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DFCI Colorectal Cancer Cohorts

ABSTRACT:

Colorectal cancer is a molecularly heterogeneous disease. Whole Exome Sequencing from patients diagnosed with colorectal cancer in the NHS and HPFS cohorts will extend our understanding of the genetic changes occurring in specific clinical contexts in the disease. This effort has the potential to discover novel recurrently mutated genes and pathways in colorectal cancer that can be functionally validated and give further insights to colorectal cancer pathogenesis. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000.

PROVIDER: phs000722 | dbGaP |

SECONDARY ACCESSION(S): PRJNA239536PRJNA239537

REPOSITORIES: dbGaP

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Project description:For sporadic Burkitt lymphoma (BL) few genetic lesions are known besides the pathognomonic IG-MYC translocations. Thirtynine molecularly-defined BL were analyzed with high-resolution single-nucleotide polymorphism chips for genomic imbalances and uniparental disomy (UPD). Imbalances were correlated to transcript profiling and selected miRNA analysis. Translocations affecting the MYC locus were studied by fluoresence in situ hybridization. We detected 528 copy number changes, defining 29 recurrently imbalanced regions. 518 regions of UPD were found, but these were rarely recurrent. Combined imbalance mapping and transcript profiling revealed a profound correlation between copy number and expression. Several recurrent imbalances affected the MYC pathway: The miRNA-supercluster 17-92 was frequently gained and the transcription factor E2F2 was recurrently deleted. Molecular BL lacking MYC translocations showed MYC gains. Amplifications of the polymerase iota gene were associated with increased genomic instability. The present findings suggests that UPDs play no major role in the pathogenesis of BL, whereas some genes may contribute to BL development through gene dosage effects. Amplifications of the polymerase iota gene may be functionally linked with increased genomic instability in BL. The pattern and rarity of chromosomal changes detectable even at the high resolution employed here, together with aberrations of genes regulating MYC activity, support that deregulation of the MYC pathway is the major force driving BL pathogenesis, but show that this deregulation is more complex than previously known. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from whole tissue. Copy number and LOH analysis of 500K SNP arrays was performed for 30 molecularly-defined Burkitt lymphomas. Genotyping was performed using the BRLMM-algorithm. Only a single 250k Chip was performed for nine additional Burkitts. 20 normal references (10 of those hybridized to nsp-chips) extracted from healthy blood donors, used as normals in the analysis in addition to the HapMap references provided by Affymetrix, are included in the set.

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DFCI Colorectal Cancer Cohorts

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