Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
11477665
TITLE
Mutation analysis of the CDKN2A promoter in Australian melanoma families.
ABSTRACT
Approximately 50% of all melanoma families worldwide show linkage to 9p21-22, but only about half of these have been shown to contain germ line CDKN2A mutations. It has been hypothesized that a proportion of these families carry mutations in the noncoding regions of CDKN2A. Several Canadian families have been reported to carry a mutation in the 5' UTR, at position -34 relative to the start site, which gives rise to a novel AUG translation initiation codon that markedly decreases translation from the wild-type AUG (Liu et al., 1999). Haplotype sharing in these Canadian families suggested that this mutation is of British origin. We sequenced 1,327 base pairs (bp) of CDKN2A, making up 1,116 bp of the 5' UTR and promoter, all of exon 1, and 61 bp of intron 1, in at least one melanoma case from 110 Australian families with three or more affected members known not to carry mutations within the p16 coding region. In addition, 431 bp upstream of the start codon was sequenced in an additional 253 affected probands from two-case melanoma families for which the CDKN2A mutation status was unknown. Several known polymorphisms at positions -33, -191, -493, and -735 were detected, in addition to four novel variants at positions 120, -252, -347, and -981 relative to the start codon. One of the probands from a two-case family was found to have the previously reported Q50R mutation. No family member was found to carry the mutation at position -34 or any other disease-associated mutation. For further investigation of noncoding CDKN2A mutations that may affect transcription, allele-specific expression analysis was carried out in 31 of the families with at least three affected members who showed either complete or "indeterminate" 9p haplotype sharing without CDKN2A exonic mutations. Reverse transcription polymerase chain reaction and automated sequencing showed expression of both CDKN2A alleles in all family members tested. The lack of CDKN2A promoter mutations and the absence of transcriptional silencing in the germ line of this cohort of families suggest that mutations in the promoter and 5' UTR play a very limited role in melanoma predisposition.
Copyright 2001 Wiley-Liss, Inc.
DATE PUBLISHED
2001 Sep
HISTORY
PUBSTATUS PUBSTATUSDATE
pubmed 2001/07/31 10:00
medline 2001/10/12 10:01
entrez 2001/07/31 10:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Pollock PM Pollock P M PM Joint Experimental Oncology Program of the Queensland Institute of Medical Research, University of Queensland, and the Queensland Cancer Fund, P.O. Royal Brisbane Hospital, Brisbane, Australia.
Stark MS Stark M S MS
Palmer JM Palmer J M JM
Walters MK Walters M K MK
Aitken JF Aitken J F JF
Martin NG Martin N G NG
Hayward NK Hayward N K NK
INVESTIGATORS
JOURNAL
VOLUME: 32
ISSUE: 1
TITLE: Genes, chromosomes & cancer
ISOABBREVIATION: Genes Chromosomes Cancer
YEAR: 2001
MONTH: Sep
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Print
ISSN: 1045-2257
ISSNTYPE: Print
MEDLINE JOURNAL
MEDLINETA: Genes Chromosomes Cancer
COUNTRY: United States
ISSNLINKING: 1045-2257
NLMUNIQUEID: 9007329
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Australia
DNA Mutational Analysis methods
DNA, Neoplasm analysis
Exons genetics
Genes, p16 genetics
Humans genetics
Introns genetics
Male genetics
Melanoma genetics
Polymorphism, Genetic genetics
Promoter Regions, Genetic genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 DNA, Neoplasm
OTHER ID's