Case Study: Tumour Fusion Burden in Prostate Cancer

The following Tumour Fusion Burden (TFB) case study features published data from a paper on Cancer Immunology Research.

Study Aim

Prostate cancer is the second leading cause of cancer-associated death in men. Following conventional hormone and chemotherapy treatment, castration-resistant prostate cancer (CRPC) may emerge. CRPC is an aggressive form of prostate cancer with poor prognosis. Recent advancements in the understanding of prostate cancer pathology have led to the development of immunotherapeutic approaches with the potential to complement treatment regimens and improve patient outcomes. Tumour mutation burden (TMB) is generally low in prostate cancer, however tumour fusion burden (TFB) can be used to further optimise individual patient treatment regimes by identifying those most likely to respond to immunotherapeutic intervention.

This study therefore aimed to identify the role of Tumour Fusion Burden on the prevalence and expression of key molecular and immune effectors in prostate cancer and whether TFB enhanced tumour immunogenicity.

Analysis and Results

To evaluate the immune landscape in prostate cancer, Fios Genomics and Genentech profiled gene expression in a clinical collection of 192 prostate tissue samples encompassing the full spectrum of prostate cancer severity. Scores for tumour mutation and fusion burden, as well as for a castration-resistant prostate cancer signature were derived from RNAseq data.

TMB, TFB, and castration-resistant prostate cancer scores were associated with early-stage disease: higher scores were observed in benign prostatic hyperplasia samples compared to prostate cancer samples.

To assess changes in molecular and immune expression signatures with tumour hormone sensitivity and castration resistance, samples were clustered using the expression values of genes associated with cell division and immune processes. Samples were separated by CRPC score, where high CRPC scores correlated with androgen receptor and PI3K signalling, class 1A antigen processing and activated stromal signature scores. CRPC scores inversely correlated with signatures representing neuroendocrine biology and immune suppressors suggesting potentially enhanced immunogenicity. Further, an inverse correlation between CRPC and TMB scores was observed. Samples with low castration-resistant prostate cancer scores displayed higher and more variable TMB scores. TMB was found to be inversely correlated with Tumour Fusion Burden in all samples.

Signature data from high and low Tumour Fusion Burden quartiles were clustered separately. High TFB enhanced expression of immune signatures representing activation of M1 macrophages, checkpoint inhibitors, IFN-γ induced T-cell activity, T-effector activation and class I antigen processing, while it inversely correlated with immune suppressor signatures. High TFB also correlated with cell cycle progression and androgen receptor signalling, as well as TMPRSS2:ERG and E26 transformation-specific transcriptional activity. Samples were categorised as either ERG fusion positive or ERG fusion negative. ERG fusion positive samples had a significantly increased overall fusion burden, correlating with increased ERG transcriptional activity compared to ERG fusion negative samples.

Combined, these results demonstrated that prostate cancer samples with high tumour fusion burden had high castration-resistance, elevated immune infiltration and enhanced immunogenicity, may be more responsive to immunotherapy agents.

Conclusions

Tumour Fusion Burden was inversely correlated with TMB in prostate cancer samples and was independent of disease stage. TFB correlated strongly with various immunogenic biomarkers including immune cell infiltration and activation and PD-L1 expression within tumours. Tumour Fusion Burden may therefore serve as a more suitable biomarker than TMB in prostate cancer in identifying candidates for immunotherapeutic intervention.

Tumor Fusion Burden as a hallmark of immune infiltration in prostate cancer

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