An epigenomic mechanism in retinoblastoma: the end of the story?

Murphree, A. Linn; Triche, Timothy J.

doi:10.1186/gm314

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…Our results outline a clinically feasible scenario to use RB1 as a biomarker to stratify the TNBC patients for targeted therapy. Since RB1 is controlled by both genetic and epigenetic mechanisms, the presence of genetic mutations in RB1 fails to predict RB1 protein level 75,76 . Thus, we suggest using immunohistochemical assessment of RB1 protein in patient tumors to select patients suitable for targeted therapy in TNBC.…”

Section: Discussionmentioning

confidence: 99%

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Ba-Alawi

Deblois

et al. 2019

Preprint

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Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data implicates E2F Targets pathway activity as a surrogate of OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) are strongly correlated with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.

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Section: Discussionmentioning

confidence: 99%

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Ba-Alawi

Deblois

et al. 2019

Preprint

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Section: Discussionmentioning

confidence: 99%

“…Further, the treatment of RB cell lines (Weri Rb 1 and RB 355) with SYK inhibitors (BAY 61-3606 or R406) had resulted in the caspase mediated cell death, suggesting that the SYK could be a target for chemotherapeutic interventions in RB management. 34,37 In the present study, response of Ect2 and pRAME was validated by qRT-PCR in the primary RB tumors (n = 9, post-chemotherapy, and n = 12, prechemotherapy). Surprisingly, there was no significant association of PRAME expression with chemotherapy status as observed in other childhood cancers such as leukemia.…”

Section: Multidrug Resistance Genes In Rbmentioning

confidence: 91%

Molecular Insights on Post-chemotherapy Retinoblastoma by Microarray Gene Expression Analysis

Venkatesan

Segu

Deepa

et al. 2013

Bioinform Biol Insights

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PurposeManagement of Retinoblastoma (RB), a pediatric ocular cancer is limited by drug-resistance and drug-dosage related side effects during chemotherapy. Molecular de-regulation in post-chemotherapy RB tumors was investigated.Materials and MethodscDNA microarray analysis of two post-chemotherapy and one pre-chemotherapy RB tumor tissues was performed, followed by Principle Component Analysis, Gene ontology, Pathway Enrichment analysis and Biological Analysis Network (BAN) modeling. The drug modulation role of two significantly up-regulated genes (p≤0.05) − Ect2 (Epithelial-cell-transforming-sequence-2), and PRAME (preferentially-expressed-Antigen-in-Melanoma) was assessed by qRT-PCR, immunohistochemistry and cell viability assays.ResultsDifferential up-regulation of 1672 genes and down-regulation of 2538 genes was observed in RB tissues (relative to normal adult retina), while 1419 genes were commonly de-regulated between pre-chemotherapy and post- chemotherapy RB. Twenty one key gene ontology categories, pathways, biomarkers and phenotype groups harboring 250 differentially expressed genes were dys-regulated (EZH2, NCoR1, MYBL2, RB1, STAMN1, SYK, JAK1/2, STAT1/2, PLK2/4, BIRC5, LAMN1, Ect2, PRAME and ABCC4). Differential molecular expressions of PRAME and Ect2 in RB tumors with and without chemotherapy were analyzed. There was neither up- regulation of MRP1, nor any significant shift in chemotherapeutic IC50, in PRAME over-expressed versus non-transfected RB cells.ConclusionCell cycle regulatory genes were dys-regulated post-chemotherapy. Ect2 gene was expressed in response to chemotherapy-induced stress. PRAME does not contribute to drug resistance in RB, yet its nuclear localization and BAN information, points to its possible regulatory role in RB.

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“…Указанием на комплексность молекулярных изменений в развитии рБ являются обнаруженные эпигенетические изменения в экспрессии разных генов. Установлено нарушение регуляции протоонкогена SYK (spleen tyrosine kinase) и было предположено, что эпигенетическая модификация экспрессии (метилирование) гена SYK требуется для выживания клеток рБ [18,25]. Полногеномное секвенирование опухолевой ткани рБ обнаружило специфические изменения в числе копий других генов, увеличение до 4-10 копий в онкогенах MDM4, KIF14 (1q32), MYCN (2p24), DEK, и E2F3 (6p22) и потерю гена-супрессора CDH11 (16q22-24) [5,22].…”

Section: Introductionunclassified

Study of Retinoblastoma Penetrance and Phenotype

Kazubskaya¹,

Alekseeva²,

Ushakova³

et al. 2018

Problems in oncology

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In this study we characterized hereditary forms of retinoblastoma (RB). Mutational analysis was conducted among 85 RB patients and 156 their relatives. Using a combination of NGS (next generation sequencing) and MLPA (Multiplex Ligation-dependent Probe Amplification) assays we found RB1 germinal mutations in majority of RB patients (96,4% - 27/28) with binocular disease and in 21% (12/57) with monocular RB.A relationship between different types of RB1 germline mutations and clinical manifestation was analyzed. Mainly., hereditary RB developed into severe binocular clinical form with high penetrance. However in some families low penetrance was observed (when patients carrying germline mutation didn’t develop RB). We confirmed that 3 mutations at splice sites: с.607 + 1G>T (intron 6); c.1422-8delT (exon 16); g.61807 G>A (exon 9); and 2 missense mutations: p. 1364 G>C (14 exon); с.1981 C>T (20 exon) were inherited from not affected fathers. These RB cases were less severe (unilateral RB developed later in life). Of the 85 tested RB patients, germline mutations were detected in 45.8% (39/85), 41% (16/39) among which were localized in exons 12-18, 19-23. Hence, different RB mutations were associated with various phenotype. We suggest conducting genetic testing among all RB patients. This will allow identification of asymptomatic carriers with low penetrance mutations, germline mosaicism, lead to early diagnosis, facilitate development of individual treatment plans and determine genetic risk among affected families.

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An epigenomic mechanism in retinoblastoma: the end of the story?

Cited by 7 publications

References 11 publications

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Molecular Insights on Post-chemotherapy Retinoblastoma by Microarray Gene Expression Analysis

Study of Retinoblastoma Penetrance and Phenotype

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