title: Differential expression of p16INK4a and p16beta transcripts in B-lymphoblastoid cells from members of hereditary melanoma families without CDKN2A exon mutations.
abstract: Mutations in the CDKN2A (p16INK4a) tumour suppressor gene on chromosome 9p21 are associated with inherited predisposition to melanoma, yet some 9p-linking hereditary melanoma families show no mutations in this gene. Splicing of CDKN2A exons 2 and 3 to an alternative first exon produces a transcript (p16beta) encoding a protein with cell cycle regulatory properties. We have analysed allele-specific expression levels of both the p16INK4a and p16beta transcripts in B-lymphoblastoid cells from 18 members of hereditary melanoma kindreds including four unrelated control individuals. In 15 of the 18 individuals examined, steady-state levels of each transcript either originated equally from each parental chromosome, or one parental chromosome was dominant for both transcripts. However, in three affected members of two 9p-linking hereditary melanoma kindreds, without exonic CDKN2A mutations, this pattern of coordinate expression was disrupted. In these individuals there was underexpression of the p16beta transcript, relative to the p16INK4a transcript, from the chromosome segregating with disease susceptibility. Loss of coordinate expression of the p16INK4a and p16beta transcripts may be an alternative genetic basis for melanoma susceptibility in certain 9p-linking kindreds.
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney Westmead Hospital, NSW, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Rizos
authors.forename: T M
authors.initials: TM
authors.lastname: Becker
authors.forename: E A
authors.initials: EA
authors.lastname: Holland
authors.forename: R F
authors.initials: RF
authors.lastname: Kefford
authors.forename: G J
authors.initials: GJ
authors.lastname: Mann
mesh_terms: D017398:Alternative Splicing; D001402:B-Lymphocytes / Q000473:pathology; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16