AbstractGenomic alterations (GA) inNF2tumor-suppressor gene have been associated with aggressive behavior in kidney tumors. We used comprehensive genomic profiling (CGP) to evaluate the frequencies ofNF2GA in histologic subtypes of kidney tumors and co-occurring GA in other genes and biomarkers. Advanced kidney tumors included 1875 clear cell (ccRCC), 405 papillary (pRCC), 108 chromophobe (chRCC), 171 sarcomatoid (sRCC), 61 collecting duct (cdRCC), 49 medullary (mRCC), 134 unclassified (uRCC), 906 urothelial carcinoma of renal pelvis (UC), and 147 Wilms tumors underwent hybrid-capture based CGP to evaluate all classes of GA. 192 (4.9%) of kidney tumors featuredNF2GA which were predominantly structural variant mutations (89%), followed by copy number alterations (9%). Gender and age were similar betweenNF2-mutant (NF2mut) andNF2-wild type (NF2wt) cohorts with male preponderance.NF2GA frequency was highest in cdRCC (30%), sRCC (21%), uRCC (15%), and pRCC (12%) while lowest in ccRCC (3%), UC (3%) Wilms tumor (1%), and chRCC (0%).NF2mutational status was associated with loss of Ch 22 (P< .001).NF2mut RCC harbored co-occurring GA includingCDKN2A,CDKN2B,SETD2, andBAP1.VHL,PBRM1,PTEN, andFGFR3GA were significantly more frequent inNF2wt than inNF2mut tumors. MTOR pathway GAs were uncommon inNF2mut tumors. NoNF2mutated RCC featured MSI-high or high TMB. sRCC was associated with high PD-L1 expression. PD-L1 SP142 tumoral (P= .04) and immune cells (P= .013) were more frequent inNF2mut as compared toNF2wt group. Among histologic subtypes of RCC, cdRCC, sRCC, pRCC, and uRCC are enriched inNF2GA. Co-occurrent GA inCDKN2A/B,SETD2, andBAP1may represent potential therapeutic targets. Higher level of PD-L1 expression inNF2mut cohort suggests that these tumors might be sensitive to immune checkpoint inhibitor therapies.