Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma

Abstract

Central nervous system primitive neuroectodermal tumor (CNS PNET) and pineoblastoma are highly malignant embryonal brain tumors with poor prognoses. Current therapies are based on the treatment of pediatric medulloblastoma, even though these tumors are distinct at both the anatomical and molecular level. CNS PNET and pineoblastoma have a worse clinical outcome than medulloblastoma; thus, improved therapies based on an understanding of the underlying biology of CNS PNET and pineoblastoma are needed. To this end, we characterized the genomic alterations of 36 pediatric CNS PNETs and 8 pineoblastomas using Affymetrix single nucleotide polymorphism arrays. Overall, the majority of CNS PNETs contained a greater degree of genomic imbalance than pineoblastomas, with gain of 19p (8 [27.6%] of 29), 2p (7 [24.1%] of 29), and 1q (6 [20.7%] of 29) common events in primary CNS PNETs. Novel gene copy number alterations were identified and corroborated by Genomic Identification of Significant Targets In Cancer (GISTIC) analysis: gain of PCDHGA3, 5q31.3 in 62.1% of primary CNS PNETs and all primary pineoblastomas and FAM129A, 1q25 in 55.2% of primary CNS PNETs and 50% of primary pineoblastomas. Comparison of our GISTIC data with publically available data for medulloblastoma confirmed these CNS PNET-specific copy number alterations. With use of the collection of 5 primary and recurrent CNS PNET pairs, we found that gain of 2p21 was maintained at relapse in 80% of cases. Novel gene copy number losses included OR4C12, 11p11.12 in 48.2% of primary CNS PNETs and 50% of primary pineoblastomas. Loss of CDKN2A/B (9p21.3) was identified in 14% of primary CNS PNETs and was significantly associated with older age among children (P = .05). CADPS, 3p14.2 was lost in 27.6% of primary CNS PNETs and was associated with poor prognosis (P = .043). This genome-wide analysis revealed the marked molecular heterogeneity of CNS PNETs and enabled the identification of novel genes and clinical associations potentially involved in the pathogenesis of these tumors.

Copy Number Gain of 1q25 Predicts Poor Progression-Free Survival for Pediatric Intracranial Ependymomas and Enables Patient Risk Stratification: A Prospective European Clinical Trial Cohort Analysis on Behalf of the Children's Cancer Leukaemia Group (CCLG), Société Française d'Oncologie Pédiatrique (SFOP), and International Society for Pediatric Oncology (SIOP)

“…DNA was extracted from 10 mg of frozen tumor tissue and peripheral blood mononuclear cells as described previously (18). Before tissue extraction, hematoxylin/eosin stained…”

DNA copy number alterations in central primitive neuroectodermal tumors and tumors of the pineal region: an international individual patient data meta-analysis

“…After the search cut-off date imposed by the IPD meta-analysis criteria, another study was published recently focusing on CNS-PNET/pineoblastoma only in pediatric patients [17]. By evaluating the genomic array data which are available from NCBI's Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/; accession number GSE12370), we were able to generate CNA profiles for 38 patients (8 of whom had pineoblastoma, and 30 had a CNS-PNET; CGH data from 35 CNS-PNET cases were 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 The approach of an IPD meta-analysis -a specific method of systematic review based on a systematic search -is in our opinion both necessary and efficient to increase the patient number in rare tumor diseases.…”

“…Due to the low incidence of CNS-PNET and pineoblastoma, only a few CGH studies have been reported in these tumors [2,[15][16][17]. So far, results have suggested that CNS-PNET are genetically heterogeneous with frequent and diverse CNAs and that CNA patterns are distinct from those observed in medulloblastoma [2,[15][16][17].…”

“…So far, results have suggested that CNS-PNET are genetically heterogeneous with frequent and diverse CNAs and that CNA patterns are distinct from those observed in medulloblastoma [2,[15][16][17].…”

Common molecularcytogenetic alterations in tumors originating from the pineal region

“…One of the grade II PPTIDs in the present study did not reveal any chromosomal imbalances, while the other grade II PPTID, in addition to gains of 16p, showed a wide range of gains and losses. By using CGH (1) and array-CGH (26,27), grade IV pineoblastomas show relatively low chromosomal rearrangements, with gains at 1, 12q, 13q and 19p, and losses at 13q, 16q and 22q being the most frequent aberrations. In 2 out of 4 grade IV pineoblastomas in the present study, gains at 16p could also be observed.…”