Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer.
Date
2018-10-01ICR Author
Author
Nava Rodrigues, D
Rescigno, P
Liu, D
Yuan, W
Carreira, S
Lambros, MB
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, KP
Sumanasuriya, S
Fontes, MS
Bianchini, D
Zafeiriou, Z
Teixeira Mendes, LS
Mouw, K
Schweizer, MT
Pritchard, CC
Salipante, S
Taplin, M-E
Beltran, H
Rubin, MA
Cieslik, M
Robinson, D
Heath, E
Schultz, N
Armenia, J
Abida, W
Scher, H
Lord, C
D'Andrea, A
Sawyers, CL
Chinnaiyan, AM
Alimonti, A
Nelson, PS
Drake, CG
Van Allen, EM
de Bono, JS
Type
Journal Article
Metadata
Show full item recordAbstract
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, 8.1% 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 CD200R1, 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. FUNDING: We acknowledge funding support from Movember, Prostate Cancer UK, The Prostate Cancer Foundation, SU2C, and Cancer Research UK.
Collections
Subject
Humans
Prostatic Neoplasms
Neoplasm Proteins
Immunotherapy
Mutation
Adult
Aged
Middle Aged
Male
Microsatellite Instability
DNA Mismatch Repair
High-Throughput Nucleotide Sequencing
B7-H1 Antigen
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Language
eng
Date accepted
2018-07-10
License start date
2018-10
Citation
The Journal of clinical investigation, 2018, 128 (10), pp. 4441 - 4453
Publisher
AMER SOC CLINICAL INVESTIGATION INC