Integrative Genomic Analyses Identify BRF2 as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma

Lockwood, William W.; Chari, Raj; Coe, Bradley P.; Thu, Kelsie L.; Garnis, Cathie; Malloff, Chad A.; Campbell, John Y.; Williams, Ariane C.; Hwang, Dorothy; Zhu, Chang-Qi; Buys, Timon P.H.; Yee, John; English, John; MacAulay, Calum; Tsao, Ming‐Sound; Gazdar, Adi F.; Minna, John D.; Lam, Stephen; Lam, Wan L.

doi:10.1371/journal.pmed.1000315

Cited by 95 publications

(113 citation statements)

References 62 publications

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“…Importantly, previously identified lineage specific oncogenes including SOX2 and BRF2 were identified, validating our approach [17,47]. Although some of the regions and genes have previously been shown to be Figure 8.…”

Section: Discussionsupporting

confidence: 79%

“…These studies emphasize the capability and potential of SELDI for the detection and characterization of differentially expressed proteins or proteomic patterns for detection and prediction of diseases. For serum proteomics to realize its full potential, however, several potential problems and controversy in sensitivity and reproducibility concerning the SELDI profiling approach needs to be addressed (32,34,46,47). Semmes et al (48) has recently assessed the platform reproducibility using SELDI-mediated serum protein profiling for the detection of prostate cancer and demonstrated the reproducibility of SELDI serum profiling between laboratories and suggested that this approach could provide a reproducible diagnostic assay platform.…”

Section: Methodsmentioning

confidence: 99%

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PROSPECT: Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

Hong¹

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE June 2012 REPORT TYPE SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTWe will develop a high throughput therapeutic-target focused (TTF) profiling platform and will combine this with tumor genome wide mRNA profiling and with serum or plasma profiling of phosphopeptides and DNA. We will use these molecular profiles to help define how various molecular factors alone and in combination relate to resistance to therapy, to prognosis, and to metastatic patterns at relapse. Using tumor and blood samples from non-small cell lung cancer (NSCLC) patients as well as NSCLC cell lines with defined chemotherapy resistance patterns, we will examine how molecular profiles may confer resistance and will identify new, potential therapeutic targets. The PROSPECT approach will be novel in that we will assess tumors from NSCLC patients undergoing surgical resection after having received neoadjuvant therapy as a model of resistance. Tumor surviving neoadjuvant therapy would be expected to be enriched for resistant cells. We will define what combinations of targeted therapies are most effective against resistant cell lines with similar molecular profiles, and this will drive later clinical trials (beyond the scope of this Program). Similar studies will be conducted in patients with mesotheliomas undergoing surgical resection of tumor after neoadjuvant therapy with the new Src inhibitor dasatinib. SUBJECT TERMS Provided is our 2012 FINAL report of the DOD-funded research program PROSPECT (Profiling of Resistance Patterns and Oncogenic Signaling Pathways in Evaluation of Cancer of the Thorax and INTRODUCTIONLung cancer is the leading cause of cancer death in the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Only 15% of patients diagnosed with lung cancer survive five years from diagnosis. Therapy for advanced disease ...

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Section: Discussionsupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

PROSPECT: Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

Hong¹

2012

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“…1 F; Bild et al, 2006;Lockwood et al, 2010). Genomic loss of at least one copy of RBPJ was associated with significantly reduced transcript levels in primary lung tumors (Fig.…”

Section: Rbpj Deficiency Promotes Tumor Growthmentioning

confidence: 95%

Loss of the Notch effector RBPJ promotes tumorigenesis

Kulic¹,

Robertson²,

Chang³

et al. 2014

J Cell Biol

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“…Previous work had shown that Ubqln mRNA and protein levels are increased in primary lung adenocarcinomas, a cancer type that also features high BCLb protein levels (14,37). To build on these observations, we examined Ubqln mRNA in an independent set of 46 primary adenocarcinomas and matched normal lung samples (38). Both Ubqln probes demonstrated significantly increased mRNA levels in the primary adenocarcinoma samples compared to their corresponding normal lung samples (p < 0.0001 for both probes, shaded boxes correspond to "normal lung" samples, Fig.…”

mentioning

confidence: 99%

Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1

Beverly

Lockwood

Shah

et al. 2012

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

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We have previously shown that all six members of the anti-apoptotic BCL2 gene family can cooperate with (myelocytomatosis oncogene) MYC in a mouse model of leukemia, but three of them are significantly less potent contributors to leukemogenicity than the other three. The protein encoded by one of these less potent genes, BCL2L10∕BCLb, was recently shown to vary dramatically in many primary human cancers by immunohistochemistry, and the protein levels were inversely correlated with survival in patients with several cancer types. We examined BCLb mRNA in a panel of human cancer cell lines and did not observe the extensive variation in mRNA that would be required to explain the vast differences in protein levels. We found that the levels of BCLb protein diminish quickly after inhibition of protein synthesis with cycloheximide, so we searched for interacting proteins that might affect posttranslational stability of BCLb. Using a variety of approaches, including immunoaffinity and mass spectrometry, we identified a protein, Ubiquilin1 (Ubqln), that specifically interacts with BCLb, and not with other anti-apoptotic BCL2-like proteins. Ubqln stabilizes BCLb protein, while also promoting monoubiquitination on multiple lysine residues and relocation to the cytosol. Furthermore, primary lung adencarcinomas have more Ubqln mRNA than normal adjacent lung tissue, and higher Ubqln mRNA levels are associated with shorter survival of lung cancer patients, suggesting that potentiation of the anti-apoptotic potential of BCLb through regulation of its stability by Ubqln may be an important factor in tumor progression.

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Integrative Genomic Analyses Identify BRF2 as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma

Abstract: William Lockwood and colleagues show that the focal amplification of a gene, BRF2, on Chromosome 8p12 plays a key role in squamous cell carcinoma of the lung.

Cited by 95 publications

References 62 publications

PROSPECT: Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

PROSPECT: Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

Loss of the Notch effector RBPJ promotes tumorigenesis

Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1

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