Concurrent AURKA and MYCN Gene Amplifications Are Harbingers of Lethal TreatmentRelated Neuroendocrine Prostate Cancer

Abstract

Neuroendocrine prostate cancer (NEPC), also referred to as anaplastic prostate cancer, is a lethal tumor that most commonly arises in late stages of prostate adenocarcinoma (PCA) with predilection to metastasize to visceral organs. In the current study, we explore for evidence that Aurora kinase A (AURKA) and N-myc (MYCN) gene abnormalities are harbingers of treatment-related NEPC (t-NEPC). We studied primary prostate tissue from 15 hormone naïve PCAs, 51 castration-resistant prostate cancers, and 15 metastatic tumors from 72 patients at different stages of disease progression to t-NEPC, some with multiple specimens. Histologic evaluation, immunohistochemistry, and fluorescence in situ hybridization were performed and correlated with clinical variables. AURKA amplification was identified in overall 65% of PCAs (hormone naïve and treated) from patients that developed t-NEPC and in 86% of metastases. Concurrent amplification of MYCN was present in 70% of primary PCAs, 69% of treated PCAs, and 83% of metastases. In contrast, in an unselected PCA cohort, AURKA and MYCN amplifications were identified in only 5% of 169 cases. When metastatic t-NEPC was compared to primary PCA from the same patients, there was 100% concordance of ERG rearrangement, 100% concordance of AURKA amplification, and 60% concordance of MYCN amplification. In tumors with mixed features, there was also 100% concordance of ERG rearrangement and 94% concordance of AURKA and MYCN co-amplification between areas of NEPC and adenocarcinoma. AURKA and MYCN amplifications may be prognostic and predictive biomarkers, as they are harbingers of tumors at risk of progressing to t-NEPC after hormonal therapy.

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…Considering the TCGA cohort had 10 total mortality, it is intriguing that 8 of these 10 deaths occurred in patients with SigMuc1NW‐positive PC (Fig. 2B, P  = 0.00212), which are consistent with VAV2, ASNS, DNMT3B, and AURKA being factors promoting CRPC development (Gravina et al ., 2011; Magani et al ., 2017; Mosquera et al ., 2013; Sircar et al ., 2012). As expected, SigMuc1NW displays an overlapping pattern with the 9‐gene genomic signature used to select DEGs (Fig.…”

“…VAV2 is a coactivator of androgen receptor (AR) and sustains AR signaling under androgen deprivation therapy (ADT) (Magani et al ., 2017); it also promotes angiogenesis and metastasis (Barrio‐Real and Kazanietz, 2012). AURKA plays a critical role in mitosis (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015) and promotes the development of neuroendocrine PC under ADT (Beltran et al ., 2011; Mosquera et al ., 2013). DNMT3B may regulate epigenetic events to facilitate CRPC development (Hoffmann et al ., 2007).…”

The role of epigenetics and long noncoding RNA MIAT in neuroendocrine prostate cancer

“…NEPC progression is often associated with genetic alterations including AR inactivation, the loss of specific tumor suppressors (RB1, PTEN, TP53), TMPRSS2-ERG rearrangement, and amplification of MYCN and AURKA oncogenes [21,34,35]. Although the roles of these irreversible genetic events have been well characterized, no effective targeted treatment has been developed so far.…”

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

“…N-myc amplification rarely occurs in other lung cancer histologies. N-myc amplification also occurs in approximately 40% of neuroendocrine/small-cell prostate cancers, is commonly seen concurrently with amplification of the aurora kinase A gene (AURKA), and associated with poor prognosis (35,36). In both small-cell lung and prostate cancers, N-myc amplification may occur early before the development of metastasis.…”