Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer Journal Article

Authors: Rodrigues, D. N.; Rescigno, P.; Liu, D.; Yuan, W.; Carreira, S.; Lambros, M. B.; Seed, G.; Mateo, J.; Riisnaes, R.; Mullane, S.; Margolis, C.; Miao, D.; Miranda, S.; Dolling, D.; Clarke, M.; Bertan, C.; Crespo, M.; Boysen, G.; Ferreira, A.; Sharp, A.; Figueiredo, I.; Keliher, D.; Aldubayan, S.; Burke, K. P.; Sumanasuriya, S.; Fontes, M. S.; Bianchini, D.; Zafeiriou, Z.; Mendes, L. S. T.; Mouw, K.; Schweizer, M. T.; Pritchard, C. C.; Salipante, S.; Taplin, M. E.; Beltran, H.; Rubin, M. A.; Cieslik, M.; Robinson, D.; Heath, E.; Schultz, N.; Armenia, J.; Abida, W.; Scher, H.; Lord, C.; D'Andrea, A.; Sawyers, C. L.; Chinnaiyan, A. M.; Alimonti, A.; Nelson, P. S.; Drake, C. G.; Van Allen, E. M.; de Bono, J. S.
Article Title: Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer
Abstract: BACKGROUND. Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection. METHODS. Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures. Transcriptomic data, available for 168 samples, was also performed. RESULTS. Overall, 81% of patients in the RMH cohort had some evidence of dMMR, which associated with decreased overall survival. Higher MSINGS scores associated with dMMR, and these APCs were enriched for higher T cell infiltration and PD-L1 protein expression. Exome MSINGS scores strongly correlated with targeted panel MSINGS scores (r = 0.73, P < 0.0001), and higher MSINGS scores associated with dMMR mutational signatures in APC exomes. dMMR mutational signatures also associated with MMR gene mutations and increased immune cell, immune checkpoint, and T cell-associated transcripts. APC with dMMR mutational signatures overexpressed a variety of immune transcripts, including CO200R1, BTLA, PD-L1, PD-L2, ADORA2A, PIK3CG, and TIGIT. CONCLUSION. These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC.
Keywords: ipilimumab; tumors; microsatellite instability; double-blind; expression; deficiency; genetic-variation; pd-1 blockade; mutational signatures; matrix factorization
Journal Title: Journal of Clinical Investigation
Volume: 128
Issue: 10
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2018-10-01
Start Page: 4441
End Page: 4453
Language: English
ACCESSION: WOS:000446063600029
DOI: 10.1172/jci121924
PMCID: PMC6159966
PUBMED: 30179225
Notes: Corrigendum issued, see DOI: 10.1172/JCI125184 -- Article -- Source: Wos
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