The puzzling case of the 3p25 homozygous deletion: the target is notVHLbutVGLL4andATG7

Abstract

AbstractThe 3p25 locus experiences recurrent homozygous deletions in diverse carcinomas. A validated tumor suppressor gene (TSG),VHLhas long been assumed to be the target of this deletion.Here, we show that homozygous deletions at the 3p25 locus are common in renal clear cell carcinoma (RCC) and squamous cell carcinomas but that these do not center onVHLbut on two nearby overlapping genes,VGLL4andATG7. While hypomorphic mutations ofVHLcoupled with heterozygous deletions are undoubtedly a driver in RCC, DepMap CRISPR data indicate that the complete absence ofVHLis broadly detrimental to cancer cells. Re-examination of TCGA and PDX data calls into question whetherVHLis ever homozygous deleted, even in RCC.Instead, multiple lines of evidence support the homozygous deletion ofVGLL4as a driver event in squamous cell carcinomas and the homozygous deletion ofATG7as a driver in RCC, with important implication for precision oncology. VGLL4 is the major negative regulator of the YAP/TEAD complex, with elimination of VGLL4 leading to hyperactive oncogenic YAP-dependent transcriptional activity which could be targeted by clinically emerging YAP/TEAD inhibitors. ATG7 is a critical regulator of autophagy, limiting proliferation in conditions of nutrient limitation and its deletion may open novel vulnerabilities for synthetic lethality.