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.

Genomic sequencing identifies WNK2 as a driver in hepatocellular carcinoma and a risk factor for early recurrence

“…First, our WGS cohort was based on patients with HCC who had early tumor recurrence, and higher mutational burden has been associated with poor prognosis in several types of cancer. [23][24][25][26] Second, we identified 5 prominent mutational signatures; Signature A (aristolochic acid) and Signature C (aflatoxin) were the dominant signatures in 34.7% (17/49) of the patients, which was different from other HCC cohort studies. [5][6][7] Exposures to aristolochic acid or aflatoxin are important environmental risk factors for HCC development, especially in China, and are known to contribute to hypermutation in cancer.…”

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

“…15 alterations such as PTEN or CHD1 deletion remain undetectable when ctDNA constitutes a few percent of total cfDNA. Many of the alterations identified by either cfDNA or tissue sequencing alone have clinical relevance, from DDR gene defects and potential sensitivity to PARPi or immunotherapy [25,26], to TP53 and SPOP mutations that infer poor and favourable prognosis, respectively [10,27,28]. Therefore, the optimal approach for correlative studies or biomarker development in the de novo mCSPC setting should incorporate both tissue and plasma analyses, or risk undersampling disease.…”

Patient-derived xenografts and organoids model therapy response in prostate cancer

“…MSI status has been proposed as a predictive biomarker of response to anti-PD1 immunotherapy with pembrolizumab with positive responses reported for patients with hypermutated MSI who have already been treated with enzalutamide [43,44]. In 2017 the FDA approved anti-PD-1 treatment for patients with MSI or defective MMR mechanism for prostate [45] as well as other types of cancer, regardless of their original location. Among the patients with defined MSI-H/dMMR molecular phenotype, approximately 50% respond to anti-PD1/PDL1 immunotherapy [44].…”