Translations by: The LUMC team, particularly Frans van Nieuwpoort
Reference Type: Journal Article Record Number: 4599 Author: Kefford, R. F.; Newton Bishop, J. A.; Bergman, W.; Tucker, M. A. Year: 1999
Title:Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: A consensus statement of the Melanoma Genetics Consortium
Author Address: Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, New South Wales, Australia. kefford@westgate.wh.usyd.edu.au
Reference Type: Journal Article Record Number: 4598 Author: Harland, M.; Holland, E. A.; Ghiorzo, P.; Mantelli, M.; Bianchi-Scarra, G.; Goldstein, A. M.; Tucker, M. A.; Ponder, B. A.; Mann, G. J.; Bishop, D. T.; Newton Bishop, J. Year: 2000
Title:Mutation screening of the CDKN2A promoter in melanoma families
Keywords: Adolescence
Adult
Aged
DNA, Neoplasm/analysis/genetics
Genetic Predisposition to Disease
Genetic Screening/*methods
Germ-Line Mutation/genetics
Guanine/analysis
Human
Linkage Disequilibrium/genetics
Melanoma/*genetics
Pedigree
Point Mutation
Promoter Regions (Genetics)/*genetics
Protein p16/*genetics
Support, Non-U.S. Gov't
Thymine/analysis
Abstract: Germline mutations of CDKN2A, at 9p21, are responsible for predisposition to melanoma in some families. However, evidence of linkage to 9p21 has been demonstrated in a significant proportion of kindreds with no detectable mutations in CDKN2A. It is possible that mutations in noncoding regions may be responsible for predisposition to melanoma in these families. We have analyzed approximately 1 kb of the CDKN2A promoter upstream of the start codon in an attempt to identify causal mutations in 107 melanoma families. Four sequence variants were detected. Two of these (A-191G and A-493T) did not segregate with disease and were present in a control population at a comparable frequency, indicating that they are unlikely to predispose to melanoma. The A-493T variant appeared to be in linkage disequilibrium with the previously described CDKN2A polymorphism Ala148Thr. The variant G-735A was detected in the control population, but segregation of this variant with melanoma within families could not be discounted. The fourth variant (G-34T), located in the 5' UTR, creates an aberrant initiation codon. This variant appeared to segregate with melanoma and was not detected in a control population. G-34T has recently been identified in a subset of Canadian melanoma families and was concluded to be associated with predisposition to melanoma. The creation of an aberrant initiation site in the 5' UTR may have an important role in carcinogenesis in a small percentage of families; however, mutations in the CDKN2A promoter appear to have a limited role in predisposition to melanoma.
Author Address: ICRF Genetic Epidemiology Laboratory, St. James' University Hospital, Leeds, England.
Reference Type: Journal Article Record Number: 4751 Author: Bishop, D. T.; Demenais, F.; Goldstein, A. M.; Bergman, W.; Bishop, J. N.; Bressac-de Paillerets, B.; Chompret, A.; Ghiorzo, P.; Gruis, N.; Hansson, J.; Harland, M.; Hayward, N.; Holland, E. A.; Mann, G. J.; Mantelli, M.; Nancarrow, D.; Platz, A.; Tucker, M. A. Year: 2002
Title:Geographical variation in the penetrance of CDKN2A mutations for melanoma
Keywords: Australia
Comparative Study
Europe
Family
Genes, p16
*Genetic Predisposition to Disease
Geography
Human
Melanoma/epidemiology/*genetics
*Mutation
Protein p16/*genetics
Risk Factors
Support, Non-U.S. Gov't
United States
Variation (Genetics)
Abstract: BACKGROUND: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium. METHODS: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14ARF protein, and population melanoma incidence rates. All statistical tests were two- sided. RESULTS: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P =.003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. CONCLUSIONS: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.
Author Address: Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds, UK. tim.bishop@cancer.org.uk
Reference Type: Journal Article Record Number: 7224 Author: Kefford, R.; Bishop, J. N.; Tucker, M.; Bressac-de Paillerets, B.; Bianchi-Scarra, G.; Bergman, W.; Goldstein, A.; Puig, S.; Mackie, R.; Elder, D.; Hansson, J.; Hayward, N.; Hogg, D.; Olsson, H. Year: 2002
Author Address: Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute, New South Wales, 2145, Australia.
Reference Type: Journal Article Record Number: 10251 Author: Gillanders, E.; Hank Juo, S. H.; Holland, E. A.; Jones, M.; Nancarrow, D.; Freas-Lutz, D.; Sood, R.; Park, N.; Faruque, M.; Markey, C.; Kefford, R. F.; Palmer, J.; Bergman, W.; Bishop, D. T.; Tucker, M. A.; Bressac-de Paillerets, B.; Hansson, J.; Stark, M.; Gruis, N.; Bishop, J. N.; Goldstein, A. M.; Bailey-Wilson, J. E.; Mann, G. J.; Hayward, N.; Trent, J. Year: 2003
Title:Localization of a novel melanoma susceptibility locus to 1p22
Journal: Am J Hum Genet Volume: 73 Issue: 2 Pages: 301-13 Date: Aug Accession Number: 12844286
Keywords: Adolescent
Adult
Age of Onset
Aged
Australia
Child
Chromosome Mapping
Chromosomes, Human, Pair 1/*genetics
Human
Lod Score
Melanoma/*genetics
Middle Aged
Pedigree
Skin Neoplasms/*genetics
Support, Non-U.S. Gov't
Support, U.S. Gov't, P.H.S.
Abstract: Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.
Author Address: Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Reference Type: Journal Article Record Number: 10514 Author: Fung, D. C.; Holland, E. A.; Becker, T. M.; Hayward, N. K.; Bressac-de Paillerets, B.; Mann, G. J. Year: 2003
Title:eMelanoBase: an online locus-specific variant database for familial melanoma
Journal: Hum Mutat Volume: 21 Issue: 1 Pages: 2-7 Date: Jan Accession Number: 12497626
Keywords: Computer Security
Cyclin-Dependent Kinases/genetics
*Databases, Nucleic Acid/standards
Forecasting
Genes, p16
Genetic Predisposition to Disease
Genotype
Germ-Line Mutation
Human
Information Storage and Retrieval
Internet
Melanoma/*genetics
Molecular Sequence Data
*Mutation
Quality Control
Software
Support, Non-U.S. Gov't
Terminology
Abstract: A proportion of melanoma-prone individuals in both familial and non-familial contexts has been shown to carry inactivating mutations in either CDKN2A or, rarely, CDK4. CDKN2A is a complex locus that encodes two unrelated proteins from alternately spliced transcripts that are read in different frames. The alpha transcript (exons 1alpha, 2, and 3) produces the p16INK4A cyclin-dependent kinase inhibitor, while the beta transcript (exons 1beta and 2) is translated as p14ARF, a stabilizing factor of p53 levels through binding to MDM2. Mutations in exon 2 can impair both polypeptides and insertions and deletions in exons 1alpha, 1beta, and 2, which can theoretically generate p16INK4A-p14ARF fusion proteins. No online database currently takes into account all the consequences of these genotypes, a situation compounded by some problematic previous annotations of CDKN2A-related sequences and descriptions of their mutations. As an initiative of the international Melanoma Genetics Consortium, we have therefore established a database of germline variants observed in all loci implicated in familial melanoma susceptibility. Such a comprehensive, publicly accessible database is an essential foundation for research on melanoma susceptibility and its clinical application. Our database serves two types of data as defined by HUGO. The core dataset includes the nucleotide variants on the genomic and transcript levels, amino acid variants, and citation. The ancillary dataset includes keyword description of events at the transcription and translation levels and epidemiological data. The application that handles users' queries was designed in the model-view-controller architecture and was implemented in Java. The object-relational database schema was deduced using functional dependency analysis. We hereby present our first functional prototype of eMelanoBase. The service is accessible via the URL www.wmi.usyd.edu.au:8080/melanoma.html.
