Comprehensive genomic profiling of metastatic collecting duct carcinoma,renal medullary carcinoma,and clear cell renal cell carcinoma |
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Authors: | Gennady Bratslavsky Stephanie Gleicher Joseph M. Jacob Thomas H. Sanford Oleg Shapiro Dimitra Bourboulia Laurie M Gay Julie Andrea Elvin Jo-Anne Vergilio James Suh Shakti Ramkissoon Eric Allan Severson Jonathan Keith Killian Alexa Betzig Schrock Jon H. Chung Vincent A. Miller Mehdi Mollapour Jeffrey S. Ross |
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Affiliation: | 1. Upstate Medical University, Syracuse NY;2. Foundation Medicine, Cambridge MA |
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Abstract: | Introduction and ObjectiveUnlike clear cell renal cell carcinoma (CCRCC), collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are rare tumors that progress rapidly and appear resistant to current systemic therapies. We queried comprehensive genomic profiling to uncover opportunities for targeted therapy and immunotherapy.Material and MethodsDNA was extracted from 40 microns of formalin-fixed, paraffin-embedded specimen from relapsed, mCDC (n = 46), mRMC (n = 24), and refractory and metastatic (m) mCCRCC (n = 626). Comprehensive genomic profiling was performed, and Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated. We analyzed all classes of genomic alterations.ResultsmCDC had 1.7 versus 2.7 genomic alterations/tumor in mCCRCC ( = 0.04). Mutations in VHL (P < 0.0001) and TSC1 (P = 0.04) were more frequent in mCCRCC. SMARCB1 (P < 0.0001), NF2 (P = 0.0007), RB1 (P = 0.02) and RET (P = 0.0003) alterations were more frequent in mCDC versus mCCRCC. No VHL alterations in mRMC and mCDC were identified. SMARCB1 genomic alterations were significantly more frequent in mRMC than mCDC (P = 0.0002), but were the most common alterations in both subtypes. Mutations to EGFR, RET, NF2, and TSC2 were more frequently identified in mCDC versus mRMC. The median TMB and MSI-High status was low with <1% of mCCRC, mCDC, and mRMC having ≥ 20 mut/Mb.ConclusionGenomic alteration patterns in mCDC and mRMC differ significantly from mCCRCC. Targeted therapies for mCDC and mRMC appear limited with rare opportunities to target alterations in receptor tyrosine kinase and MTOR pathways. Similarly, TMB and absence of MSI-High status in mCDC and mRMC suggest resistance to immunotherapies. |
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