Grant Number:	5R01CA088363-03 Interpret this number
Primary Investigator:	Hayward, Nicholas
Organization:	Queensland Institute Of Medical Research
Project Title:	Pathways From Genotype and Environment to Melanoma
Fiscal Year:	2003

DESCRIPTION: The incidence of cutaneous malignant melanoma has increased dramatically in white-skinned populations throughout the world over past decades. The Australian state of Queensland has the highest incidence of melanoma in the world with lifetime incidences of 1 in 13 males and 1 in 16 females. While these rates are almost five times those in the USA, the shape of the age-specific incidence curve is almost the same in the two populations, suggesting similar causal factors. Over the past 20 years we have conducted several large-scale studies into the molecular genetics and genetic epidemiology of melanoma and its risk factors, particularly nevus density and pigmentation. We shall follow up a population-based sample of 1,912 melanoma families to update survival status and risk factor information, and to obtain DNA from all melanoma cases and a sample of unaffected relatives, and do likewise in studies of melanoma in children (under l4y), adolescents (14-19y) and older men (over 50y). 3,440 family members of twins for whom we have nevus counts and 600 controls will also be included in the total of 6,248 DNA samples for molecular analysis. We shall sequence the CDKN2A and P genes in 100 subjects of diverse melanoma risk and pigmentation, and type all subjects for single-nucleotide polymorphisms (SNPs) in these and other genes of the cell cycle (CDKN2B, CDK4), and pigmentation (MCI R) pathways. We shall perform within-family and case-control analyses for association of melanoma risk variables including status, age-at-onset, survival and severity, with SNPs and environmental risk factors, stratified by familial risk. Similar analyses will be conducted for mediating variables such as nevus density, freckling, and pigmentation. We shall test for gene-gene interactions (epistasis) between SNPs of cell-cycle genes and pigmentation axis genes, and for gene-environment interactions of SNPs with measured environmental risk factors, on melanoma risk variables. We shall also test whether melanoma in childhood or adolescence can be solely explained by the same risk factors that operate in adults or whether they carry rare alleles in cell cycle or pigmentation genes. Finally, segregation-association analysis will test whether familial aggregation for melanoma can be completely explained by our measured risk factors. In addition, we shall fine map a major locus affecting nevus density linked to CDKN2A, and extend a 10cM genome scan to 900 twin families (about 1100 sib pairs) so we can use sib pair linkage analysis to locate loci influencing nevus density, freckling, pigmentation phenotypes, and other risk factors.





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