title: Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential.
abstract: Fanconi anaemia (FA) is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tβ and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average). Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population.
authors.affiliation: Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisboa, Portugal; CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Hélio
authors.initials: H
authors.lastname: Belo
authors.affiliation: Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisboa, Portugal; CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Silva
authors.affiliation: Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisboa, Portugal; CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Cardoso
authors.affiliation: Laboratório de Citogenética do Instituto de Ciências Biomédicas de Abel Salazar, Porto, Portugal.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Porto
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER) and Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Minguillon
authors.affiliation: Unidade de Hematologia Pediátrica do Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Barbot
authors.affiliation: Unidade de Hematologia Pediátrica do Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Coutinho
authors.affiliation: Hematopoiesis and Gene Therapy Division, CIEMAT, Madrid, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Casado
authors.affiliation: Serviço de hematologia do Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Benedito
authors.affiliation: Serviço de hematologia do Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Hema
authors.initials: H
authors.lastname: Saturnino
authors.affiliation: Unidade de Hematologia Pediátrica do Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Emília
authors.initials: E
authors.lastname: Costa
authors.affiliation: Unidade de Hematologia Pediátrica do Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER) and Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Surralles
authors.affiliation: Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisboa, Portugal; CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Antonio
authors.initials: A
authors.lastname: Almeida
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000737:chemistry; D043171:Chromosomal Instability; D019295:Computational Biology; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005199:Fanconi Anemia / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D007107:Immune System; D015994:Incidence; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000517:prevention & control*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D000077337:Vorinostat
chemical_list: D002843:Chromatin; D003432:Cross-Linking Reagents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D004247:DNA; D006655:Histone Deacetylases