Cooperative Epigenetic Modulation by Cancer Amplicon Genes

Li, Rui; Emre, N. C. Tolga; Kruhlak, Michael J.; Chung, Hye Jung; Steidl, Christian; Slack, Graham W.; Wright, George W.; Lenz, Georg; Ngo, Vu N.; Shaffer, Arthur L.; Xu, Weihong; Zhao, Hong; Yang, Yandan; Lamy, Laurence; Davis, R. Eric; Xiao, Wenming; Powell, John; Maloney, David J.; Thomas, Craig J.; Möller, Peter; Rosenwald, Andreas; Ott, German; Müller‐Hermelink, Hans Konrad; Savage, Kerry J.; Connors, Joseph M.; Rimsza, Lisa M.; Campo, Elı́as; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Weisenburger, Dennis D.; Chan, Wing C.; Gascoyne, Randy D.; Levens, David; Staudt, Louis M.

doi:10.1016/j.ccr.2010.11.013

Cited by 260 publications

(263 citation statements)

References 52 publications

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“…Our results demonstrate that FXR1 is a critical member of this large amplicon (176 genes included between 3q26-29) and contributes to the pathogenesis of lung cancer. The single gene driver theory has been challenged by recent studies (26,27), supporting that in fact multiple oncogenes work in concert to drive the cancer, sometime as a driver, sometime a passenger gene. Genomic amplifications happen in different size (Mb) and intensity (copy number between 4 and 25).…”

Section: Discussionmentioning

confidence: 99%

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Qian

Hassanein

Hoeksema

et al. 2015

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

111

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Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.

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Section: Discussionmentioning

confidence: 99%

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Qian

Hassanein

Hoeksema

et al. 2015

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

111

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“…We and others have performed large scale, lossof-function short hairpin RNA (shRNA) screens to identify essential cancer genes and recently reported PAX8 and ID4 as ovarian cancer dependencies (4,5). In other cancer types, both genome-wide and targeted loss-of-function studies were used to identify novel tumor suppressors in hepatocellular carcinoma (6) and epigenetic regulators in lymphomas (7). In addition, gain-offunction, cDNA-based approaches have uncovered novel driver roles for IKBKE (8) and PAK1 (9) in breast cancer, ERBB3 in endometrial cancer (10), and FGF19 in hepatocellular cancer (11).…”

mentioning

confidence: 99%

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

Dunn

Cheung

Agarwalla

et al. 2014

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

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Significance High-grade serous ovarian cancers are characterized by widespread gain and loss of copy number involving large numbers of genes; however, the functional consequences of many of these changes remain unclear. To determine which of the many amplified genes exhibited tumor-promoting behavior, we developed a novel in vivo method to systematically screen potential oncogenes for tumor formation. We identified GAB2, a signaling adaptor protein, as a potent oncogene that is also significantly amplified in ovarian and breast cancer. GAB2 overexpression activates the phosphatidylinositol 3-kinase (PI3K) pathway and confers sensitivity to PI3K pathway inhibition. These results credential GAB2 as a potent oncogene in ovarian cancer and emphasize the importance of PI3K signaling in this cancer.

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“…The activation of this pathway in ABC tumors seems to occur through BCR signaling with acquired activating mutations in elements of this pathway including CD79a, CARD11, and MYD88 and inactivating mutations of the NFkB inhibitor A20. 29,31 The clinical, pathological, and biological features of these two types of molecular DLBCL are different, supporting the idea that they may correspond to different entities (reviewed by J Said in this course). 41,42 Other expression profiling studies have identified alternative subgroups of DLBCL characterized by expression signatures related to potential pathogenetic mechanisms.…”

Section: Characterization Of Known Entities and Recognition Of New Camentioning

confidence: 66%

“…The simultaneous amplification and overexpression of these genes has an additive effect modulating the expression of several genes including MYC. 31 Interestingly, these tumors also have deletions in 16p13 associated with inactivating mutations of SOCS1, a negative regulator of JAK2. 32 SOCS1 inactivation by biallelic mutations or mutations and deletions promotes the activity of JAK2.…”

Section: Platformsmentioning

confidence: 99%

Whole genome profiling and other high throughput technologies in lymphoid neoplasms—current contributions and future hopes

Campo

2013

Modern Pathology

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The development of high throughput technologies based on the knowledge of the human genome has opened the possibility to search for global genomic alterations in tumors responsible for their development and progression that may have important clinical implications. One of the major applications of this genomic knowledge has been the design of different types of microarray platforms for the analysis of DNA alterations and gene expression profiling (GEP). The main contributions of the DNA studies in lymphoid neoplasms include the definition of relatively characteristic genomic profiles for specific disease entities, the demonstration of common chromosomal alterations across entities, the identification of genes and pathways targeted by the altered chromosomal regions, and the identification of chromosomal alterations with prognostic implications. RNA GEP studies in these tumors have enhanced the molecular characterization of known entities and facilitated the recognition of new subtypes and categories of lymphoid neoplasms, the identification of new biomarkers and prognostic models, and the detection of oncogenic pathways with potential implications for targeted therapies. The recent development of the next generation sequencing (NGS) technologies and its application in lymphoid neoplasms already have provided an initial view of the complex landscape of somatic mutations in these tumors and some findings with important functional and clinical implications. This review addresses the major contributions and limitations of the microarray technologies in the understanding of lymphoid neoplasms and discusses how this knowledge may be transferred into the clinics. The initial results of the NGS studies are also presented.

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Cooperative Epigenetic Modulation by Cancer Amplicon Genes

Cited by 260 publications

References 52 publications

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

Whole genome profiling and other high throughput technologies in lymphoid neoplasms—current contributions and future hopes

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