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J Clin Invest. 2018 Oct 1;128(10):4441-4453. doi: 10.1172/JCI121924. Epub 2018 Sep 4.

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

Author information

1
The Institute of Cancer Research, London, United Kingdom.
2
The Royal Marsden, London, United Kingdom.
3
Department of Clinical Medicine and Surgery, Department of Translational Medical Sciences, Azienda Ospedaliera Universitaria (AOU) Federico II, Naples, Italy.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
5
The Broad Institute, Cambridge, Massachusetts, USA.
6
University of Washington, Seattle, Washington, USA.
7
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
8
Weill Medical College of Cornell University, New York, New York, USA.
9
University of Michigan Medical School, Ann Arbor, Michigan, USA.
10
Karmanos Cancer Institute, Detroit, Michigan, USA.
11
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
12
Institute of Oncology Research (IOR), Bellinzona and Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland.
13
Columbia University Medical Center, New York, New York, USA.

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, 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.

KEYWORDS:

Cancer immunotherapy; DNA repair; Genetics; Oncology; Prostate cancer

PMID:
30179225
PMCID:
PMC6159966
DOI:
10.1172/JCI121924
[Indexed for MEDLINE]
Free PMC Article

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