HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas.

Abstract

Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of <i>HNF1B</i> loss is unique to ChRCC. We also observed a strong correlation between reduced <i>HNF1B</i> expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, <i>HNF1B</i> deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of <i>Mad2l1</i>, <i>Bub1b</i>, and <i>Rb1</i> genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed <i>TP53</i> mutations in 33% of ChRCC where <i>HNF1B</i> expression was repressed. In clinical specimens, combining <i>HNF1B</i> loss with <i>TP53</i> mutation produced an association with poor patient prognosis. In cells, combining <i>HNF1B</i> loss and <i>TP53</i> mutation increased cell proliferation and aneuploidy. Our results show how <i>HNF1B</i> loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of <i>HNF1B</i> and <i>TP53</i> may enhance cellular survival and confer an aggressive phenotype in ChRCC. <i>Cancer Res; 77(19); 5313-26. ©2017 AACR</i>.