title: Differential promoter methylation of kinesin family member 1a in plasma is associated with breast cancer and DNA repair capacity.
abstract: Methylation alterations of CpG islands, CpG island shores and first exons are key events in the formation and progression of human cancer, and an increasing number of differentially methylated regions and genes have been identified in breast cancer. Recent studies of the breast cancer methylome using deep sequencing and microarray platforms are providing a novel insight on the different roles aberrant methylation plays in molecular subtypes of breast cancer. Accumulating evidence from a subset of studies suggests that promoter methylation of tumor-suppressor genes associated with breast cancer can be quantified in circulating DNA. However, there is a paucity of studies that examine the combined presence of genetic and epigenetic alterations associated with breast cancer using blood-based assays. Dysregulation of DNA repair capacity (DRC) is a genetic risk factor for breast cancer that has been measured in lymphocytes. We isolated plasma DNA from 340 participants in a breast cancer case control project to study promoter methylation levels of five genes previously shown to be associated with breast cancer in frozen tissue and in cell line DNA: MAL, KIF1A, FKBP4, VGF and OGDHL. Methylation of at least one gene was found in 49% of the cases compared to 20% of the controls. Three of the four genes had receiver characteristic operator curve values of ≥ 0.50: MAL (0.64), KIF1A (0.51) and OGDHL (0.53). KIF1A promoter methylation was associated with breast cancer and inversely associated with DRC. This is the first evidence of a significant association between genetic and epigenetic alterations in breast cancer using blood-based tests. The potential diagnostic utility of these biomarkers and their relevance for breast cancer risk prediction should be examined in larger cohorts.
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Guerrero-Preston
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Tal
authors.initials: T
authors.lastname: Hadar
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Kimberly Laskie
authors.initials: KL
authors.lastname: Ostrow
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Soudry
authors.affiliation: Cancer Center, Auxilio Mutuo Hospital, San Juan, Puerto Rico.
authors.forename: Miguel
authors.initials: M
authors.lastname: Echenique
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ili-Gangas
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Pérez
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Jimena
authors.initials: J
authors.lastname: Perez
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Brebi-Mieville
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: José
authors.initials: J
authors.lastname: Deschamps
authors.affiliation: Department of Pharmacology and Toxicology, Ponce School of Medicine and Health Sciences, Ponce 00732-7004, Puerto Rico.
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales
authors.affiliation: Public Health Program, Ponce School of Medicine and Health Sciences, Ponce 00732-7004, Puerto Rico.
authors.forename: Manuel
authors.initials: M
authors.lastname: Bayona
authors.affiliation: Department of Otolaryngology - Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: Department of Pharmacology and Toxicology, Ponce School of Medicine and Health Sciences, Ponce 00732-7004, Puerto Rico.
authors.forename: Jaime
authors.initials: J
authors.lastname: Matta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D019175:DNA Methylation; D004260:DNA Repair; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008875:Middle Aged; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics; D011401:Promoter Regions, Genetic; D022021:Tacrolimus Binding Proteins / Q000235:genetics
chemical_list: C094065:KIF1A protein, human; C569026:MAL protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D009414:Nerve Growth Factors; C510637:VGF protein, human; D016547:Kinesins; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4