Work

Mp71-10 Clinical Features of Recurrent Somatic Mutations in Clear Cell Renal Cell Carcinoma: a Large Cohort

Year: 2016

Type: article

Abstract: INTRODUCTION AND OBJECTIVES: To study the mutual exclusivity of arm-level chromosomal (Chr) alterations in clear cell renal cell carcinoma (ccRCC) and its therapeutic potential.METHODS: We conducted an in silico analysis using the Cancer Genome Atlas (TCGA) and COSMIC databases to identify chromosomal changes (Copy number variance, CNV, and mutation) in ccRCC samples and cell lines.In vitro genetic silencing assays were performed to compare proliferation, cell cycle, and apoptosis in a series of ccRCC cells.RESULTS: Querying hallmark genes on Chr 9p (CDKN2A and CDKN2B) and Chr 3p (VHL, PBRM1, SETD2, and BAP1) on TCGA, we found no cases with simultaneous homogenous deletion of 9p and 3p.Genetic alteration (CNV/mutation) of CDKN2A/CDKN2B was significantly mutually exclusive to those of SETD2 and PBRM1.Worsened prognosis of 9p was neutralized when queried with alteration of either 3p or 9p genes.In ccRCC cell lines however, loss of >¼ 2 3p genes other than VHL were associated with CN neutral CDKN2A/CDKN2B.Silencing both PBRM1 and BAP1 exhibited strongest synthetic lethality in CDKN2A/CDKN2B loss ccRCC cells, followed by PBRM1 and SETD2, and BAP1 and SETD2.Addition of VHL silencing in VHL wildtype cell lines did not show additive effect.Silencing of any two major 3p genes (PBRM1/BAP1/SETD2) in combination with loss of either major 9p genes (CDKN2A/CDKN2B) induced potent apoptosis but not cell cycle arrest.CONCLUSIONS: Mutual exclusivity and synthetic lethality assays revealed novel approaches against ccRCC with specific genotypes.

Source: The Journal of Urology

DOI: 10.1016/j.juro.2016.02.1456