PO-311 Multifocality complicates molecular classification of primary prostate cancer

Abstract

IntroductionProstate cancer is the most common cancer type among men in the Western developed world. The majority of cases are multifocal, with several distinct tumours within the same gland. It is of particular interest to classify prostate cancer into different molecular subgroups to stratify it´s aggressiveness. Recently, The Cancer Genome Atlas (TCGA) proposed seven subtypes based on the expression of particular fusion genes or fusion gene partners, or mutation in particular genes. However, TCGA based their classification on a single sample per patient and did therefore not take the multifocal nature of the disease into account. We have therefore utilised the proposed subtypes on a large series of multifocal primary prostate cancers to understand the distribution and heterogeneity of subtypes within each prostate gland.Material and methodsIn this study, 153 tumour and benign samples from 41 prostatectomies performed between 2010 and 2012 at Oslo university hospital were selected. The samples represent 89 distinct tumour foci, with 2–3 included tumours per patient. All samples were analysed with high-coverage whole exome sequencing. Mutations relevant for the molecular classification were validated with PCR and Sanger sequencing. Expression levels and fusion transcripts were investigated in all samples with regular and real-time RT-PCR.Results and discussionsOur results show both intra- and interfocal heterogeneity in the observed subtypes. For individual samples, 60% can be classified into one defined subtype. However, heterogeneity is observed in 47% of patients where tumours belong to more than one of the proposed subtypes. Investigating individual tumour foci, 53% belong to one subtype whereas the rest are classified into either multiple subtypes (12%) or do not harbour any of the molecular traits used in the proposed classification (35%). Interestingly, classification of samples into more than one subtype was mainly due to overexpression or fusion of multiple ETS-transcription factors (7%).ConclusionIn this study, we observe a large degree of genomic dissonance both within and between tumour foci in the same prostate, resulting in heterogeneity in the classification of individual tumours. In fact, in 47% of the cases, patients can be classified into several subtypes, depending on which tumour the sample originates from. This heterogeneity greatly complicates the implementation of this particular classification in a clinical setting.