Triple Aberrant Prostate Cancer (TAPC) - Aggregate role of aberrations in TP53, PTEN and RB1 on ETS gene fusions and prognosis in metastatic castrate resistant prostate cancer.

BACKGROUND Aberrations in TP53, PTEN and RB1 are key drivers of therapy resistance in prostate cancer. Up to 50% of prostate cancers harbor ETS gene rearrangements, a potentially compounding aggressive biological event. Little is known about the impact of aggregate aberrations and gene fusion events in prostate cancer. METHODS Using cBioportal for Cancer Genomics, an open-access resource for exploration of multidimensional cancer genomics data, we integrate whole-exome sequencing, gene expression, and histopathology with longitudinal clinical outcomes. Subsets of prostate tumors with aberrations in all three genes TP53, PTEN and RB1 were identified and correlated with prevalence of gene fusions. Prostate tumors with aberrations in TP53, PTEN, and RB1 were termed "triple aberrant prostate cancer" (TAPC). RESULTS Of 479 metastatic prostate tumors, 195 (40.7%) were TAPC, versus 21 of 594 (3.5%) of primary prostate tumors. Patients with metastatic TAPC showed a trend toward poorer overall survival than patients harboring 0, 1 or 2 of these aberrations. Twenty-five distinct fusions were identified, all involving ETS transcription factors. Both primary and metastatic prostate cancers with ETS fusions were significantly more likely to be TAPC than those without ETS fusions. CONCLUSIONS This study identified a unique molecular signature consisting of combined aberrations in TP53, PTEN and RB1 that is associated with poorer overall survival, as well as increasing prevalence of ETS gene fusions and differential gene expression patterns favoring aggressive disease and tumor progression. Identification of this subset of patients could inform prognostic decisions and provide a rationale for more aggressive or unique therapeutic approaches.