Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa continued...
The melanoma-astrocytoma syndrome is another phenotype caused by mutations in CDKN2A. The possible existence of this disorder was first described in 1993. A study of 904 individuals with melanoma and their families found 15 families with 17 members who had both melanoma and multiple types of tumors of the nervous system. Another study found a family with multiple melanoma and neural cell tumors that appeared to be caused by loss of p14ARF function or to disruption of expression of p16.
CDK4 and CDK6
Cyclin-dependent kinases have important roles in progression of cells from G1 to S phase. CDK4 and CDK6 partner with the cyclin–D associated kinases to accelerate the function of the cell cycle. Phosphorylation of the retinoblastoma (Rb) protein in G1 by cyclin-dependent kinases releases transcription factors, inducing gene expression and metabolic changes that precede DNA replication, thus allowing the cell to progress through the cell cycle. These genes are of conceptual significance because they are in the same signaling pathway as CDKN2A.
Germline CDK4 mutations are very rare, being found in only a handful of melanoma kindreds.[104,105,106] All described families demonstrated a substitution of amino acid 24, suggesting this position as a mutation hotspot within the CDK4 gene. Mutation of CDK4 affects binding of p16 with its subsequent inhibition of CDK4 functionality. With constitutive activation of germline CDK4, CDK4 acts as a dominant oncogene.
Despite its functional similarity to CDK4, germline mutations in CDK6 have not been identified in any melanoma kindreds.
DNA repair genes
Xeroderma pigmentosum (XP) patients with defective DNA repair have a more than 1,000-fold increase in melanoma risk. These patients are diagnosed with melanoma at a significantly younger age than individuals in the general population; on average, melanoma diagnosis occurs at age 22 years in XP patients. The anatomic site distribution of melanomas in XP patients is similar to that of the general population.[109,110]
Genetic polymorphisms associated with DNA repair genes have been associated with mildly increased melanoma risk in the general population.
(Refer to the Xeroderma pigmentosum section in the Squamous Cell Carcinoma section of this summary for more information.)
Additional evidence for 9p21 loci
When the first data linking CDKN2A mutations to melanoma risk became available, it was clear that these mutations did not account for all the melanoma tumors in which 9p21 loss of heterozygosity could be demonstrated. In fact, 51% of informative cases had deletions that did not involve somatic mutations in CDKN2A. The specific genes involved have remained elusive but are still under intense investigation.
Additional candidate regions for familial melanoma susceptibility
Several additional loci for familial melanoma have been identified through genome-wide studies. A melanoma susceptibility locus on 1p22 was identified through a linkage analysis of 49 Australian families who had at least three melanoma cases and who were mutation-negative for CDKN2A and CDK4. Deletion mapping in tumors shows a minimal region of loss of a 9-Mb interval within the peak linkage region, but none of the linkage families have mutations in the genes tested thus far. A genome-wide association study of individuals from 34 high-risk melanoma families revealed three single nucleotide polymorphisms (SNPs) on 10q25.1 associated with melanoma risk. The ORs for risk for the SNPs ranged from 6.8 to 8.4. Subsequent parametric linkage analysis in one family showed logarithm of the odd scores of 1.5, whereas the other two families assessed did not show linkage. No obvious candidate gene was identified in the genomic region of interest. A genome-wide linkage study of 35 Swedish families identified evidence of linkage on chromosomal regions 17p11-12 and 18q22. No causitive genes have been confirmed, but candidates map to all of the loci. None of these loci have been confirmed in independent studies.