Abstract A28: Mutational landscape of TP53 in localized prostate cancer
Authors: Mahamud Osman , Chua Melvin L.K , Supiot Stephane , Lalonde Emilie , Pra Alan Dal , Berlin Alejandro , Orain Michèle , Picard Valerie , Hovington Helene , Bergeron Alain , Fradet Yves , Têtu Bernard , Zafarana Gaetano , Meng Alice , Livingstone Julie , Pintilie Melania , Fraser Michael , Kwast Theodorus van der , Boutros Paul C. , Robert Bristow G. 
Published: April 2017

Background: We performed a comprehensive interrogation of the mutational landscape of TP53 in the context of localized prostate cancer using a large clinical/molecular-paired dataset from the Canadian Prostate Cancer Gene Network (CPC-GENE). We further test the associations of TP53 mutations with outcomes post-image-guided radiotherapy (IGRT) or radical prostatectomy (RadP).

Methods: Copy number status (N = 284), single nucleotide variants (SNV) (N = 123), methylation status (N = 117), and mRNA abundance profiling (N = 115) were assessed using the Affymetrix Oncoscan FFPE express v3.0 assay, whole genome sequencing (up to 100-200x), Illumina 450K methylation array, and Affymetrix HuGene 2.0 array, respectively. Patient cohort comprised of NCCN-defined intermediate-risk prostate cancer who underwent either IGRT (N = 146) or RadP (N = 137). Biochemical-relapse free rate (bRFR) was assessed as the primary clinical end-point.

Results: We identified 65 cases (22.9%) with mono-/bi-allelic copy number alteration (CNA) of TP53, and 7 cases (5.7%; 6 non-synonymous and 1 splice variant) with TP53 SNV in our cohort, which was comparable with the TCGA (30% CNA, 7% SNV) and MSKCC (17% CNA, 2.9% SNV) cohorts of low to high-risk localized prostate cancers. Epigenomic profiling revealed specific sites of DNA hypermethylation (β-value &gt;0.7) within the body and 5' UTR gene-regions, while the TSS gene-region was unaffected. Genomic mutations (CNA and/or SNV) of TP53 were associated with global genomic instability (percent genome aberration of 9.5 vs 6.4, p = 0.001) and reduced mRNA levels (mRNA abundance Z-Score: -0.58 vs 0.22, p-value = 0.0011), but methylation status had no consequence on these indices. Neither TP53 genomic mutations (HR = 1.35, 95% CI 0.91-2.00, Wald's p = 0.14) nor mRNA abundance (HR = 1.39, 95% CI 0.71-2.75, Wald's p = 0.34) was associated with bRFR on multivariable analyses. However, stratification by combinatorial genomic and mRNA abundance indices identified an unfavorable subgroup that was associated with poorer bRFR on multivariable analysis (HR = 2.95, 95% CI 1.42-6.12, Wald's p = 0.004).

Conclusions: This is the first comprehensive interrogation of the mutational landscape of TP53 in localized prostate cancer. Our findings suggest that functional TP53 loss at both the copy number and transcription level accounts for a subset of non-indolent localized prostate cancer.

Citation Format: Osman Mahamud, Melvin L.K Chua, Stephane Supiot, Emilie Lalonde, Alan Dal Pra, Alejandro Berlin, Michèle Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Yves Fradet, Bernard Têtu, Gaetano Zafarana, Alice Meng, Julie Livingstone, Melania Pintilie, Michael Fraser, Theodorus van der Kwast, Paul C. Boutros, Bristow G. Robert. Mutational landscape of TP53 in localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A28.