Integrative molecular analyses define the genomic, transcriptomic, and epigenomic correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer

doi:10.21203/rs.3.rs-1726587/v1

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Integrative molecular analyses define the genomic, transcriptomic, and epigenomic correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer

https://doi.org/10.21203/rs.3.rs-1726587/v1

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published 02 Nov, 2022

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B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was positively associated with resistance signaling pathways. Using a machine learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes epigenetic mechanisms and molecular profiles of B7-H3-expressing mCRPC tumors, which informs optimal precision approaches for mCRPC patients.

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Sup figure 1. mRNA expression of B7 superfamily genes in mCRPC and normal prostate tissues. WTS data was obtained and analyzed from SU2C/PCF (n=208, mCRPC), SUWC (n=101, mCRPC), and GTEx (n=245, benign prostate tissue). All data are median with 95% CI. Statistical significance was assessed using one-way ANOVA for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
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Sup figure 2. B7-H3 high mCRPC is associated with certain genomic and transcriptional features in mCRPC. (A) Frequency of genomic alterations in mCRPC patients with high B7H3 expression. (B) AR-V7 variants and (C) mRNA expression of key mCRPC genes in high and low B7-H3-expressing mCRPC. WTS, copy number variation, structural variant, and mutation data were obtained and analyzed from mCRPC dataset SU2C/PCF (n=208). High B7-H3 group was defined as the top 25% of B7H3 expressing samples and low B7H3 group is defined as the bottom 25% of B7H3 expressing samples. Only one sample from each patient was counted and patients with samples within both high and low B7H3 groups were excluded from the analysis. A total of 48 samples in B7H3 high group and 50 samples in B7H3 low group were included in the analysis. Statistical significance was assessed using Chi-square and Fisher’s exact tests for categorical comparison between B7-H3 and genetic alterations. Student t-test was applied for AR-V7 and mRNA expression comparison. All data are mean with 95% CI. *P<0.05, **P<0.01, ****P<0.0001. Amp, amplification. Del, deletion. Mut, mutation.

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Journal Publication

published 02 Nov, 2022

Read the published version in npj Precision Oncology →

Editorial decision: revise
18 Jul, 2022
Review #2 received at journal
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Review #1 received at journal
04 Jul, 2022
Reviewer #2 agreed at journal
28 Jun, 2022
Reviewer #1 agreed at journal
18 Jun, 2022
Reviewers invited by journal
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Submission checks completed at journal
10 Jun, 2022
Editor assigned by journal
10 Jun, 2022
First submitted to journal
05 Jun, 2022

You are reading this latest preprint version

Integrative molecular analyses define the genomic, transcriptomic, and epigenomic correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer

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