title: Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer.
abstract: Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs.
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Torabi
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Miró
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Present address: Epigenetics Group, International Agency for Research on Cancer 69008, Lyon, France.
authors.forename: Nora
authors.initials: N
authors.lastname: Fernández-Jiménez
authors.affiliation: Gastrointestinal and Pancreatic Oncology Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia 08036, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Quintanilla
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Present address: Unitat de Genòmica i Bioinformàtica, Institut de Medicina Predictiva i Personalitzada del Càncer (IMPPC), Badalona, Catalonia 08916, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Ramos
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Present address: Laboratori de Genètica Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Catalonia 08908, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Prat
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: del Rey
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Pujol
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Department of Pathology, Hospital Clínic/IDIBAPS, Universitat de Barcelona, Barcelona, Catalonia 08036, Spain and.
authors.forename: Pedro Luis
authors.initials: PL
authors.lastname: Fernández
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Bioinformatics Unit, CIBERehd, Barcelona, Catalonia 08036, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Gastrointestinal and Pancreatic Oncology Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia 08036, Spain, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jordi
authors.initials: J
authors.lastname: Camps
authors.affiliation: Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain, imma.ponsa@uab.cat.
authors.forename: Immaculada
authors.initials: I
authors.lastname: Ponsa
mesh_terms: D002869:Chromosome Aberrations; D015179:Colorectal Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D024182:Uniparental Disomy / Q000235:genetics* / Q000473:pathology