Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study

Abstract

Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.

Keywords: Consensus; DNA methylation profiling; Molecular groups; Pineal parenchymal tumors of intermediate differentiation; Pineoblastoma; Risk-stratification.

Figure 1.

(a) Composition of the consensus study cohort (* including six new patients). (b) t-SNE representation of consensus molecular groups of pineal parenchymal tumors. (c) Relationship between consensus methylation classes and original institutional designations. (d) Relationship between histologic diagnosis and methylation groups. DKFZ, German Cancer Research Center; PPTID, pineal parenchymal tumor of intermediate differentiation; RB, retinoblastoma; RBTC/HSC, Rare Brain Tumor Consortium/Hospital for Sick Children; SJCRH, St. Jude Children’s Research Hospital.

Figure 2.

Recurrent genomic events in pineal parenchymal tumors. (a) Oncoprint depicting nature of driver alterations and recurrent copy-number variations (CNVs) by methylation group. (b) Composite genome-wide CNV plots by methylation groups. (c) Comparison of DICER1 variants and (d) types of DICER1 alterations identified in PB-miRNA1 vs. PB-miRNA2 tumor samples. chr, chromosome; DKFZ, German Cancer Research Center; FTV, frameshifting or truncating variant; RBTC/HSC, Rare Brain Tumor Consortium/Hospital for Sick Children; LOH, loss of heterozygosity; SJCRH, St. Jude Children’s Research Hospital; y, year(s)

Figure 3.

Transcriptomic analysis of study samples (n=18). (a) Clustering based on top 100 differentially expressed genes. (b) Comparison of expression level of CRX – canonical pinealocyte marker, FOXR2, RB1 among tumor groups. (c) Differential expression analysis between tumors from specific groups versus all other samples. DKFZ, German Cancer Research Center; SJCRH, St. Jude Children’s Research Hospital

Figure 4.

Progression-free (PFS) and overall survival (OS) of (a-b) the entire study cohort by methylation groups; and (c-d) outcome of molecularly defined pineoblastomas according to clinical and molecular factors. Bx, biopsy; CSI, craniospinal irradiation; GTR, gross-total resection; M0, non-metastatic; M+, metastatic; NTR, near-total resection; STR, subtotal resection; y, year(s)

Figure 5.

Summary of clinical and molecular characteristics of consensus pineal parenchymal tumor groups. M0, non-metastatic; M+, metastatic; OS, overall survival