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.
The CDKN2A gene has been implicated in cutaneous malignant melanoma (CMM) in about 40% of families with linkage to chromosome 9p21, while a small proportion of families have mutations in the CDK4 gene.
: Inherited mutations in the CDKN2A tumor suppressor gene, which encodes the p16(INK4a) protein, and in the cyclin-dependent kinase 4 (CDK4) gene confer susceptibility to cutaneous malignant melanoma.
Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM.
We performed a genome-wide scan of two Danish pedigrees with multiple cases of OMM (N = 10) and CMM (N = 3) and other malignancies (with no germline mutations in CDKN2A, CDK4, BRCA1, and BRCA2) to identify melanoma susceptibility genes.
Integrative sequencing of cutaneous melanoma metastases using different sequencing platforms revealed a new somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C (a CDK4 inhibitor).
We found an association between the risk of CMM and peripheral blood mononuclear cell methylation levels of TNFα [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18], CDK4 (OR=0.76, 95% CI=0.64-0.91), and MLH1 (OR=1.12, 95% CI=1.02-1.22).
This is the first estimate of the contribution of BAP1 and CDK4 to a population-based sample of CMM and supports the previously reported estimate of CDKN2A germline mutation prevalence.
To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM.
We identified germline mutations in highly CM-associated genes (CDKN2A and CDK4) and low/medium-penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first- or second-degree relatives.