Pediatric Precision Sequencing (PIPseq, Columbia, 2017)

Overview

The Precision in Pediatric Sequencing (PIPseq) program at Columbia University Medical Center is a prospective CLIA-certified clinical genomics program for high-risk pediatric hematology-oncology patients. The study enrolled 101 consecutive patients (mean age 9.3 years; range 2 weeks–26 years; sequenced January 2014–April 2016) who met eligibility criteria including <50% estimated 5-year survival, outlier phenotype, rare cancers without standard-of-care, suspected germline predisposition, or relapsed/refractory disease. VCFs, translocations, and gene expression data were released through cBioPortal under CUMC IRB approval.

Composition

  • 101 patients, 120 samples (85 primary disease, 35 relapse/refractory); 60% male, 41% female.
  • Solid tumors (64%): sarcoma (n=17), brain tumors (n=16), and other solid histologies across >20 OncoTree codes including NBL, OS, ES, ARMS, MBL, WT, RCC, LIHB, HCC, ATRT, IMT.
  • Hematologic disease (36%): AML, BLL, JMML, AMKL, CML, TLL, ALCL, HL, PTLD.
  • Sequencing platforms (n=120): cancer WES + transcriptome 63 (53%), cancer WES alone 19 (16%), constitutional WES 22 (18%), transcriptome only 3 (2%), targeted 467-gene panel 13 (11%).
  • Reads aligned to GRCh37/hg19; WES achieved >150-fold and targeted capture >500-fold average coverage with >98% of coding sequence at ≥10X.

Assays / panels (linked)

  • whole-exome sequencing — Agilent SureSelectXT All Exon V5+UTRs on HiSeq2500 (paired-end 125 cycle ×2); paired tumor/normal.
  • RNA-seq — TruSeq Stranded Total RNA LT kit; fusion detection via FusionMap; quantification with TopHat2/Cufflinks.
  • Columbia Comprehensive Cancer Panel — 467-gene targeted panel (5.59 Mb custom Agilent SureSelectXT library), optimized for FFPE material, >500-fold average coverage.
  • CNV inferred from WES via EXCAVATOR v2.2.

Papers using this cohort

  • PMID:28007021 — Oberg et al. 2016. First 101 patients in the PIPseq program; comprehensive characterization of actionable somatic findings (38%), germline predisposition variants (14%), and RNA-seq diagnostic/prognostic impact (70% unique clinical contribution in patients with full cWES+RNA-seq).

Notable findings derived from this cohort

  • Potentially actionable somatic alterations identified in 38/101 patients (38%); only 6/38 (16%) received matched targeted therapy, demonstrating the gap between actionability and treatment access PMID:28007021.
  • Clinically impactful findings (diagnostic, prognostic, pharmacogenomic, or actionable) in 66/101 patients (66%) overall and 75% (45/60) of those with full cWES + RNA-seq PMID:28007021.
  • RNA-seq uniquely contributed clinical impact in 23/33 patients (70%) through fusion detection, expression-based subtyping, and BCR-ABL1-like signature identification PMID:28007021.
  • Germline cancer-predisposition variants in 14/90 patients (14%); ACMG secondary findings returned to six patients (BRCA1 ×2, TP53, TNNT2, RYR1, VHL) PMID:28007021.
  • Most frequently mutated genes: TP53 in solid tumors (n=9, 9%); RAS-pathway genes in hematologic samples (NRAS n=5, KRAS n=3) PMID:28007021.
  • 94% of consented patients opted in to receive ACMG secondary findings, supporting broad return-of-results policies in pediatric oncology PMID:28007021.
  • Mean mutational load 216.9 variants per patient (SD 829.3, median 69); lower than adult-cancer benchmarks, higher in solid tumors than hematologic conditions PMID:28007021.

Sources

  • cBioPortal study: mixed_pipseq_2017
  • CUMC IRB-approved data release (VCFs, translocations, gene expression).

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