title: Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer.
abstract: OBJECTIVE
  Somatic mutations occur at early stages of adenoma and accumulate throughout colorectal cancer progression. The aim of this study was to characterize the mutational landscape of stage II tumors and to search for novel recurrent mutations likely implicated in colorectal cancer tumorigenesis.
  
  
  METHODS
  The exomic DNA of 42 stage II, microsatellite-stable colon tumors and their paired mucosae were sequenced. Other molecular data available in the discovery dataset [gene expression, methylation, and copy number variations (CNV)] were used to further characterize these tumors. Additional datasets comprising 553 colorectal cancer samples were used to validate the discovered mutations.
  
  
  RESULTS
  As a result, 4,886 somatic single-nucleotide variants (SNV) were found. Almost all SNVs were private changes, with few mutations shared by more than one tumor, thus revealing tumor-specific mutational landscapes. Nevertheless, these diverse mutations converged into common cellular pathways, such as cell cycle or apoptosis. Among this mutational heterogeneity, variants resulting in early stop codons in the AMER1 (also known as FAM123B or WTX) gene emerged as recurrent mutations in colorectal cancer. Losses of AMER1 by other mechanisms apart from mutations such as methylation and copy number aberrations were also found. Tumors lacking this tumor suppressor gene exhibited a mesenchymal phenotype characterized by inhibition of the canonical Wnt pathway.
  
  
  CONCLUSIONS
  In silico and experimental validation in independent datasets confirmed the existence of functional mutations in AMER1 in approximately 10% of analyzed colorectal cancer tumors. Moreover, these tumors exhibited a characteristic phenotype.
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Sanz-Pamplona
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Lopez-Doriga
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Paré-Brunet
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Kira
authors.initials: K
authors.lastname: Lázaro
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bellido
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: M Henar
authors.initials: MH
authors.lastname: Alonso
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Susanna
authors.initials: S
authors.lastname: Aussó
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Guinó
authors.affiliation: Centre Nacional d'Anàlisi Genòmica (CNAG), Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Beltrán
authors.affiliation: Centre Nacional d'Anàlisi Genòmica (CNAG), Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Castro-Giner
authors.affiliation: Centre Nacional d'Anàlisi Genòmica (CNAG), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Pathology Service, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sanjuan
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Adria
authors.initials: A
authors.lastname: Closa
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Cordero
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Francisco D
authors.initials: FD
authors.lastname: Morón-Duran
authors.affiliation: Gastroenterology Service, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Department of Medical Oncology, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Salazar
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Valle
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain. Department of Clinical Sciences, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain. v.moreno@iconcologia.net.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000236:Adenoma / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D025521:Tumor Suppressor Proteins