorders, including acute myeloid leukemia (AML), multiple myeloma (MM), myelodysplastic syndrome (MDS), and chronic myelogenous leukemia (CML), with complete response rates in AML and MDS of up to approximately 15%. [2][3][4][5][6] FTIs function by competitively inhibiting the addition of a farnesyl moiety to a number of important signaling molecules, including RAS. 1,7 Historically, the mutation status of the RAS gene was considered to be a candidate biomarker for patient response to FTIs. This rationale was based on the finding that specific point mutations within RAS genes cause constitutive activation of the RAS pathway in many cancers, 8 and on preclinical evidence that FTIs could block RAS-transformed cells. 9,10 Since it is generally accepted that tumors are heavily reliant on the activation of 1 or 2 pathways ("oncogene addiction" hypothesis), it follows that patients whose tumors are promoted by aberrant expression of one or more components of those pathways should respond to drugs that inhibit those components. 11 However, pathways can be activated by multiple events, and it has been found that RAS can be up-regulated in the absence of activating RAS mutations. 12 Furthermore, no correlation between RAS mutations and response to FTIs has been demonstrated in clinical studies. 2,13 Indeed, while several early clinical studies focused on cancers that exhibited high frequencies of RAS mutations, the response rates to FTIs were disappointingly low in those trials. 3,14,15 Microarray technology has been used to identify gene expression profiles that are predictive of respo...

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Developing gene expression signatures of pathway deregulation in tumors

Abstract: Recent advances in our understanding

Cited by 29 publications

References 53 publications

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma

A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia

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