Succinate dehydrogenase B deficient renal cell carcinoma (RCC): A genomic landscape study.

551 Background: In addition to the association of SDHB genomic alterations (GA) with paraganglioma and pheochromocytoma, SDHB GA are also linked to a rare form of RCC with inactivation or homozygous deletion (complete loss) of the SDHB gene (SDHBdef-RCC) which carries a high risk for metastasis and adverse prognosis. We studied the GA landscape of SDHBdef-RCC and compared it to RCC lacking SDHB GA (SDHBwt-RCC) . Methods: 9,462 cases of clinically advanced RCC underwent hybrid capture based comprehensive genomic profiling (CGP) using the FoundationOneCDx assay to identify all classes GA. Microsatellite instability status (MSI) and tumor mutational burden (TMB) were determined from the sequencing data. PD-L1 expression was determined by IHC using the Dako TPS score (0% = negative; 1-49% = low positive and ≥50% = high positive). All cases had relapsed either loco-regionally or with metastatic disease at the time sequencing. Results: 17 (0.6%) of the sequenced advanced RCC were SDHBdef-RCC) and included 7 (41.2%) with germline short variant (SV) SDHB mutations, 6 (35.5%) with somatic SV SDHB mutations and 4 (23.5%) with homozygous SDHB deletions (complete loss of 8 of 8 exons). Their histologic RCC subtypes included 5 sarcomatoid, 5 high grade NOS, 4 oncocytic, 2 clear cell and 1 collecting duct RCC morphology; 10 RCC were sequenced using the primary kidney tumor and 7 from a metastatic site biopsy for CGP. Patients with SDHBdef-RCC were younger (mean age 45.9 yrs vs 62.5 yrs; p<.0001) and had a similar gender distribution (29.4% - 30.9% female). Biomarkers of checkpoint inhibitor efficacy including MSI-high status (0% - 0.6%), TMB level (mean 3.6 to 3.9 mutations/Mb) and any level of PD-L1 expression (40.0% vs 35.7%) were similar in both groups. Noteworthy GA summaries are shown in attached Table. Conclusions: SDHBdef-RCC is a rare form of clinically advanced RCC with predominantly oncocytic and sarcomatoid non-clear cell histology featuring either inactivating short variant SDHB germline or somatic mutations or homozygous deletion of SDHB gene. When compared with SDHDwt-RCC, SDHBdef-RCC occurs in younger patients, features non-clear cell histology, less frequent GA in tumor suppressor genes ( VHL , PBRM1 , SETD2 , BAP1 ), less frequent GA in cell cycle regulatory genes ( CDKN2A / B , T P53 ) and significant increased GA in NF2 . Further investigation of GA in this rare RCC type for clinical trial design and germline screening strategies is warranted. Limitations of this study include its retrospective nature, potential selection bias, and lack of clinically relevant data. Genomic alteration summaries of sequenced advanced RCC. SDHBmut RCC (N=17) SDHBwt RCC (N=9445) P value VHL 23.5% 43.7% NS PBRM1 0.0% 24.9% .011 SETD2 0.0% 17.0% NS BAP1 0.0% 11.3% NS CDKN2A 11.8% 25.6% NS CDKN2B 11.8% 20.1% NS MTAP 7.7% 15.0% NS TP53 5.9% 21.1% NS NF2 23.5% 6.7% .024