title: HOXA9, ISL1 and ALDH1A3 methylation patterns as prognostic markers for nonmuscle invasive bladder cancer: array-based DNA methylation and expression profiling.
abstract: DNA methylation patterns are associated with the development and prognosis of cancer. The aim of this study was to identify novel methylation markers for the prediction of patient outcomes using microarray analysis of DNA methylation and RNA expression patterns in samples from long-term follow-up patients with nonmuscle invasive bladder cancer (NMIBC). A total of 187 human bladder specimens were used for microarray array or pyrosequencing (PSQ) analyses: 6 normal controls (NC) and 181 NMIBC. Tumor-specific hypermethylated genes were selected from a data set comprising 24 matched microarray-based DNA methylation and gene expression profiles (6 controls and 18 NMIBC), and their clinical relevance was verified by quantitative PSQ analysis. The methylation status of Homeobox A9 (HOXA9), ISL LIM homeobox 1 (ISL1) and Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) was significantly associated with decreased gene expression levels and aggressive clinicopathological characteristics. Multivariate regression analyses showed that hypermethylation of these genes was an independent predictor of disease recurrence (HOXA9, ISL1 and ALDH1A3, either alone or in combination) and progression (ISL1 and ALDH1A3, either alone or in combination) (each p < 0.05). The results of this study suggest that these novel methylation markers are independent prognostic indicators in NMIBC patients, which may facilitate the assessment of disease recurrence and progression in NMIBC patients and inform clinical decision making regarding treatment.
authors: Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors: Yong-June
authors: YJ
authors: Kim
authors: Hyung-Yoon
authors: HY
authors: Yoon
authors: Ji Sang
authors: JS
authors: Kim
authors: Ho Won
authors: HW
authors: Kang
authors: Byung-Dal
authors: BD
authors: Min
authors: Seon-Kyu
authors: SK
authors: Kim
authors: Yun-Sok
authors: YS
authors: Ha
authors: Isaac Yi
authors: IY
authors: Kim
authors: Keun Ho
authors: KH
authors: Ryu
authors: Sang-Cheol
authors: SC
authors: Lee
authors: Wun-Jae
authors: WJ
authors: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000445:Aldehyde Oxidoreductases / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C063843:insulin gene enhancer binding protein Isl-1; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)
keywords: gene expression; methylation; microarray analysis; prognosis; urinary bladder neoplasms