title: Exome sequencing in diagnostic evaluation of colorectal cancer predisposition in young patients.
abstract: OBJECTIVE
  Early-onset colorectal cancer (CRC), defined here as age of onset less than 40 years, develops frequently in genetically predisposed individuals. Next-generation sequencing is an increasingly available option in the diagnostic workup of suspected hereditary susceptibility, but little is known about the practical feasibility and additional diagnostic yield of the technology in this patient group.
  
  
  METHODS
  We analyzed 38 young CRC patients derived from a set of 1514 CRC cases. All 38 tumors had been tested in our laboratory for microsatellite instability (MSI), and Sanger sequencing had been used to screen for MLH1 and MSH2 mutations in MSI cases. Also, gastrointestinal polyposis had been diagnosed clinically and molecularly. Family histories were acquired from national registries. If inherited syndromes had not been diagnosed in routine diagnostic efforts (n = 23), normal tissue DNA was analyzed for mutations in a comprehensive set of high-penetrance genes (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, SMAD4, BMPR1A, LKB1/STK11, and PTEN) by exome sequencing.
  
  
  RESULTS
  CRC predisposition syndromes were confirmed in 42% (16/38) of early-onset CRC patients. Hereditary nonpolyposis colorectal cancer was diagnosed in 12 (32%) patients, familial adenomatous polyposis in three (7.9%), and juvenile polyposis in one (2.6%) patient. Exome sequencing revealed one additional MLH1 mutation. Over half of the patients had advanced cancers (Dukes C or D, 61%, 23/38). The majority of nonsyndromic patients had unaffected first-degree relatives and microsatellite-stable tumors.
  
  
  CONCLUSIONS
  Microsatellite instability positivity or gastrointestinal polyposis characterized all patients with unambiguous highly penetrant germline mutations. In our series, exome sequencing produced little added value in diagnosing the underlying predisposition conditions.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, P.O. Box 63, FIN-00014 University of Helsinki, Helsinki, Finland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Tanskanen
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gylfe
authors.forename: Riku
authors.initials: R
authors.lastname: Katainen
authors.forename: Minna
authors.initials: M
authors.lastname: Taipale
authors.forename: Laura
authors.initials: L
authors.lastname: Renkonen-Sinisalo
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000175:diagnosis* / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D044483:Intestinal Polyposis / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D008297:Male; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D051901:Smad4 Protein / Q000235:genetics; D055815:Young Adult
chemical_list: C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes