Pilocytic Astrocytoma — DKFZ/Heidelberg ICGC PedBrain 2013

Overview

Whole-genome sequencing cohort of 96 pediatric pilocytic astrocytomas (PAST) with matched germline DNA, generated by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project based at the German Cancer Research Center (DKFZ), Heidelberg. Published by Jones et al. 2013 in Nature Genetics. Sequence data deposited in the European Genome-phenome Archive under accession EGAS00001000381. An additional independent screening cohort of 45 non-cerebellar PAST (negative for KIAA1549:BRAF) was sequenced for targeted validation.

Composition

  • 96 pilocytic astrocytomas (PAST) with matched blood DNA; Illumina HiSeq 2000 whole-genome sequencing.
  • Matched RNA sequencing (n=73) and long-insert mate-pair sequencing (n=68) for structural variant detection.
  • Tumor locations: approximately half cerebellar, half non-cerebellar/extra-cerebellar/midline.
  • Additional screening cohort: 45 non-cerebellar PAST (KIAA1549:BRAF negative) screened for FGFR1 exons 12 & 14 and PTPN11 exon 3.
  • Gene expression array: 118 pilocytic astrocytomas (Affymetrix U133 Plus2.0, 66 from this series) vs. 158 other astrocytic tumors.
  • Comparison cohort: 48 pediatric glioblastoma exomes re-examined for cross-disease FGFR1 alteration finding.
  • Alignment: BWA + samtools + Picard to hg19.

Assays / panels (linked)

Papers using this cohort

  • PMID:23817572 — Jones et al. 2013, “Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma,” Nature Genetics.

Notable findings derived from this cohort

  • 100% of 96 pilocytic astrocytomas harbored a MAPK pathway alteration; pilocytic astrocytoma is a prototypic single-pathway disease PMID:23817572.
  • Extremely low somatic mutation rate (<0.1/Mb; mean 1.6 non-synonymous SNVs per tumor, range 0–9); mutation rate positively correlated with patient age (Pearson r=0.42, P=2.3×10⁻⁵) PMID:23817572.
  • 70/96 cases harbored KIAA1549:BRAF fusion; four novel BRAF fusion partners identified (RNF130:BRAF n=2, CLCN6:BRAF, MKRN1:BRAF, GNAI1:BRAF); novel BRAF p.R506_insVLR insertion confirmed to stabilize BRAF dimers and match V600E for ERK activation PMID:23817572.
  • Two novel NTRK2 fusions in 3 non-cerebellar cases: QKI:NTRK2 and NACC2:NTRK2; both 5’ partners contribute dimerization domains PMID:23817572.
  • Recurrent FGFR1 kinase-domain hotspot mutations at N546 and K656 in 14 total tumors (5 WGS + 9 screening); all FGFR1-mutant tumors extra-cerebellar/midline; phospho-FGFR1 IHC positive in 7/7 FGFR1-mutant vs. 0/11 wildtype PMID:23817572.
  • Recurrent PTPN11 (SHP-2) mutations E69K and E76A exclusively co-occurring with FGFR1 mutations; PTPN11 acts as a modifier of FGFR1-driven ERK activation PMID:23817572.
  • Same FGFR1 hotspot mutations found in 3/48 (6%) pediatric glioblastomas with H3-3A K27M + somatic NF1 alteration, extending the therapeutic target to GB PMID:23817572.
  • BRAF, FGFR1, KRAS, and NF1 were the only significantly mutated genes (max-FDR 0.05); alterations were mutually exclusive except for FGFR1+PTPN11 co-occurrence (permutation test P<0.0001) PMID:23817572.

Sources

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