Journal Article

Gene expression signatures of neuroendocrine prostate cancer and primary small cell prostatic carcinoma

Alshalalfa, Mohammed, Lehrer, Jonathan, Tsai, Harrison K., Erho, Nicholas, Lotan, Tamara L., Davicioni, Elai

2017

Overview

Background Neuroendocrine prostate cancer (NEPC) may be rising in prevalence as patients with advanced prostate cancer potentially develop resistance to contemporary anti-androgen treatment through a neuroendocrine phenotype. While prior studies comparing NEPC and prostatic adenocarcinoma have identified important candidates for targeted therapy, most have relied on few NEPC patients due to disease rarity, resulting in thousands of differentially expressed genes collectively and offering an opportunity for meta-analysis. Moreover, past studies have focused on prototypical NEPC samples with classic immunohistochemistry profiles, whereas there is increasing recognition of atypical phenotypes. In the primary setting, small cell prostatic carcinoma (SCPC) is frequently admixed with adenocarcinomas that may be clonally related, and a minority of SCPCs express markers typical of prostatic adenocarcinoma while rare cases do not express neuroendocrine markers. We derived a meta-signature of prototypical high-grade NEPC, then applied it to develop a classifier of primary SCPC incorporating disease heterogeneity. Methods Prototypical NEPC samples from 15 patients across 6 frozen tissue microarray datasets were assessed for genes with consistent outlier expression relative to adenocarcinomas. Resulting genes were used to determine subgroups of primary SCPCs (N=16) and high-grade adenocarcinomas (N=16) profiled by exon arrays using formalin-fixed paraffin-embedded (FFPE) material from our institutional archives. A subgroup classifier was developed using differential expression for feature selection, and applied to radical prostatectomy cohorts. Results Sixty nine and 375 genes demonstrated consistent outlier expression in at least 80% and 60% of NEPC patients, with close resemblance in expression between NEPC and small cell lung cancer. Clustering by these genes generated 3 subgroups among primary samples from our institution. Nearest centroid classification based on the predominant phenotype from each subgroup (9 prototypical SCPCs, 9 prototypical adenocarcinomas, and 4 atypical SCPCs) achieved a 4.5% error rate by leave-one-out cross-validation. The classifier identified SCPC-like expression in 40% (2/5) of mixed adenocarcinomas and 0.3-0.6% of adenocarcinomas from prospective (4/2293) and retrospective (2/355) radical prostatectomy cohorts, where both SCPC-like retrospective cases subsequently developed metastases. Conclusions Meta-analysis generates a robust signature of prototypical high-grade NEPC, and may facilitate development of a primary SCPC classifier based on FFPE material with potential prognostic implications.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Analysis / Biomarkers, Tumor / Biomedical and Life Sciences / Biomedicine / Cancer genetics / Cancer Research / Carcinoma / Carcinoma, Neuroendocrine - genetics / Carcinoma, Neuroendocrine - pathology / Care and treatment / Computational Biology - methods / Databases, Genetic / Development and progression / FFPE / Formaldehyde / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Gene signature / Genes / Genetic aspects / Genetic Heterogeneity / Genetic research / Genetics / genomics and epigenetics / Health Promotion and Disease Prevention / Humans / Immunohistochemistry / Male / Medicine/Public Health / Meta-analysis / Meta-Analysis as Topic / Mixed prostatic adenocarcinoma / Neoplasm Grading / Neuroendocrine prostate cancer / Oncology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Research Article / Small cell carcinoma / Surgical Oncology / Transcriptome