The puzzling case of the 3p25 homozygous deletion: the target is not VHL but VGLL4 and ATG7

The 3p25 locus experiences recurrent homozygous deletions in diverse carcinomas. A validated tumor suppressor gene (TSG), VHL has 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 on VHL but on two nearby overlapping genes, VGLL4 and ATG7. While hypomorphic mutations of VHL coupled with heterozygous deletions are undoubtedly a driver in RCC, DepMap CRISPR data indicate that the complete absence of VHL is broadly detrimental to cancer cells. Re-examination of TCGA and PDX data calls into question whether VHL is ever homozygous deleted, even in RCC. Instead, multiple lines of evidence support the homozygous deletion of VGLL4 as a driver event in squamous cell carcinomas and the homozygous deletion of ATG7 as 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.