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Comprehensive molecular characterization of human colon and rectal cancer.

Nature | Jul 18, 2012

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

Pubmed ID: 22810696 RIS Download

Mesh terms: Colonic Neoplasms | DNA Copy Number Variations | DNA Methylation | Exome | Gene Expression Profiling | Humans | Mutation | Mutation Rate | Polymorphism, Single Nucleotide | Rectal Neoplasms | Sequence Analysis, DNA

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Associated grants

  • Agency: NCI NIH HHS, Id: U24CA143840
  • Agency: NCI NIH HHS, Id: P30 CA016672
  • Agency: NCI NIH HHS, Id: U24 CA143882
  • Agency: NHGRI NIH HHS, Id: U54 HG003067
  • Agency: NHGRI NIH HHS, Id: U54HG003273
  • Agency: NCI NIH HHS, Id: U24 CA143835
  • Agency: NCI NIH HHS, Id: U24 CA143866
  • Agency: NCI NIH HHS, Id: U24CA143858
  • Agency: NCI NIH HHS, Id: U24CA143882
  • Agency: NCI NIH HHS, Id: U24CA144025
  • Agency: NCI NIH HHS, Id: P30 CA016086
  • Agency: NHGRI NIH HHS, Id: U54HG003067
  • Agency: NCI NIH HHS, Id: U24 CA143845
  • Agency: NCI NIH HHS, Id: U24 CA143799
  • Agency: NHGRI NIH HHS, Id: U54 HG003273
  • Agency: NCI NIH HHS, Id: U24 CA144025
  • Agency: NCI NIH HHS, Id: U24CA143883
  • Agency: NHGRI NIH HHS, Id: U54HG003079
  • Agency: NCI NIH HHS, Id: U24 CA126554
  • Agency: NCI NIH HHS, Id: U24 CA143840
  • Agency: NCI NIH HHS, Id: U24 CA143843
  • Agency: NCI NIH HHS, Id: U24CA143867
  • Agency: NCI NIH HHS, Id: U24CA143835
  • Agency: NCI NIH HHS, Id: U24 CA143858
  • Agency: NCI NIH HHS, Id: U24CA143843
  • Agency: NHGRI NIH HHS, Id: R01 HG006272
  • Agency: NCI NIH HHS, Id: U24 CA143848
  • Agency: NCI NIH HHS, Id: U24CA143848
  • Agency: NHGRI NIH HHS, Id: U54 HG003079
  • Agency: NCI NIH HHS, Id: U24CA143799
  • Agency: NCI NIH HHS, Id: U24 CA143883
  • Agency: NCI NIH HHS, Id: U24CA143866
  • Agency: NCI NIH HHS, Id: U24CA143845
  • Agency: NCI NIH HHS, Id: U24 CA143867

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The Cancer Genome Atlas

Project exploring the spectrum of genomic changes involved in more than 20 types of human cancer that provides a platform for researchers to search, download, and analyze data sets generated. As a pilot project it confirmed that an atlas of changes could be created for specific cancer types. It also showed that a national network of research and technology teams working on distinct but related projects could pool the results of their efforts, create an economy of scale and develop an infrastructure for making the data publicly accessible. Its success committed resources to collect and characterize more than 20 additional tumor types. Components of the TCGA Research Network: * Biospecimen Core Resource (BCR); Tissue samples are carefully cataloged, processed, checked for quality and stored, complete with important medical information about the patient. * Genome Characterization Centers (GCCs); Several technologies will be used to analyze genomic changes involved in cancer. The genomic changes that are identified will be further studied by the Genome Sequencing Centers. * Genome Sequencing Centers (GSCs); High-throughput Genome Sequencing Centers will identify the changes in DNA sequences that are associated with specific types of cancer. * Proteome Characterization Centers (PCCs); The centers, a component of NCI's Clinical Proteomic Tumor Analysis Consortium, will ascertain and analyze the total proteomic content of a subset of TCGA samples. * Data Coordinating Center (DCC); The information that is generated by TCGA will be centrally managed at the DCC and entered into the TCGA Data Portal and Cancer Genomics Hub as it becomes available. Centralization of data facilitates data transfer between the network and the research community, and makes data analysis more efficient. The DCC manages the TCGA Data Portal. * Cancer Genomics Hub (CGHub); Lower level sequence data will be deposited into a secure repository. This database stores cancer genome sequences and alignments. * Genome Data Analysis Centers (GDACs) - Immense amounts of data from array and second-generation sequencing technologies must be integrated across thousands of samples. These centers will provide novel informatics tools to the entire research community to facilitate broader use of TCGA data. TCGA is actively developing a network of collaborators who are able to provide samples that are collected retrospectively (tissues that had already been collected and stored) or prospectively (tissues that will be collected in the future).

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