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Search for genetic variants associated with cutaneous malignant melanoma in the Ashkenazi Jewish population
  1. J C Y Loo1,
  2. A D Paterson2,
  3. A Hao3,
  4. M Shennan3,
  5. H Peretz4,
  6. Y Sidi5,
  7. D Hogg6,
  8. E Yakobson5
  1. 1Department of Medical Biophysics, University of Toronto, Toronto, Canada
  2. 2Program in Genetic and Genomic Biology, Hospital for Sick Children, Toronto
  3. 3Department of Clinical Sciences, University of Toronto
  4. 4Laboratory of Clinical Biochemistry, Tel Aviv University, Sourasky Medical Centre, Tel Aviv, Israel
  5. 5Molecular Cell Biology Laboratory, Department of Internal Medicine “C”, Sheba Medical Centre, Tel-Hashomer, Israel
  6. 6Department of Medicine, University of Toronto
  1. Correspondence to:
 Dr David Hogg
 University of Toronto, Medical Sciences Building, Room 7368, Toronto, Ontario, M5S 1A8 Canada;

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Cutaneous malignant melanoma (CMM; MIM #155601) comprises about 1% of all cancer cases in European populations, but its mortality is over 2% because of the propensity of this tumour to metastasise. Surveillance of CMM-prone individuals and populations should decrease the morbidity and mortality associated with this disease.

In approximately 5–12% of all melanoma cases, there is a family history of the disease, defined as having one or more affected first degree relatives.1 Germline mutations of CDKN2A, located on chromosome 9p21, cosegregate with affected cases in an estimated 20% of melanoma families worldwide (reviewed by Goldstein2). CDKN2A encodes two different tumour suppressor proteins: the CDK4/6 cell cycle inhibitor p16INK4A from exons 1α, 2, and 3; and the MDM2 inhibitor p14ARF from exons 1β, 2, and 3. The frequency of discovering a CDKN2A mutation within a family increases with the number of affected relatives, ranging from ∼15% in families with two affected members, to 20–40% in those with three, and 70% in those with four or more (unpublished data from Hogg’s laboratory; Kefford and Mann1). In addition, mutations in the CDK4 gene3,4 and polymorphisms in the MC1R gene5 have been implicated rarely in melanoma predisposition.

To date, mutations in the two major predisposition genes, CDKN2A and CDK4, account for melanoma susceptibility in less than half of all melanoma families,6 and the genetic bases of the disease in the remaining families have not been found. Gillanders et al recently provided strong evidence for another melanoma predisposition locus at chromosome 1p22.7 Current research in melanoma genetics is hindered by the allelic and locus heterogeneities, which render whole genome linkage analysis difficult. In addition, the sample sizes required to study the effects of weak or modifier alleles in a genetically heterogeneous …

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  • Competing interests: none declared