Reciprocal relationship between methylation status and loss of heterozygosity at the p14(ARF) locus in Australian and South African hepatocellular carcinomas.
Chromosome 9p21, a locus comprising the tumor suppressor genes (TSG) p16(INK4a) and p14(ARF), is a common region of loss of heterozygosity (LOH) in hepatocellular carcinoma (HCC). p14(ARF) shares exon 2 with p16 in a different reading frame. p14 binds to MDM2 resulting in a stabilization of functional p53. This study examined the roles of p14, p16 and p53 in hepatocarcinogenesis, in 37 Australian and 24 South African patients. LOH at 9p21 and 17p13.1, p14 and p16 mutation analysis, p14 and p16 promoter methylation and p14, p16 and p53 protein expression was examined. LOH at 9p21 was detected more frequently in South African HCC (P = 0.04). Comparable rates of p53 LOH were observed in Australian and South African HCC (10/22, 45%vs 13/22, 59%, respectively). Hypermethylation of the p14 promoter was more prevalent in Australian HCC than in South African HCC (17/37, 46%vs 7/24, 29%, respectively). In Australian HCC the prevalence of p14 methylation increased with age (P = 0.03). p16 promoter methylation was observed in 12/37 (32%) and 6/24 (25%) in Australian and South African HCC, respectively. Loss of p16 protein expression was detected in 14/36 Australian HCC whereas p53 protein expression was detected in 9/36. Significantly, a reciprocal relationship between 9p21 LOH and p14 promoter hypermethylation was observed (P < or = 0.05). No significant association between p14 and p53 was seen in this study. The reciprocal relationship identified indicates different pathways of tumorigenesis and likely reflects different etiologies of HCC in the two countries.
Herath
Nirmitha I
NI
Conjoint Gastroenterology Laboratory, Clinical Research Center, Royal Brisbane Hospital Research Foundation, The Queensland Institute of Medical Research, Queesland, Australia. nirmithH@qimr.edu.au
Kew
Michael C
MC
Walsh
Michael D
MD
Young
Joanne
J
Powell
Lawrie W
LW
Leggett
Barbara A
BA
MacDonald
Graeme A
GA
D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D015801:Helminth Proteins / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D016133:Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000096985:Calponins
D019941:Cyclin-Dependent Kinase Inhibitor p16; D015801:Helminth Proteins; D009124:Muscle Proteins; D016159:Tumor Suppressor Protein p53; C118619:calponin homolog protein, Schistosoma japonicum; D000096985:Calponins