MMR defects study in mCRPC using targeted DNA repair panel

Elucidating the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection. In 127 APC biopsies from 124 patients, 8.1% of patients had dMMR by immunohistochemistry (IHC) and/or microsatellite instability by PCR (MSI), associating with worse overall survival; MSI by next generation sequencing (MSINGS) was able to detect dMMR tumors as well as IHC/MSI. dMMR APC T-cell infiltration and PD-L1 protein expression associated with higher MSINGS. We then evaluated MSINGS on 254 samples from the PCF/SU2C cohort with whole exome sequencing (WES) with 176 having matching transcriptomes. Exome MSINGS scores correlated with target panel MSINGS scores (r=0.73, p<0.0001). We subsequently evaluated APC exome mutational signatures and transcript expression, identifying defective mismatch repair (dMMR), defective homologous recombination repair (HRD), and aging signatures in APC. dMMR mutational signatures associated with a) higher MSINGS; b) MMR gene mutations; and c) increased immune cell, immune checkpoint, and T-cell-associated, transcripts. APC with dMMR mutational signatures overexpressed potentially actionable immune transcripts, including CD200R1, BTLA, PD-L1, PD-L2, CD33, PIK3CG, JAK2 and TIGIT. These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC.