Abstract
509 Background: Sarcomatoid transformation in renal cell carcinoma (ccRCC) is one of the worst prognostic factors and outcome is extremely poor. We evaluate genetic alterations implicated in this process. Methods: Nephrectomy specimens from ccRCC with sarcomatoid transformation had DNA extracted from carcinoma, sarcomatoid, and normal kidney regions. Exome capture/Illumina sequencing was performed in 21 samples. Somatic mutation calling was accomplished by comparing sarcomatoid-normal and carcinoma-normal pairs. Results: Two tumors had evidence of hypermutation and a mutational signature consistent with mismatch repair deficiency. In the remaining tumors, 42.6% of somatic mutations were shared. Sarcomatoid regions had a greater mutation burden (p = 4.0x10-4). A low percentage (57.9%) of tumors had mutations in VHL. Mutations in ccRCC driver genes, including PBRM1, PTEN, SETD2, ARID1A, and BAP1, were common. All mutations in ARID1A and BAP1 were specific to sarcomatoid regions. A high percentage (31.5%) of TP53 mutations were observed, all specific to sarcomatoid regions and occurring with loss of heterozygosity. Lastly, mutations in genes not previously described in ccRCC were observed, most sarcomatoid-specific. These include genes implicated in cell adhesion, polarity, motility, and WNT signaling (FAT1, FAT2, FAT3, PTK7), retinoic acid-regulated cell differentiation (RQCD1, LRIF1), and ubiquitinated protein trafficking and cytokinesis (TSG101). Conclusions: Sarcomatoid transformation in ccRCC results from clonal divergence from a common somatic cell of origin. The sarcomatoid region has significantly greater mutational burden of known cancer driver genes. TP53 mutations occurred at a high frequency and were exclusive to the sarcomatoid region. Hypermutation is a unique characteristic observed in a subset of tumors. Additional cohorts and mechanistic studies are critical to elucidate the role of candidate driver alterations.
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