Concurrent AURKA and MYCN Amplification in Primary Prostate Adenocarcinoma Is Associated with the Development of Lethal Neuroendocrine Prostate Cancer
Kyung Park, Himisha Beltran, Theresa Y MacDonald, Scott T Tagawa, David M Nanus, Mark A Rubin, Juan Miguel Mosquera. Weill Medical College of Cornell University, New York, NY
Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that most commonly arises from existing prostate adenocarcinoma (PCa), with likely clonal origin. There is currently no effective therapy with most patients surviving less than one year. Recent work identified the overexpression and amplification of Aurora kinase A (AURKA) and N-myc (MYCN) in metastatic NEPC, evidence that they cooperate to directly induce a neuroendocrine (NE) phenotype in PCa, and are targetable with Aurora kinase inhibitor therapy (AKI). We evaluated primary prostate tumors of patients that later developed lethal NEPC and metastases for presence of AURKA and MYCN alterations.
Design: 180 primary PCa tumors were evaluated, of which 64 tumors were from patients who later developed NEPC (low serum PSA, increased serum Chromogranin A, metastatic disease). These included 19 acinar PCa, and 45 mixed small cell/ acinar to pure small cell carcinoma. 8 metastatic tumors were available, 6 of which had matching primary PCa for evaluation. Histology of metastases included 6 mixed small cell/acinar to pure small cell carcinoma (pleura, pelvic bone/soft tissue, epidural, colon), and poorly differentiated adenocarcinoma (liver, brain, spine). Fluorescence in situ hybridization (FISH) using centromeric and target gene probes was performed and correlated with histological findings. 20 benign prostate tissue samples were used as controls.
Results: AURKA and concurrent MYCN amplification were identified in 75% of evaluable primary PCa of patients that later developed NEPC. In contrast, AURKA and MYCN amplifications were identified in 5% of 116 cases of an unselected PCa cohort. When metastatic NEPC was compared to primary PCa of same patient, there was 100% concordance of AURKA and MYCN amplification. In metastatic tumors with mixed features, there was 94% concordance between AURKA and MYCN amplification. 0% benign prostate harbored AURKA and MYCN amplification.
Conclusions: AURKA and MYCN amplification occurs early and is nearly always concurrent despite their location in separate chromosomes. Its presence in primary PCa identifies patients predisposed to the development of an aggressive and lethal NEPC variant. These patients may benefit from early intervention with AKI therapy. Therefore, AURKA and MYCN amplification may be new prognostic and predictive biomarkers.
Category: Genitourinary (including renal tumors)
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 113, Tuesday Afternoon