The contributions of KDM5C mutation and Y chromosome loss to clear cell renal cell carcinoma

• Applicant: Professor Dr. Ian Frew
• Subject Area: Reproductive Medicine, Urology ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555843009

Clear cell renal cell carcinoma (ccRCC) represents 70-80% of all renal malignancies and is one of the ten most frequently occurring tumours in adults. Men are approximately twice as likely as women to develop ccRCC. The molecular basis of the sex-specific difference in ccRCC is unknown. In this project we will investigate the interrelated roles of the X chromosome-encoded KDM5C tumour suppressor gene, the Y chromosome-encoded KDM5D tumour suppressor gene, as well as loss of the entire Y chromosome in ccRCC. We will generate multiple new cell models to allow investigation of the effects of single and combined loss of function of KDM5C, KDM5D or loss of the entire Y chromosome. We will take advantage of the unique panels of genetically modified cells to conduct an extensive range of assays of transformed cellular behaviour and of genomic instability. We aim to understand if and how the different genetic alterations affect cancer-relevant phenotypes. To complement these phenotypic analyses we will analyse all cultures of cells using RNA-seq to identify transcriptional alterations. We will compare between the different cell lines, genotypes, sexes and between human and mouse to determine whether there are sets of genes that are common, or whether the genetic mutations produce highly context-specific effects. We will use CUT&RUN assays to understand the molecular mechanisms acting on histone H3K4 that underlie these effects. Using quantitative proteomics we will also address the question of whether KDM5C and KDM5D are found in the same protein complexes or whether they may have different interaction partners that could explain the differing effects of their mutation.

• DFG Programme: Research Grants