Melanoma Predisposition via the CDK4 Gene

Melanoma is a malignant tumor that originates in melanocytes, a specialized cell type that produces melanin pigments that determine skin, hair and eye color (Lin and Fisher. Nature 445:843–850, 2007). Over the past few decades there has been a rise in the incidence of melanoma due to improved awareness leading to additional diagnoses and to lifestyle changes that have resulted in an increase in sun exposure (Mehnert and Kluger. Curr Oncol Rep 14:449–457, 2012). Most melanomas occur as sporadic cases with no recognized familial component; however, melanoma appears to be twice as common in people with an affected parent, three times as common if a sibling is affected, and nine times as common if both a parent and a sibling are affected (Hemminki et al. J Invest Dermatol 120:217–223, 2003). Familial clustering is likely the result of genetic and environmental factors. Heritable alleles for melanoma susceptibility range from high-risk, high-penetrance alleles that are rare, to low-risk, low-penetrance alleles that are rather ubiquitous (Nelson et al. Clinics in Dermatology 27, 46–52, 2009). Mutations in the highly penetrant CDKN2A, and less commonly the CDK4 gene, are responsible for the majority of predisposition to melanoma cases. CDK4 mutations appear to be associated with a similar median age at melanoma diagnosis as CDKN2A mutations (i.e. 36 years) (Meyle at al. Hum Genet 126:499–510, 2009; Goldstein et al. Cancer Res 66:9818–9828, 2006).

Melanoma predisposition is inherited in an autosomal dominant manner. The strongest genetic risk for the development of melanoma results from heritable alterations in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, however mutations in the CDK4 gene have been reported. CDK4 is an oncogene that encodes a protein kinase. The two most common CDK4 mutations leading to melanoma are both at codon 24 (ie, Arg24Cys and Arg24His). Mutations in CDK4 are therefore oncogenic alleles, with only a single mutation necessary to result in tumorigenesis (Nelson et al. Clinics in Dermatology 27, 46–52, 2009). The function of the upstream p16/INK4a protein is to inhibit CDK4/6 protein-mediated phosphorylation of the Rb (Retinoblastoma) protein; p16/INK4a therefore keeps the Rb protein dephosphorylated, which is the active state of Rb. Mutated CDK4 protein is resistant to the inhibition of p16/INK4a (Ibrahim et al. Annu. Rev. Pathol. Mech. Dis. 4:551-579, 2009), thus causing the phosphorylation of the Rb protein, which leads to release of the bound transcription factor, E2F, which then allows the cell to undergo unregulated cell division leading to the development of melanoma.

Only 2% of the families in the Geno-MEL study carried CDK4 mutations (Goldstein et al. Cancer Res 66:9818–9828, 2006), and less than 15 families have been reported worldwide (Meyle at al. Hum Genet 126:499–510, 2009). To our knowledge, no causative copy number variants have been reported in the CDK4 gene.

This test provides full coverage of all coding exons of the CDK4 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.