806P - New insights in oncogenic alterations in clear-cell renal cell carcinoma with sarcomatoid dedifferentiation

Abstract

Sarcomatoid dedifferentiation in renal cell carcinoma (sRCC) has been associated with aggressive disease and poor outcome. However, the molecular landscape of sRCC remains largely unknown, notably regarding chromatin remodeling genes alterations and the alterations of wild-type VHL tumors. Sixteen primary sRCCs and matched normal tissues underwent whole-exome sequencing, with a median coverage of 110x and 50x for cancer and normal samples, respectively. These data were compared to 417 non-sarcomatoid RCCs from the Cancer Genome Atlas RCC data set. Associations with clinical and pathological tumor features were performed. Most frequent somatic mutations included VHL (11/16, 69%), and chromatin remodeling genes PBRM1 (7/16, 44%) and SETD2 (3/16, 19%). BAP1 mutations were only present in 2 cases (12%). These alterations of chromatin remodeling genes were not enriched compared to the TCGA cohort of clear-cell RCC. Of note, chromatin remodeling genes alterations were not mutually exclusive, with concurrent mutations of PBRM1 and BAP1, and PBRM1 and KDM5C reported in one and two patients, respectively. No recurrent alterations of known oncogenic pathways such as MAPK, PIK3Ca/mTOR, p53 or tumor metabolism were reported. Out of 5 patients (31%) without VHL alterations, 2 (40%) had a metastatic evolution compared to only 18% in patients with VHL mutations. All had at least one alteration of chromatin remodeling genes including BAP1, PBRM1 and SMARCA4. Interestingly, mutational load was not correlated with clinical and pathological tumor features such as Fuhrman grade and TNM stage, nor with alterations of known described oncogenes. The genetic landscape of sRCC of clear-cell type might not be different from other clear-cell RCC. Patients with wild-type VHL tumors represent nearly one third of those cancers, had more aggressive tumors and constant chromatin remodeling gene alterations. These data underline the urgent need for the characterization of epigenetic modifications that might further explain the distinctive features of sRCC.