title: Genome-wide DNA methylation profiles in both precancerous conditions and clear cell renal cell carcinomas are correlated with malignant potential and patient outcome.
abstract: To clarify genome-wide DNA methylation profiles during multistage renal carcinogenesis, bacterial artificial chromosome array-based methylated CpG island amplification (BAMCA) was performed. Non-cancerous renal cortex tissue obtained from patients with clear cell renal cell carcinomas (RCCs) (N) was at the precancerous stage where DNA hypomethylation and DNA hypermethylation on multiple bacterial artificial chromosome (BAC) clones were observed. By unsupervised hierarchical clustering analysis based on BAMCA data for their N, 51 patients with clear cell RCCs were clustered into two subclasses, Clusters A(N) (n = 46) and B(N) (n = 5). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster B(N), and the overall survival rate of patients in Cluster B(N) was significantly lower than that of patients in Cluster A(N). By unsupervised hierarchical clustering analysis based on BAMCA data for their RCCs, 51 patients were clustered into two subclasses, Clusters A(T) (n = 43) and B(T) (n = 8). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster B(T), and the overall survival rate of patients in Cluster B(T) was significantly lower than that of patients in Cluster A(T). Multivariate analysis revealed that belonging to Cluster B(T) was an independent predictor of recurrence. Cluster B(N) was completely included in Cluster B(T), and the majority of the BAC clones that significantly discriminated Cluster B(N) from Cluster A(N) also discriminated Cluster B(T) from Cluster A(T). In individual patients, DNA methylation status in N was basically inherited by the corresponding clear cell RCC. DNA methylation alterations in the precancerous stage may generate more malignant clear cell RCCs and determine patient outcome.
authors.affiliation: Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Arai
authors.forename: Saori
authors.initials: S
authors.lastname: Ushijima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujimoto
authors.forename: Fumie
authors.initials: F
authors.lastname: Hosoda
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kondo
authors.forename: Sana
authors.initials: S
authors.lastname: Yokoi
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hirohashi
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D022202:Chromosomes, Artificial, Bacterial; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011230:Precancerous Conditions / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis