对具有非洲血统的驱动基因阴性肾细胞癌进行全基因组测序，发现了靶向panel测序遗漏的MET结构变异

Clear cell renal cell carcinoma (ccRCC) is more prevalent in patients with European (EUR) ancestry, whereas non-clear cell subtypes, such as papillary renal cell carcinoma (pRCC), are more common in patients with African (AFR) ancestry. ccRCC is primarily driven by biallelic inactivation of VHL while pRCC is driven by MET activation. We recently revealed an enrichment of MET mutations and a substantial depletion of other known RCC drivers from patients of African (AFR) ancestry compared to patients of European (EUR) ancestry in a retrospective meta-analysis of clinical panel sequencing data from Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) and FoundationOne CDx. ​​Additionally, pRCC tumors are more likely than ccRCC to lack known driver alterations. To detect genomic alterations in “driver-negative” RCC cases, we performed short-read, matched tumor-normal whole-genome sequencing (WGS) on 13 RCC cases from the MSK-IMPACT clinical sequencing cohort with at least 60% AFR ancestry and lacked OncoKB-annotated oncogenic or likely oncogenic somatic driver alterations in known RCC driver genes - restricted to VHL in ccRCC, or VHL plus other known RCC driver genes in non-ccRCC. These 13 cases comprising VHL -negative ccRCC (n=3) and driver-negative non-ccRCC (n=10) were sequenced to median coverage of 68x-129x. WGS data were processed using the Isabl ( https://www.isabl.io/ ) pipeline based on GRCh37 and included germline and somatic variant calling for single nucleotide variants and indels, copy number alterations, and structural variations (SVs). We found novel somatic ME​​T SVs in two cases. In one case of VHL -negative ccRCC (Patient #1), we identified an inverted tandem duplication spanning exons 15-21 of MET , which code for the tyrosine kinase catalytic domain and C-terminal docking sites. In another case of driver-negative pRCC (Patient #2), we identified a previously unreported fusion partner for MET involving intron 11 of MET and intron 7 of KLRG2 . Both SVs are likely oncogenic and likely gain-of-function according to OncoKB, suggesting potential MET activation resulting from these SVs. RNAseq is underway to determine expression of MET SV products and MET -responsive genes. Although MET SVs were found in both patients only patient #1 received MET-targeted therapy. Cabozantinib was initiated in fourth line in the setting of advanced liver metastases where outcomes are generally poor. Knowledge of the MET SV at diagnosis might have altered therapeutic sequencing favoring earlier treatment with MET-targeted therapy. Our findings underscore the importance of WGS analysis, particularly for RCC cases in which oncogenic alterations are missed on conventional cancer panel sequencing. Our results also reveal novel somatic MET SVs as potential sources of MET activation although further studies with larger sample sizes are required to investigate the frequency of activating MET SVs and MET mutations among RCC patients with AFR ancestry.