Molecular Characterization of Choroid Plexus Tumors Reveals Novel Clinically Relevant Subgroups

Abstract

Purpose: To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options.Experimental Design: One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copynumber (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes.Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%-46.5% vs. 66.7%, 28.2%-87.8%, respectively, P ¼ 0.04; EFS: 0% vs. 44.4%, 13.6%-71.9%, respectively, P ¼ 0.03). CPPs and aCPPs exhibited favorable survival.Discussion: Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs.

Pediatric atypical choroid plexus papilloma reconsidered: increased mitotic activity is prognostic only in older children

“…Our series thus might help to explain the discrepancy between results obtained in previous pediatric series [1,4] as compared to older patient collectives [2]. The majority of aCPP occur in children younger than three years.…”

“…In the latter series, however, patients harboring atypical CPP were younger than in the first study [2], raising the possibility that increased mitotic activity might not have an adverse prognostic effect in younger children. Indeed, two recent studies suggested that CPP and aCPP in younger children show not only similar molecular profiles, but also comparable outcome [1,4]. These results are questioning the concept of aCPP, but might well be related to an age-dependent effect.…”

“…According to the World Health Organization (WHO) classification, choroid plexus tumors can be divided into choroid plexus papillomas (CPP, WHO grade I), atypical choroid plexus papillomas (aCPP, WHO grade II) and choroid plexus carcinomas (CPC, WHO grade III) [6]. While CPC show histopathological signs of malignancy and distinct molecular features [4,7,8], CPP are benign papillary neoplasms closely resembling non-neoplastic choroid plexus. The observation that increased mitotic activity (≥2 mitoses/10 Electronic supplementary material The online version of this article (doi:10.1007/s00401-015-1434-z) contains supplementary material, which is available to authorized users.…”

Cross-Species Genomics Identifies TAF12, NFYC, and RAD54L as Choroid Plexus Carcinoma Oncogenes

“…Thus, the concurrent gain of TAF12, NFYC and RAD54L may serve to model an aberrant epigenome that promotes a proliferative, and relatively undifferentiated state ( TAF12 and NFYC ), while tolerating genotoxic stress ( RAD54L ). Interestingly, recent data indicate that CPCs that do not gain chromosome 1 retain both copies of this chromosome in an otherwise hypodiploid genome (Merino et al, 2014). Thus absolute or relative gain of this chromosome might be required for CPC development.…”

Establishing a Preclinical Multidisciplinary Board for Brain Tumors

“…The radio-resistance of mCPC may reflect the Tp53 null status of these tumors, since this gene mediates cell death mechanisms in irradiated cells (39). Notably, 60% of human CPCs contain mutant Tp53 : these tumors also tend to be radio-resistant, clinically aggressive and to develop in infants (40, 41). It is interesting that our mCPC model is initiated in embryonic choroid plexus; therefore, these tumors likely model radio-resistant, aggressive and TP53 -mutant infant CPC (18).…”