title: NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva.
abstract: Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles. To overcome this lack of relevance, we used the HumanMethylation27 BeadChip, publicly available methylation and expression array data, and quantitative methylation specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles. A two stage design consisting of discovery and prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and neck squamous cell carcinoma. Promoter methylation of KIF1A (κ = 0.64), HOXA9 (κ = 0.60), NID2 (κ = 0.60), and EDNRB (κ = 0.60) had a moderate to substantial agreement with clinical diagnosis in the discovery screen. HOXA9 had 68% sensitivity, 100% specificity, and a 0.81 Area Under the Curve (AUC). NID2 had 71% sensitivity, 100% specificity, and a 0.79 AUC. In the prevalence screen, HOXA9 (κ = 0.82) and NID2 (κ = 0.80) had an almost perfect agreement with histologic diagnosis. HOXA9 had 85% sensitivity, 97% specificity, and a 0.95 AUC. NID2 had 87% sensitivity, 95% specificity, and a 0.91 AUC. A HOXA9 and NID2 gene panel had 94% sensitivity, 97% specificity, and a 0.97 AUC. In saliva, from OSCC cases and controls, HOXA9 had 75% sensitivity, 53% specificity, and a 0.75 AUC. NID2 had 87% sensitivity, 21% specificity, and a 0.73 AUC. This phase I Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. This panel may be useful for early detection and cancer prevention studies.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21231, USA.
authors.forename: R
authors.initials: R
authors.lastname: Guerrero-Preston
authors.forename: E
authors.initials: E
authors.lastname: Soudry
authors.forename: J
authors.initials: J
authors.lastname: Acero
authors.forename: M
authors.initials: M
authors.lastname: Orera
authors.forename: L
authors.initials: L
authors.lastname: Moreno-López
authors.forename: G
authors.initials: G
authors.lastname: Macía-Colón
authors.forename: A
authors.initials: A
authors.lastname: Jaffe
authors.forename: M
authors.initials: M
authors.lastname: Berdasco
authors.forename: C
authors.initials: C
authors.lastname: Ili-Gangas
authors.forename: P
authors.initials: P
authors.lastname: Brebi-Mieville
authors.forename: Y
authors.initials: Y
authors.lastname: Fu
authors.forename: C
authors.initials: C
authors.lastname: Engstrom
authors.forename: R A
authors.initials: RA
authors.lastname: Irizarry
authors.forename: M
authors.initials: M
authors.lastname: Esteller
authors.forename: W
authors.initials: W
authors.lastname: Westra
authors.forename: W
authors.initials: W
authors.lastname: Koch
authors.forename: J
authors.initials: J
authors.lastname: Califano
authors.forename: D
authors.initials: D
authors.lastname: Sidransky
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002135:Calcium-Binding Proteins; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics* / Q000517:prevention & control; D015815:Cell Adhesion Molecules / Q000235:genetics*; D019175:DNA Methylation; D042241:Early Diagnosis; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016547:Kinesins / Q000235:genetics; D009055:Mouth / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000517:prevention & control; D009959:Oropharyngeal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000517:prevention & control; D011401:Promoter Regions, Genetic; D012463:Saliva / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D018398:Homeodomain Proteins; C094065:KIF1A protein, human; C114729:NID2 protein, human; C097899:homeobox protein HOXA9; D016547:Kinesins