Summary - In the current study, loss of HNF1B and TP53 enhances cellular survival and confers an aggressive phenotype in chromophobe renal cell carcinoma (ChRCC)

Methods
The molecular drivers of ChRCC were studied.

Results
HNF1B was shown to be down-regulated in the majority of ChRCCs;  the magnitude of HNF1B loss was unique to ChRCC.
A strong correlation was demonstrated between reduced HNF1B expression and aneuploidy in ChRCC patients.
In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced the expression of spindle checkpoint proteins (MAD2L1 and BUB1B) and cell cycle checkpoint proteins (RB1 and p27). 
HNF1B was shown to alter chromatin accessibility of Mad2l1, Bub1b, and Rb1 genes and triggered aneuploidy development.
TP53 mutations were detected in 33% of ChRCCs in which HNF1B expression was repressed. 
HNF1B loss with a TP53 mutation was associated with poor patient prognosis.
Combining HNF1B loss and a TP53 mutation increased cell proliferation and aneuploidy.