Computational analysis of the mutations in BAP1, PBRM1 and SETD2 genes reveals the impaired molecular processes in renal cell carcinoma

Piva, Francesco; Giulietti, Matteo; Occhipinti, Giulia; Santoni, Matteo; Massari, Francesco; Sotte, Valeria; Iacovelli, Roberto; Burattini, Luciano; Santini, Daniele; Montironi, Rodolfo; Cascinu, Stefano; Principato, Giovanni

doi:10.18632/oncotarget.5147

Cited by 30 publications

(18 citation statements)

References 26 publications

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“…ccRCC patients can show different clinical manifestation and treatment response because of the tumor heterogeneity in histology, oncogenicity and molecular alterations in tumor suppressor genes [ 24 ]. Furthermore, previous reports have shown that the mutations on Von Hippel-Lindau ( VHL ), Polybromo-1 ( PBRM1 ) and BRCA1 associated protein-1 ( BAP1 ) are the most common somatic mutations in ccRCC which induces the occurrence and development of ccRCC [ 25 ]. In this study, we found that LOC653786 was upregulated in ccRCC tissues compared to normal tissues by analyzing TCGA data, but it is unclear whether the higher level of LOC653786 in ccRCC tissues was associated with the mutations of VHL, BAP1 and PBRM1 .…”

Section: Discussionmentioning

confidence: 99%

LncRNA LOC653786 promotes growth of RCC cells via upregulating FOXM1

Yang

Zhang

et al. 2018

Oncotarget

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Renal cell carcinoma (RCC) is the most common kidney malignancy with poor prognosis. Recently, long noncoding RNAs (lncRNAs) have been demonstrated as important regulators in multiple cancers including RCC. LOC653786 is a lncRNA, but its role in cancer remains unclear. In this study, we for the first time found that LOC653786 was upregulated in RCC tissues and cell lines, and this lncRNA promoted growth and cell cycle progression of RCC cells. Moreover, we showed that LOC653786 elevated the expression of forkhead box M1 (FOXM1) and its downstream target genes cyclin D1 and cyclin B1 in RCC cells. Reporter assay revealed that LOC653786 enhanced the transcriptional activity of FOXM1 gene promoter. Additionally, knockdown of FOXM1 attenuated the LOC653786-enhanced growth and cell cycle progression of RCC cells. Meanwhile, silencing of LOC653786 suppressed RCC cell growth and cell cycle progression, which was alleviated by overexpression of FOXM1. The in vivo experiments in nude mice showed knockdown of LOC653786 repressed xenograft tumor growth and FOXM1 expression. In conclusion, our results demonstrate that LOC653786 accelerates growth and cell cycle progression of RCC cells via upregulating FOXM1, suggesting that the ‘LOC653786/FOXM1’ pathway may serve as a novel target for RCC treatment.

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Section: Discussionmentioning

confidence: 99%

LncRNA LOC653786 promotes growth of RCC cells via upregulating FOXM1

Yang

Zhang

et al. 2018

Oncotarget

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“…Moreover, germline BAP1 mutations are associated with more aggressive UM [6]. BAP1 also plays a prognostic role in other cancers such as RCC and cholangiocarcinoma [7–9].…”

Section: Introductionmentioning

confidence: 99%

BAP1 expression is prognostic in breast and uveal melanoma but not colon cancer and is highly positively correlated with RBM15B and USP19

2019

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BAP1 is a tumor suppressor gene important to the development and prognosis of many cancers, especially uveal melanoma (UM). Its role in more common cancers such as breast and colon cancer is largely unknown. We collected the transcriptome profiling data sets from the TCGA uveal melanoma (TCGA-UVM), breast cancer (TCGA-BRCA), and colon cancer (TCGA-COAD) projects to analyze the expression of BAP1. We found that patients with UM and breast cancer, but not colon cancer, who died had a lower level of BAP1 gene expression compared to surviving patients. Importantly, in breast cancer patients, the lowest BAP1 expression levels corresponded to the dead young patients (age at diagnosis < 46). Since the number of cases in TCGA-BRCA was much higher than TCGA-UVM, we obtained highly correlated genes with BAP1 in invasive breast carcinomas. Then, we tested if these genes are also highly correlated with BAP1 in UM and colon cancer. We found that BAP1 is highly positively correlated with RBM15B and USP19 expression in invasive breast carcinoma, UM, and colon adenocarcinoma. All three genes are located in close proximity on the 3p21 tumor suppressor region that is commonly altered in many cancers.

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“…A predominant role in kidney cancer is played by inactivation of Von Hippen Lindau (VHL) tumor suppressor gene with consequent increased cellular amount of Hypoxia-Inducible Factor-1 alpha (HIF-1a) that cause abnormal cellular growth and angiogenesis [2–4]. Therefore inhibition of angiogenesis represents the mainstay of treatment of metastatic RCC [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Systemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib

et al. 2016

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BackgroundIn this retrospective analysis, we explored the prognostic and predictive value of the systemic immune-inflammation index (SII), based on lymphocyte, neutrophil, and platelet counts, at baseline and changes at week 6 during first-line sunitinib in patients with metastatic renal cell cancer (RCC).ResultsPatients were stratified into high SII (≥ 730) and low SII (< 730) groups. SII was associated with objective response, p < 0.0001. The median PFS was 6.3 months (95% CI 5.5–8.9) in patients with SII ≥ 730 and 18.7 months (95% CI 14.7–22.8) in those with SII < 730, p < 0.0001. The median OS was 43.6 months (95% CI 35.3–52.1) in patients with SII < 730, and 13.5 months (95% CI 9.8–18.5) in those with SII ≥ 730, p < 0.0001. In multivariate analysis, performance status, IMDC score and SII were able to predict OS (HR = 3.29, HR = 1.71 and HR = 1.79, respectively).Materials and MethodsWe included 335 consecutive RCC patients treated with first-line sunitinib. The X-tile 3.6.1 software (Yale University, New Haven, CT) was used for bioinformatic analysis of the data to determine the cutoff value of SII. Progression-free survival (PFS), overall survival (OS) and their 95% confidence interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of SII conversion at week 6 of treatment on PFS and OS was evaluated by Cox regression analyses.ConclusionsThe SII and its changes during treatment represent a powerful prognostic indicator of clinical outcome in patients with metastatic RCC.

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Computational analysis of the mutations in BAP1, PBRM1 and SETD2 genes reveals the impaired molecular processes in renal cell carcinoma

Cited by 30 publications

References 26 publications

LncRNA LOC653786 promotes growth of RCC cells via upregulating FOXM1

LncRNA LOC653786 promotes growth of RCC cells via upregulating FOXM1

BAP1 expression is prognostic in breast and uveal melanoma but not colon cancer and is highly positively correlated with RBM15B and USP19

Systemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib

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