Genetic Epidemiology, Psychiatric Genetics, Asthma 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
11500805
TITLE
MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations.
ABSTRACT
Mutations in the exons of the cyclin-dependent kinase inhibitor gene CDKN2A are melanoma-predisposition alleles which have high penetrance, although they have low population frequencies. In contrast, variants of the melanocortin-1 receptor gene, MC1R, confer much lower melanoma risk but are common in European populations. Fifteen Australian CDKN2A mutation-carrying melanoma pedigrees were assessed for MC1R genotype, to test for possible modifier effects on melanoma risk. A CDKN2A mutation in the presence of a homozygous consensus MC1R genotype had a raw penetrance of 50%, with a mean age at onset of 58.1 years. When an MC1R variant allele was also present, the raw penetrance of the CDKN2A mutation increased to 84%, with a mean age at onset of 37.8 years (P=.01). The presence of a CDKN2A mutation gave a hazard ratio of 13.35, and the hazard ratio of 3.72 for MC1R variant alleles was also significant. The impact of MC1R variants on risk of melanoma was mediated largely through the action of three common alleles, Arg151Cys, Arg160Trp, and Asp294His, that have previously been associated with red hair, fair skin, and skin sensitivity to ultraviolet light.
DATE PUBLISHED
2001 Oct
HISTORY
PUBSTATUS PUBSTATUSDATE
pubmed 2001/08/14 10:00
medline 2001/10/19 10:01
received 2001/00/26
accepted 2001/00/19
aheadofprint 2001/00/08
entrez 2001/08/14 10:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Box NF Box N F NF Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4029, Australia.
Duffy DL Duffy D L DL
Chen W Chen W W
Stark M Stark M M
Martin NG Martin N G NG
Sturm RA Sturm R A RA
Hayward NK Hayward N K NK
INVESTIGATORS
JOURNAL
VOLUME: 69
ISSUE: 4
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 2001
MONTH: Oct
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Print
ISSN: 0002-9297
ISSNTYPE: Print
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Alleles
Chromosome Segregation
Consensus Sequence genetics
Cyclin-Dependent Kinase Inhibitor p16 genetics
Disease-Free Survival genetics
Female genetics
Gene Frequency genetics
Genetic Predisposition to Disease genetics
Genetic Variation genetics
Genotype genetics
Humans genetics
Male genetics
Melanoma genetics
Mutation genetics
Mutation, Missense genetics
Pedigree genetics
Penetrance genetics
Pigmentation genetics
Proportional Hazards Models genetics
Radiation Tolerance genetics
Receptors, Corticotropin genetics
Receptors, Melanocortin genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Cyclin-Dependent Kinase Inhibitor p16
0 Receptors, Corticotropin
0 Receptors, Melanocortin
OTHER ID's
OTHERID SOURCE
PMC1226062 NLM