Additional file 5 of The Swedish childhood tumor biobank: systematic collection and molecular characterization of all pediatric CNS and other solid tumors in Sweden
Creators: name: Díaz de Ståhl, Teresita
name: Shamikh, Alia
name: Mayrhofer, Markus
name: Juhos, Szilvester
name: Basmaci, Elisa
name: Prochazka, Gabriela
name: Garcia, Maxime
name: Somarajan, Praveen Raj
name: Zielinska-Chomej, Katarzyna
name: Illies, Christopher
name: Øra, Ingrid
name: Siesjö, Peter
name: Sandström, Per-Erik
name: Stenman, Jakob
name: Sabel, Magnus
name: Gustavsson, Bengt
name: Kogner, Per
name: Pfeifer, Susan
name: Ljungman, Gustaf
name: Sandgren, Johanna
name: Nistér, Monica
Publisher: name: figshare
Year: 2024
Subjects: subject: Genetics
subject: FOS: Biological sciences

description: Additional file 5: Figure S1. Copy number alterations detected in CNS tumors. Heatmap of CNVs across the series of tumors studied as determined by Control-FREEC. The x-axis shows the copy number status along the chromosomes (1-22, X, Y). Areas painted in blue or red indicate regions of loss or gain, respectively. A deeper color indicates a relatively higher copy number change, with the scale displayed to the right of the heatmap. CNVs are common events in pediatric brain tumors, and CNVs with clinical relevance were observed in several samples. Focal SMARCB1 deletions were identified in ATRT-MYC subgroup tumors (P1315_108T, P2233_115T), while whole chr22 deletions were observed in ATRT-TYR subgroup tumors (P1148_109T, P4551_208T). In MBs, deletion of the whole chr6 was observed in a MB of the WNT class (P7708_102T), and 9q and/or 10q loss was observed in MBs of the SHH class (FAM2T, F0025678-0810, F0025679-0775, BTB0001T). PAs generally exhibit different types of aberrations that indicate activation of mitogen-activating protein kinase (MAPK) signaling. Most of the profiled PAs (15 of 20 tumors) displayed the typical tandem duplication at 7q34 that results in KIAA1459::BRAF in-frame fusion and leads to a constitutively active kinase lacking the BRAF autoregulatory domain. One PA (P4552_110T) presented with a QKI::RAF1 fusion resulting from a translocation between chr3 and chr6; these rearrangements also led to small telomeric 3p gain and 6q deletions. Mutations and amplifications of tyrosine-kinase receptors, such as PDGFRA and PDGFRB, or their ligands, result in activation of the PI3K and Ras/Raf pathways and are of clinical relevance. Amplification of PDGFRA on chr4 was observed among GBM/PNET/embryonal tumor samples (P7708_127T, P7708_128T, P4551_209T, see also Additional file 2: Table S1). In agreement with previous knowledge, PDGFRA alterations were found in older children (P7708_127T and P4551_209T, both adolescents) and in combination with H3F3A K27M in one tumor and with MET amplification (chr7, 35 copies) in the other [25, 31]. MET signaling aberrations are found in many human malignancies, and MET amplification as well as MET fusions have been observed in pediatric GBMs [19]. Additional alterations, such as homozygous loss of CDKN2A (P1148_112T, P4551_218T, P2233_106T) and amplification of CDK6 (P4551_211T, P4551_209T, P2233_101T), were also observed in this series. Regarding ependymomas, the methylation classifier assigned three of them as ependymoma posterior fossa group A (EP-PFA) and four as ependymoma RELA fusion (EP-RELA). The methylation class EP-PFA mainly comprises tumors with scarce copy number changes [38]. Driving molecular changes in this class currently unknown. Two of the tumors in this class presented a flat profile (P2233_113T and P7708_111T), and the third showed 17q gain and 22q loss (F0025588-0809). The EP-RELA class almost exclusively comprises with an oncogenic fusion between C11ORF95 and RELA, a member of the NF kappa B signaling pathway [38]. CNVs on 11q13.1, involving C11ORF95 and RELA, were observed in four cases (P1148_114T, P7708_114T, P7708_115T and P7708_201T). In one of the EP-RELA samples (P1148_114T), gain of 1q was also observed, an alteration associated with poor prognosis [22]. In a pineoblastoma (P2233_112T) classified by methylation profiling as pineoblastoma group B, we found various numeric whole chromosome changes, which are frequently seen in this methylation class, including gain of chromosomes 7, 9, 12, 13, 15, 17, 18, 19 and 20. Furthermore, chromothripsis affecting chr11 was detected in the sample (Additional file 6: Fig. S2). In an atypical choroid plexus papilloma, classified as choroid plexus papilloma subclass pediatric A (P7708_108T), several whole chromosome gains, including trisomy 7, 8, 12, 18 and 19, were observed. Numeric whole chromosome changes are frequently observed in this tumor class; however, additional characteristic molecular features are unknown ( https://www.molecularneuropathology.org/mnp/ ). One investigated hypophysis adenoma (A: P7708_125T) was classified as pituitary adenoma somatotropin producing, densely granulated group B. Pituitary adenomas (STH producing, densely granulated) form two methylation classes, group A and B, with unknown clinical significance. While group A tumors often present with several numeric whole chromosome changes, group B tumors seldom show chromosomal imbalances. The tumor studied here presented a flat profile that fits the methylation classification.