title: Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy.
abstract: Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, 601 North Caroline Street, 6th Floor, Baltimore, MD 21287-0910, USA.
authors.forename: Kavita Malhotra
authors.initials: KM
authors.lastname: Pattani
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Semra
authors.initials: S
authors.lastname: Demokan
authors.forename: Chad
authors.initials: C
authors.lastname: Glazer
authors.forename: Myriam
authors.initials: M
authors.lastname: Loyo
authors.forename: Steven
authors.initials: S
authors.lastname: Goodman
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Francisco
authors.initials: F
authors.lastname: Bermudez
authors.forename: Germain
authors.initials: G
authors.lastname: Jean-Charles
authors.forename: Thomas
authors.initials: T
authors.lastname: McCaffrey
authors.forename: Tapan
authors.initials: T
authors.lastname: Padhya
authors.forename: Joan
authors.initials: J
authors.lastname: Phelan
authors.forename: Silvia
authors.initials: S
authors.lastname: Spivakovsky
authors.forename: Helen Yoo
authors.initials: HY
authors.lastname: Bowne
authors.forename: Judith D
authors.initials: JD
authors.lastname: Goldberg
authors.forename: Linda
authors.initials: L
authors.lastname: Rolnitzky
authors.forename: Miriam
authors.initials: M
authors.lastname: Robbins
authors.forename: A Ross
authors.initials: AR
authors.lastname: Kerr
authors.forename: David
authors.initials: D
authors.lastname: Sirois
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009055:Mouth / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D044023:Receptor, Endothelin B / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D012463:Saliva / Q000378:metabolism*; D055815:Young Adult
chemical_list: C094065:KIF1A protein, human; D044023:Receptor, Endothelin B; D016547:Kinesins
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