Dataset Information

Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma.

ABSTRACT: Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.

SUBMITTER: Kent LN

PROVIDER: S-EPMC5330731 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma.

Kent Lindsey N LN Bae Sooin S Tsai Shih-Yin SY Tang Xing X Srivastava Arunima A Koivisto Christopher C Martin Chelsea K CK Ridolfi Elisa E Miller Grace C GC Zorko Sarah M SM Plevris Emilia E Hadjiyannis Yannis Y Perez Miguel M Nolan Eric E Kladney Raleigh R Westendorp Bart B de Bruin Alain A Fernandez Soledad S Rosol Thomas J TJ Pohar Kamal S KS Pipas James M JM Leone Gustavo G

The Journal of clinical investigation 20170130 3

Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carc ...[more]

PMID: 28134624

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Project description:PRKCI is frequently overexpressed in multiple human cancers, and PKCι expression is often prognostic for poor patient survival, indicating that elevated PKCι broadly plays an oncogenic role in the cancer phenotype. PKCι drives multiple oncogenic signaling pathways involved in transformed growth, and transgenic mouse models have revealed that PKCι is a critical oncogenic driver in both lung and ovarian cancers. We now report that recurrent 3q26 copy number gain (CNG) is the predominant genetic driver of PRKCI mRNA expression in all major human cancer types exhibiting such CNGs. In addition to PRKCI, CNG at 3q26 leads to coordinate CNGs of ECT2 and SOX2, two additional 3q26 genes that collaborate with PRKCI to drive oncogenic signaling and tumor initiation in lung squamous cell carcinoma. Interestingly however, whereas 3q26 CNG is a strong driver of PRKCI mRNA expression across all tumor types examined, it has differential effects on ECT2 and SOX2 mRNA expression. In some tumors types, particularly those with squamous histology, all three 3q26 oncogenes are coordinately overexpressed as a consequence of 3q26 CNG, whereas in other cancers only PRKCI and ECT2 mRNA are coordinately overexpressed. This distinct pattern of expression of 3q26 genes corresponds to differences in genomic signatures reflective of activation of specific PKCι oncogenic signaling pathways. In addition to highly prevalent CNG, some tumor types exhibit monoallelic loss of PRKCI. Interestingly, many tumors harboring monoallelic loss of PRKCI express significantly lower PRKCI mRNA and exhibit evidence of WNT/β-catenin signaling pathway activation, which we previously characterized as a major oncogenic pathway in a newly described, PKCι-independent molecular subtype of lung adenocarcinoma. Finally, we show that CNG-driven activation of PKCι oncogenic signaling predicts poor patient survival in many major cancer types. We conclude that CNG and monoallelic loss are the major determinants of tumor PRKCI mRNA expression across virtually all tumor types, but that tumor-type specific mechanisms determine whether these copy number alterations also drive expression of the collaborating 3q26 oncogenes ECT2 and SOX2, and the oncogenic PKCι signaling pathways activated through the collaborative action of these genes. Our analysis may be useful in identifying tumor-specific predictive biomarkers and effective PKCι-targeted therapeutic strategies in the multitude of human cancers harboring genetic activation of PRKCI.

Project description:BackgroundMelanoma is an aggressive type of skin cancer whose aetiology remains elusive as both environmental and genetic factors can contribute to its development. Recent studies have demonstrated the existence of multiple copies of E2F1 gene in melanoma specimens which could explain the deregulated E2F1 activity in this type of cancer. This finding suggests a key role for this transcription factor in the malignant transformation of melanocytes. Therefore, E2F1 has been considered as a potential therapeutic target for this form of skin cancer. Since germline copy number variations (CNVs) have been associated with increased susceptibility to different types of cancer, the aim of our study was to assess germline E2F1 CNV in melanoma patients. However, CNVs not necessarily lead to gene dosage imbalance, hence, further factors, in association with CNVs, could contribute to clinical manifestations. Considering that heat stress has been hypothesised as a contributing factor to skin cancer, we also investigated the effect of heat stress on E2F1 expression.MethodsE2F1 CNV was measured in genomic DNA isolated from blood of 552 patients diagnosed with melanoma and 520 healthy subjects using TaqMan Copy Number Assays. E2F1 mRNA expression was also evaluated by RT-qPCR in the melanoma cell line, SK MEL 267, before and after exposure to heat stress.ResultsWe found that patients diagnosed with melanoma (1.6%, 9/552) harboured frequently altered germline E2F1 copies compared to healthy subjects (0%, 0/520). Moreover, the difference among the two groups was statistically significant (p = 0.004). Furthermore, we found that heat exposure alone can significantly induce E2F1 expression.ConclusionsThis is the first study that shows a relation between germline E2F1 CNV and melanoma, suggesting that altered copies of this gene might be a predisposing factor to skin cancer. Our results also suggest that environmental insults, such as heat stress, could contribute to an aberrant E2F1 activity by inducing E2F1 mRNA expression. Therefore, subjects with multiple constitutive copies of E2F1 are at greater risk of developing melanoma when exposed to heat. Altogether our results corroborate with the hypothesis that susceptibility to melanoma depends on both the environment and genetic factors.

Dataset Information

Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma.

Publications

Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma.

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