National Cancer Institute (NCI) Cancer Genome Characterization Initiative (CGCI): Medulloblastoma

The Office of Cancer Genomics (OCG) at the National Cancer Institute is sponsoring a series of studies as part of the Cancer Genome Characterization Initiative (CGCI) to assess novel emerging sequencing technologies in cancer. The CGCI program includes comprehensive characterization of the genetic aberrations found in different pediatric and/or adult tumors, including medulloblastoma.

Medulloblastoma is the most common malignant brain tumor found in children. In order to identify the genetic alterations in MB, copy number alterations were sought using high-density microarrays and sequenced all known protein-coding genes and miRNA genes using Sanger sequencing in a set of 22 pediatric MB samples and one matched normal blood sample. All tumor samples were obtained at the time of original surgery (pre-treatment) except for one sample, which was obtained at the time of MB recurrence.

Protein-encoding transcripts to be targeted for sequencing were derived from transcripts present in the Ensembl (file date 8/27/2008), RefSeq (file date 1/18/2009), and CCDS (file date 2/02/2009) databases and downloaded from the UCSC Genome Bioinformatics site. The protein encoding transcripts were supplemented with microRNA transcripts downloaded from the Sanger miRBase Sequence Database (Release 13.0) in order to yield a combined set of transcripts representing 24,893 genes (24,178 protein encoding and 715 microRNA). The regions of interest (ROIs) targeted for sequencing comprised the entire transcribed portion of the microRNA exons and the protein encoding portion plus 4 bases of flanking sequence for the protein encoding exons. Illumina Infinium II Whole Genome Genotyping Assay employing the BeadChip platform was used to analyze the same set of tumor samples at 1,199,187 (1M-Duo) SNP loci in order to detect copy number alterations in the same set of tumors.

• Study Weblinks:
  • The Cancer Genome Characterization Initiative
• Study Design:
  • Tumor vs. Matched-Normal
• Study Type:
  • Cohort

The Discovery Screen consisted of 22 tumor samples (17 primary tumors, 4 xenografts, and 1 cell line), with the Prevalence Screen including another 66 primary tumors. Clinical data is available for all samples at the following link: http://www.sciencemag.org/content/suppl/2010/12/15/science.1198056.DC1/Parsons_SOM.pdf. All samples had been given a diagnosis of MB (WHO grade IV) by institutional report. All samples with available hemotoxylin and eosin-stained (H+E) slides or available tissue blocks from which new H+E slides could be produced were subjected to central review by a pediatric neuropathologist (PB) (scanned images of H+E slides of samples are available at http://cgci.nci.nih.gov/dataMatrix/CGCI_DataMatrix.html). For each slide the percentage of tumor cells present was estimated, and the MBs were subclassified as large cell/anaplastic (LCA), nodular/desmoplastic (ND), or classic, non-nodular (C) when possible. All tumor samples were obtained at the time of the original surgery except one, which was obtained at the time of MB recurrence.

Additional information on specimen inclusion and exclusion criteria for the specific tumor types investigated as part of CGCI can be found on the CGCI website and within referenced publications for this initiative.

Cancer is a genetic disease. Alterations at the DNA level drive the cellular changes that are hallmarks of cancer including aberrant cell division and survival. Historically, genetic causes of cancer were studied by analysis of one or a few genes at a time. More recently however, novel high-throughput technologies have provided unprecedented capabilities to examine the cancer genome. These technologies allow systematic characterization of genetic and epigenetic alterations, allowing investigators to identify the underlying genetic changes found in cancer. The CGCI incorporates multiple approaches for genomic characterization including exome sequencing and transcriptome analysis using next generation sequencing. To encourage collaboration and leverage the collective knowledge and innovation of the entire cancer research community, all data collected will be publicly available through databases supported by the National Institutes of Health and National Cancer Institute.

The medulloblastoma project has been completed and data is available at the CGCI website.

• Primary Phenotype: Medulloblastoma

• Principal Investigator
  • Victor Velculescu, MD, PhD. The Johns Hopkins University Sidney Kimmel Cancer Center, Baltimore, MD, USA.
• Co-Investigator
  • D. William Parsons, MD, PhD. Texas Children's Hospital, Houston, Texas, USA.
• Institute
  • Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, The Johns Hopkins University Sidney Kimmel Cancer Center, Baltimore, MD, USA.
• Funding Source
  • N01-C0-12400. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.