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- Study Description
The somatic genetic basis of chronic lymphocytic leukemia (CLL), a common and clinically heterogenous adult leukemia, remains poorly understood. Massively parallel sequencing technology now provides a method for systematic discovery of genetic alterations that underlie disease, and for uncovering new therapeutic targets and biomarkers. In study version 2 we presented a dataset consisting of DNA sequencing from 169 CLL samples (with matched germline controls). Samples were collected from patients displaying a wide range of characteristics representing the broad clinical spectrum of CLL.
Understanding the mutational landscape of CLL provides a starting point for systematic analyses to address fundamental questions in CLL, including how mutated genes alter cellular networks and phenotypes, and thereby contribute to disease heterogeneity.
Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of >100 primary chronic lymphocytic leukemias (CLLs; data presented in study version 3). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylationdisorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.
- Study Design:
- Case Set
- Study Type:
- Case Set
- Tumor vs. Matched-Normal
- Total number of consented subjects: 186
- Subject Sample Telemetry Report (SSTR)
- Study Design:
- Authorized Access
- Publicly Available Data (Public ftp)
- Molecular Data
Type Source Platform Number of Oligos/SNPs SNP Batch Id Comment Whole Genome Genotyping Affymetrix AFFY_6.0 934940 52074 Whole Exome Sequencing Agilent Agilent selected, 76bp paired end reads N/A N/A Whole Genome Sequencing Illumina 101bp paired end reads N/A N/A Whole Genome Bisulfite Sequencing Illumina Whole-Genome Bisulfite Sequencing N/A N/A RNA Sequencing Illumina TruSeq Stranded Total RNA Sample Prep Kit N/A N/A Strand-oriented total RNA-Seq using TruSeq Stranded Total RNA Sample Prep Kit for library preparation. Paired-end reads 2x100 bases from HiSeq2500
- Study History
- March 2012 - Data release of n=91 subjects
- June 2013 - Data release of n=169 subjects
- April 2017 - Data release of n=186 subjects and n=959 samples
- Selected Publications
- Diseases/Traits Related to Study (MeSH terms)
- Links to Related Resources
- Authorized Data Access Requests
See research articles citing use of the data from this study
- Study Attribution
- Catherine Wu. Broad Institute, Cambridge, MA, Dana Farber Cancer Institute, Boston MA, USA.
- Stacey Gabriel. Broad Institute, Cambridge, MA, USA.
- Eric Lander. Broad Institute, Cambridge, MA, USA.
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- U54 HG003067. National Institutes of Health, Bethesda, MD, USA.
- Principal Investigators