The promoter has been screened but mutations were not found [1][2] with the exception of a coding variant first reported in Canadian families [3]

A deep intronic mutation was found to explain a significant proportion of English melanoma families [4] which has been reported subsequently in smaller proportions of families by other groups within the Consortium

A paper reporting comprehensive screening of the introns for other mutations was submitted for publication September 2004

In other inherited cancers germline deletions have explained susceptibility in a significant proportion of families and therefore comprehensive screening of samples from English families has been carried out and this paper was submitted for publication also in September 2004. Screening of samples across the GenoMEL sample set is currently in progress, estimated to finish Dec 1st 2004

DNA samples have been exchanged by Consortium groups, during 2004, looking in part at a comparison between DHPLC screening for mutations and sequencing, and in part auditing screening across the consortium. This study led by Mark Harland and Alisa Goldstein is nearing completion

Finally all these data are currently being pooled to allow the reporting of proportions of families with germline mutations or deletions across the Consortium by number of cases in the family, type of cancer seen, age of onset and latitude. The closing date for data submission for this project is Dec 1st 2004

The identification of break points in a family with a deletion at this locus showed that the genetic loss was of exon 1ß only and was the first evidence for p14ARF as a melanoma susceptibility gene [5].

The Spanish group within GenoMEL in conjunction with the Sydney group reported a family with a 16 base pair exon 1ß germline insertion specifically altering p14ARF, but not p16(INK4a) [6] providing further evidence for the role of p14ARF

Subsequently splice site variants have been detected in this gene and the paper reporting this has been submitted for publication October 2004

The Consortium, has reported linkage to 1p22 in a collaboration with Dr Jeffrey Trent’s group, initially at the NIH and more recently at the Translational Genomics Research Institute, Phoenix, AZ. The key collaborator here was Liz Gillanders [7].

Work continues to identify this gene.

The first estimates of the penetrance of melanoma were reported by the Consortium in 2002 [8]. This study showed that CDKN2A mutation penetrance was 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.

The current analysis led by Tim Bishop is to estimate the risk of cancers other than melanoma in mutation carriers.

The third analysis led by Florence Demenais will look at penetrance by MC1R status.

It was expected from early studies that CDKN2A gene carriers would manifest the atypical mole syndrome phenotype but in fact this was not the case in English [10] and Australian families studied by GenoMEL. By collecting phenotypic data from families across the Consortium it is our aim to clarify the determinants of this important risk factor for melanoma within melanoma families.

1. Harland, M., et al.,
Mutation screening of the CDKN2A promoter in melanoma families.
Genes Chromosomes Cancer, 2000. 28(1): p. 45-57.

2. Pollock PM, et al.,
Mutation analysis of the CDKN2A promoter in Australian melanoma families.
Genes Chromosomes Cancer. 2001 32(1):p 89-94.

3. Liu, L., et al.,
Mutation of the CDKN2A5'UTR creates an aberrant initiation codon and predisposes to melanoma.
Nature Genetics, 1999. 21: p. 1-5.

4. Harland, M., et al.,
A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees.
Hum Mol Genet, 2001. 10(23): p. 2679-86.

5. Randerson-Moor, J.A., et al.,
A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family.
Hum Mol Genet, 2001. 10(1): p. 55-62.

6. Rizos, H., et al.,
A melanoma-associated germline mutation in exon 1beta inactivates p14ARF.
Oncogene, 2001. 20(39): p. 5543-7.

7. Gillanders, E., et al.,
Localization of a novel melanoma susceptibility locus to 1p22.
Am J Hum Genet, 2003. 73(2): p. 301-13.

8. Bishop, D.T., et al.,
Geographical variation in the penetrance of CDKN2A mutations for melanoma.
J Natl Cancer Inst, 2002. 94(12): p. 894-903.

9. Wachsmuth, R.C., et al.,
Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study.
J Invest Dermatol, 2001. 117(2): p. 348-52.

10. Newton Bishop, J., et al.,
Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations.
J Invest Dermatol, 2000. 114: p. 28-33.