title: Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation.
abstract: BACKGROUND
  We previously reported that the target genes in sporadic mismatch repair (MMR)-deficient colorectal carcinomas (CRCs) in the distal colon differ from those occurring elsewhere in the colon. This study aimed to compare the target gene mutational pattern in microsatellite instability (MSI) CRC from Lynch syndrome patients stratified by tumour location and germline mutation, as well as with that of sporadic disease.
  
  
  METHODS
  A series of CRC from Lynch syndrome patients was analysed for MSI in genes predicted to be selective MSI targets and known to be involved in several pathways of colorectal carcinogenesis.
  
  
  RESULTS
  The most frequently mutated genes belong to the TGF-β superfamily pathway, namely ACVR2A and TGFBR2. A significantly higher frequency of target gene mutations was observed in CRC from patients with germline mutations in MLH1 or MSH2 when compared with MSH6. Mutations in microsatellite sequences (A)7 of BMPR2 and (A)8 of MSH3 were significantly more frequent in the distal CRC. Additionally, we observed differences in MSH3 and TGFBR2 mutational frequency between Lynch syndrome and sporadic MSI CRC regarding tumour location.
  
  
  CONCLUSIONS
  Our results indicate that the pattern of genetic changes differs in CRC depending on tumour location and between Lynch syndrome and sporadic MSI CRC, suggesting that carcinogenesis can occur by different pathways even if driven by generalised MSI.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Rua Doutor António Bernardino Almeida, 4200-072 Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Rua Doutor António Bernardino Almeida, 4200-072 Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Rua Doutor António Bernardino Almeida, 4200-072 Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Peixoto
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Rua Doutor António Bernardino Almeida, 4200-072 Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Veiga
authors.affiliation: Department of Pathology, Portuguese Oncology Institute, Rua Doutor António Bernardino Almeida, 4200-072 Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Lopes
authors.affiliation: 1] Department of Pathology, Portuguese Oncology Institute, Rua Doutor António Bernardino Almeida, 4200-072 Porto, Portugal [2] Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, University of Porto, Largo Professor Abel Salazar, 4099-003 Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.affiliation: Department of Pathology, Centro Hospitalar de São João, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Baldaia
authors.affiliation: 1] Department of Pathology, Centro Hospitalar de São João, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal [2] Medical Faculty of the University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal [3] Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr Roberto Frias, 4200-465 Porto, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: 1] Medical Faculty of the University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal [2] Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr Roberto Frias, 4200-465 Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.affiliation: 1] Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK [2] Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: 1] Research Group Human Genomics, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland [2] Medical Genetics, University Hospital Basel, Burgfelderstrasse 101, 4055 Basel, Switzerland.
authors.forename: Michal
authors.initials: M
authors.lastname: Kovac
authors.affiliation: 1] Research Group Human Genomics, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland [2] Medical Genetics, University Hospital Basel, Burgfelderstrasse 101, 4055 Basel, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.affiliation: 1] Department of Genetics, Portuguese Oncology Institute, Rua Doutor António Bernardino Almeida, 4200-072 Porto, Portugal [2] Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, University of Porto, Largo Professor Abel Salazar, 4099-003 Porto, Portugal.
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; D000077294:Receptor, Transforming Growth Factor-beta Type II; C425585:activin receptor type II-A; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein