title: Identification and validation of candidate epigenetic biomarkers in lung adenocarcinoma.
abstract: Lung cancer is the number one cause of cancer-related deaths worldwide. DNA methylation is an epigenetic mechanism that regulates gene expression, and disease-specific methylation changes can be targeted as biomarkers. We have compared the genome-wide methylation pattern in tumor and tumor-adjacent normal lung tissue from four lung adenocarcinoma (LAC) patients using DNA methylation microarrays and identified 74 differentially methylated regions (DMRs). Eighteen DMRs were selected for validation in a cohort comprising primary tumors from 52 LAC patients and tumor-adjacent normal lung tissue from 32 patients by methylation-sensitive high resolution melting (MS-HRM) analysis. Significant increases in methylation were confirmed for 15 DMRs associated with the genes and genomic regions: OSR1, SIM1, GHSR, OTX2, LOC648987, HIST1H3E, HIST1H3G/HIST1H2BI, HIST1H2AJ/HIST1H2BM, HOXD10, HOXD3, HOXB3/HOXB4, HOXA3, HOXA5, Chr1(q21.1).A, and Chr6(p22.1). In particular the OSR1, SIM1 and HOXB3/HOXB4 regions demonstrated high potential as biomarkers in LAC. For OSR1, hypermethylation was detected in 47/48 LAC cases compared to 1/31 tumor-adjacent normal lung samples. Similarly, 45/49 and 36/48 LAC cases compared to 3/31 and 0/31 tumor-adjacent normal lung samples showed hypermethylation of the SIM1 and HOXB3/HOXB4 regions, respectively. In conclusion, this study has identified and validated 15 DMRs that can be targeted as biomarkers in LAC.
authors: Department of Biomedicine, Aarhus University, Bartholins Allé 6, DK-8000 Aarhus C, Denmark.
authors: Iben
authors: I
authors: Daugaard
authors: Department of Biomedicine, Aarhus University, Bartholins Allé 6, DK-8000 Aarhus C, Denmark.
authors: Diana
authors: D
authors: Dominguez
authors: Department of Biomedicine, Aarhus University, Bartholins Allé 6, DK-8000 Aarhus C, Denmark.
authors: Tina E
authors: TE
authors: Kjeldsen
authors: Department of Biomedicine, Aarhus University, Bartholins Allé 6, DK-8000 Aarhus C, Denmark.
authors: Lasse S
authors: LS
authors: Kristensen
authors: Department of Pathology, Aarhus University Hospital, Nørrebrogade 45, DK-8000 Aarhus C, Denmark.
authors: Henrik
authors: H
authors: Hager
authors: Department of Biomedicine, Aarhus University, Bartholins Allé 6, DK-8000 Aarhus C, Denmark.|Aarhus Institute of Advanced Studies, Høegh-Guldbergs Gade 6B, DK-8000 Aarhus C, Denmark.
authors: Tomasz K
authors: TK
authors: Wojdacz
authors: Department of Biomedicine, Aarhus University, Bartholins Allé 6, DK-8000 Aarhus C, Denmark.
authors: Lise Lotte
authors: LL
authors: Hansen
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000302:isolation & purification / Q000378:metabolism; D019175:DNA Methylation; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D044367:Phase Transition; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D004247:DNA; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C090460:HOXB4 protein, human; C542921:HoxB3 protein, human; C498490:OSR1 protein, human; C491094:SIM1 protein, human