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Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations
A M Goldstein1, J P Struewing, A Chidambaram
1Genetic Epidemiology Branch, National Cancer Institute, Bethesda, MD 20892-7236, USA. goldstea@exchange.nih.gov
Background:
Two genes have been implicated in the development of cutaneous malignant melanoma (CMM). CDK4 (the gene encoding cyclin-dependent kinase 4, an oncogene) has exhibited germline mutations found in only three melanoma-prone families to date. CDKN2A is a tumor suppressor gene that encodes p16 (which inhibits activity of the cyclin D1-CDK4 complex) with germline mutations detected in 10%-25% of melanoma-prone families, some of whom are also prone to pancreatic cancer.
Methods:
We compared 104 CMM patients from 17 CDKN2A families and 12 CMM case subjects from two CDK4 families. We used nonparametric statistics to test for differences in median age at first CMM diagnosis, numbers of CMMs, and numbers of nevi. The three recurrent mutations were haplotyped. All P values were two-sided.
Results:
The median age at CMM diagnosis (P =.70) and the median numbers of CMMs (P =.73) did not differ between CMM case subjects from CDKN2A versus CDK4 families. Assessment of CMM case subjects from CDKN2A families with and without pancreatic cancer revealed no statistically significant differences in median age at diagnosis (P =.80) or in tumor number (P =.24). There was, however, a statistically significant difference in age-adjusted median numbers of nevi (P =.004), and CMM case subjects from CDKN2A families without pancreatic cancer had greater numbers of nevi. Recurrent CDKN2A mutations were a change from valine to aspartic acid at codon 126 (n = 3) and from glycine to tryptophan at codon 101 (n = 3). Six CDKN2A families had pancreatic cancer. Both CDK4 families carried a mutation resulting in an arginine-to-cysteine substitution at codon 24. Analyses of recurrent CDKN2A and CDK4 mutations suggested common haplotypes.
Conclusions:
The recurrent CDKN2A mutations were observed in families with and without pancreatic cancer, which suggests that other factors may be involved in the development of pancreatic cancer. Despite hypothetical differences in the mechanisms of action between CDKN2A and CDK4, clinical factors were indistinguishable between CMM case subjects from CDKN2A versus CDK4 families.
Insights
Cutaneous malignant melanoma (CMM) patients with CDKN2A or CDK4 gene mutations showed similar clinical features. However, CDKN2A families without pancreatic cancer had more nevi, suggesting other factors influence pancreatic cancer development.
Area of Science:
- Genetics
- Oncology
- Dermatology
Background:
- Two genes, CDK4 and CDKN2A, are implicated in cutaneous malignant melanoma (CMM) development.
- CDK4 is an oncogene with rare germline mutations in melanoma-prone families.
- CDKN2A is a tumor suppressor gene with mutations found in 10-25% of melanoma-prone families, some also prone to pancreatic cancer.
Purpose of the Study:
- To compare clinical features of CMM patients from families with CDKN2A mutations versus those with CDK4 mutations.
- To investigate the association between CDKN2A mutations, pancreatic cancer, and nevus counts.
Main Methods:
- Compared 104 CMM patients from 17 CDKN2A families and 12 CMM patients from 2 CDK4 families.
- Used nonparametric statistics to analyze age at diagnosis, CMM counts, and nevus counts.
- Haplotype analysis of recurrent mutations.
Main Results:
- No significant differences in median age at CMM diagnosis or CMM counts between CDKN2A and CDK4 families.
- No significant differences in CMM age at diagnosis or tumor number in CDKN2A families with or without pancreatic cancer.
- Significantly higher age-adjusted median nevus counts in CDKN2A families without pancreatic cancer (P =.004).
Conclusions:
- Recurrent CDKN2A mutations occurred in families with and without pancreatic cancer, suggesting other factors are involved in pancreatic cancer development.
- Clinical presentation of CMM was indistinguishable between CDKN2A and CDK4 families, despite proposed mechanistic differences.