title: Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Next Generation Sequencing Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Timmermann
authors.forename: Martin
authors.initials: M
authors.lastname: Kerick
authors.forename: Christina
authors.initials: C
authors.lastname: Roehr
authors.forename: Axel
authors.initials: A
authors.lastname: Fischer
authors.forename: Melanie
authors.initials: M
authors.lastname: Isau
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Boerno
authors.forename: Andrea
authors.initials: A
authors.lastname: Wunderlich
authors.forename: Christian
authors.initials: C
authors.lastname: Barmeyer
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
authors.forename: Jana
authors.initials: J
authors.lastname: Koenig
authors.forename: Michael
authors.initials: M
authors.lastname: Lappe
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Kathrin
authors.initials: K
authors.lastname: Trappe
authors.forename: Martin
authors.initials: M
authors.lastname: Werber
authors.forename: Bernhard G
authors.initials: BG
authors.lastname: Herrmann
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Michal R
authors.initials: MR
authors.lastname: Schweiger
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000368:Aged; D003110:Colonic Neoplasms / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation