Dataset Information

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, 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.

SUBMITTER: Nava Rodrigues D

PROVIDER: S-EPMC6159966 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Nava Rodrigues Daniel D Rescigno Pasquale P Liu David D Yuan Wei W Carreira Suzanne S Lambros Maryou B MB Seed George G Mateo Joaquin J Riisnaes Ruth R Mullane Stephanie S Margolis Claire C Miao Diana D Miranda Susana S Dolling David D Clarke Matthew M Bertan Claudia C Crespo Mateus M Boysen Gunther G Ferreira Ana A Sharp Adam A Figueiredo Ines I Keliher Daniel D Aldubayan Saud S Burke Kelly P KP Sumanasuriya Semini S Fontes Mariane Sousa MS Bianchini Diletta D Zafeiriou Zafeiris Z Teixeira Mendes Larissa Sena LS Mouw Kent K Schweizer Michael T MT Pritchard Colin C CC Salipante Stephen S Taplin Mary-Ellen ME Beltran Himisha H Rubin Mark A MA Cieslik Marcin M Robinson Dan D Heath Elizabeth E Schultz Nikolaus N Armenia Joshua J Abida Wassim W Scher Howard H Lord Christopher C D'Andrea Alan A Sawyers Charles L CL Chinnaiyan Arul M AM Alimonti Andrea A Nelson Peter S PS Drake Charles G CG Van Allen Eliezer M EM de Bono Johann S JS

The Journal of clinical investigation 20180904 10

<h4>Background</h4>Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection.<h4>Methods</h4>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 A ...[more]

PMID: 30179225

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Dataset Information

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

Background

Methods

Results

Conclusion

Funding

Publications

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

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