title: Frequent RASSF1A tumour suppressor gene promoter methylation in Wilms' tumour and colorectal cancer.
abstract: The 3p21.3 tumour suppressor gene (TSG) RASSF1A is inactivated predominantly by promoter methylation and rarely by somatic mutations. Recently we demonstrated that epigenetic inactivation of RASSF1A is frequent in both clear cell and papillary adult renal cell carcinomas (even though 3p21.3 allele loss is rare in papillary tumours). Wilms' tumour is the most common childhood kidney tumour, but relatively little is known about its molecular pathogenesis. Thus TSGs such as WT1, p16(CDKN2a) and p53 are inactivated in only a minority of cases. In view of the involvement of RASSF1A in adult renal cancers we investigated RASSF1A as a candidate Wilms' TSG. We detected RASSF1A hypermethylation in 21 of 39 (54%) primary Wilms' tumours. 3p21.3 allele loss was not detected in nine informative Wilms' tumours (five with RASSF1A methylation). In contrast to RASSF1A, only a minority (10.3%) of Wilms' tumours demonstrated p16 promoter methylation. As chromosome 3p allele loss is frequent in colorectal cancer, we proceeded to investigate RASSF1A promoter methylation in colorectal cancer and detected RASSF1A methylation in 80% (4/5) colorectal cancer cell lines and 45% (13/29) primary colorectal cancers. There was no correlation between RASSF1A and p16 methylation in colorectal cancer. We have demonstrated that RASSF1A inactivation is the most frequent genetic or epigenetic event yet reported in Wilms' tumourigenesis and that allelotyping studies may fail to identify regions containing important TSGs.
authors.affiliation: Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Wagner
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Cooper
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
authors.forename: Germaine
authors.initials: G
authors.lastname: Caldwell
authors.forename: Carolyn
authors.initials: C
authors.lastname: Jones
authors.forename: Roy B
authors.initials: RB
authors.lastname: Wadey
authors.forename: Dion
authors.initials: D
authors.lastname: Morton
authors.forename: Paul N
authors.initials: PN
authors.lastname: Schofield
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D016147:Genes, Tumor Suppressor; D016162:Genes, Wilms Tumor; D019942:Genes, p16; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D037941:Silencer Elements, Transcriptional; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: C094335:H19 long non-coding RNA; D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D025521:Tumor Suppressor Proteins