Characterizing immunogenicity of <i>MYC-</i> amplified, metastatic prostate cancer as reflected by the recovery rates of adaptive immune receptor recombinations from RNAseq files.

Abstract

241 Background: In prostate cancer, identifying biomarkers to predict patients who are at higher risk for metastatic disease remains a key question. The interaction of oncogenes such as MYC with the adaptive immune system may be a potential marker for worse progression; for example, MYC -amplified neuroblastoma has been shown to be immunologically cold both in vitro and with respect to the amount of adaptive immune receptor (IR) recombinations recovered from genomics files. Thus, we performed a correlative study identifying the relationship between MYC amplification and detection of adaptive IR recombinations in genomics files in prostate cancer. Methods: We utilized datasets for this study: The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD, n = 475), Count Me In-Metastatic Prostate Cancer (CMI-MPC, n= 63) and West Coast Dream Team – Metastatic Castration Resistant Prostate Cancer (WCDT-MCRPC, n = 76). Copy number variation (CNV) assessments were done for the cases in these studies, identifying oncogene amplification as those with high ratios of exome, tumor to blood sequencing read counts for a given gene. We also mined productive IR recombination sequencing reads from RNAseq files, with associated V and J-IDs, as described in Chobrutskiy et al. 2020, which yielded reads for TRA , TRB , TRD , TRG , IGH , IGK , and IGL . Then, MYC-amplified cases and MYC-deficient cases were compared with a two-proportion test for progression-free survival and with a t-test for the counts of IR receptors. Results: We first determined that, for TCGA-PRAD dataset, cases representing the top 20 MYC read tumor to blood count ratios, in comparison to all other cases, represented a poorer progression free survival (p = 0.01) at the 70-month timepoint. We also noted that average MYC CN in both metastatic prostate cancer datasets (CMI-MPC and WCDT-MCRPC) was higher than in the TCGA-PRAD dataset, which represented primary tumor samples (p &lt; 0.001 for both analyses). Further, for the WCDT-MCRPC dataset, we found that MYC -amplified cases were associated with significantly reduced IGH , IGK , and IGL recombination reads in RNA-seq files (p = 0.005, 0.01, 0.004 respectively). For the WCDT-MCPRC dataset, we found that MYC -amplified cases were associated with reduced TRA and TRB recombination reads in WGS files (p = 0.008 and 0.017 respectively). Conclusions: This report further evidences the negative effects of MYC amplification with regard to immune evasion and being a key driver of prostate cancer metastasis. This report thus supports risk stratification by MYC-amplification, as well as noting that patients with MYC-amplification may benefit more from immune-boosting therapies. In particular, this report identifies immunoglobulins and by proxy, B-cells, as a major deficiency in those with MYC-amplified prostate cancer.