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          Institute: MPI für molekulare Genetik     Collection: Department of Vertebrate Genomics     Display Documents



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ID: 548983.0, MPI für molekulare Genetik / Department of Vertebrate Genomics
Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis
Authors:Timmermann, B.; Kerick, M.; Roehr, C.; Fischer, A.; Isau, M.; Boerno, S. T.; Wunderlich, A.; Barmeyer, C.; Seemann, P.; Koenig, J.; Lappe, M.; Kuss, A. W.; Garshasbi, M.; Bertram, L.; Trappe, K.; Werber, M.; Herrmann, B. G.; Zatloukal, K.; Lehrach, H.; Schweiger, M. R.
Language:English
Corporate body:This work was supported by the German Federal Ministry of Education and Research (01GS08105 “Mutanom,” 01GS08111 “Intestinal Modifers”) and the Max Planck Society.
Date of Publication (YYYY-MM-DD):2010-12-10
Title of Journal:PLoS ONE
Journal Abbrev.:PLoS ONE
Volume:5
Issue / Number:12
Start Page:e15661
End Page:e15661
Full name of Issue-Editor(s):Amanda Ewart Toland, Ohio State University Medical Center, United States of America
Copyright:© 2010 Timmermann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Review Status:not specified
Audience:Experts Only
Abstract / Description:BACKGROUND: Colorectal cancer (CRC) is with approximately 1 million cases the third most common cancer worldwide. Extensive research is ongoing to decipher the underlying genetic patterns with the hope to improve early cancer diagnosis and treatment. In this direction, the recent progress in next generation sequencing technologies has revolutionized the field of cancer genomics. However, one caveat of these studies remains the large amount of genetic variations identified and their interpretation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the first work on whole exome NGS of primary colon cancers. We performed 454 whole exome pyrosequencing of tumor as well as adjacent not affected normal colonic tissue from microsatellite stable (MSS) and microsatellite instable (MSI) colon cancer patients and identified more than 50,000 small nucleotide variations for each tissue. According to predictions based on MSS and MSI pathomechanisms we identified eight times more somatic non-synonymous variations in MSI cancers than in MSS and we were able to reproduce the result in four additional CRCs. Our bioinformatics filtering approach narrowed down the rate of most significant mutations to 359 for MSI and 45 for MSS CRCs with predicted altered protein functions. In both CRCs, MSI and MSS, we found somatic mutations in the intracellular kinase domain of bone morphogenetic protein receptor 1A, BMPR1A, a gene where so far germline mutations are associated with juvenile polyposis syndrome, and show that the mutations functionally impair the protein function. CONCLUSIONS/SIGNIFICANCE: We conclude that with deep sequencing of tumor exomes one may be able to predict the microsatellite status of CRC and in addition identify potentially clinically relevant mutations.
Comment of the Author/Creator:E-mail: mschweig@molgen.mpg.de
External Publication Status:published
Document Type:Article
Communicated by:Hans Lehrach
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Biology, Chemistry and Pharmacy, Free University, Berlin, Germany;
2.Department of Gastroenterology, Charité Universitätsmedizin, Berlin, Germany;
3.Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin, Berlin, Germany;
4.Institute for Human Genetics, Ernst Moritz Arndt University, Greifswald, Germany;
5.Department of Pathology, Medical University, Graz, Austria.
Identifiers:ISSN:1932-6203 [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=... [ID No:2]
DOI:10.1371/journal.pone.0015661 [ID No:3]
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