WES of ccRCC samples with chromosome 8q deletions

Approximately 70% of clear cell renal cell carcinoma are characterised by the biallelic inactivation of VHL on chromosome 3p. ELOC-mutated renal cell carcinoma with biallelic ELOC inactivations on chromosome 8q are considered a novel subtype of renal cancer possessing a morphological overlap with ccRCC. Here we characterise 123 renal tumours with clear cell morphology with known VHL mutation status to assess morphological and molecular consequences of ELOC inactivation. Using Oncoscan and whole exome sequencing we identify 18 ELOC deleted RCC, three of which contain ELOC mutations resulting in the biallelic inactivation of ELOC. Two ELOC-mutated RCC showed monoallelic VHL alterations contrary to the notion that ELOC and VHL aberrations are mutually exclusive. Using High Ambiguity Driven Biomolecular Docking we report a novel ELOC variant containing a duplication event disrupting ELOC-VHL interaction alongside the frequently seen Y79C alteration. Using HRM mass spectrometry we show RCC with biallelic ELOC alterations have significantly reduced ELOC expression but similar CAIX and VEGFA expression when compared to classical ccRCC. These data demonstrate that RCC with ELOC and VHL alterations have comparable downstream effects with similar pathways to ccRCC tumourgesniss indicating that both entities are closely related.