Melanoma Predisposition via the CDK4 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7395 CDK4 81479 81479,81479 $540 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7395CDK481479 81479(x2) $540 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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.

Clinical Sensitivity - Sequencing with CNV PG-Select

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.

Testing Strategy

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.

Indications for Test

Individuals who have multiple family members with melanoma, multiple primary melanomas within individual members, and diagnosis of additional tumors within a family. Also individuals who want to know their carrier status of CDK4 mutations. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

Gene

Official Gene Symbol OMIM ID
CDK4 123829
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Melanoma, Cutaneous Malignant 3 AD 609048

Citations

  • Goldstein et al. (2006). "High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL." Cancer Res 66:9818–9828. PubMed ID: 17047042
  • Hemminki et al. (2003). "Familial and attributable risks in cutaneous melanoma: effects of proband and age." J Invest Dermatol 120:217–223. PubMed ID: 12542525
  • Ibrahim et al. (2009). "Molecular pathogenesis of cutaneous melanocytic neoplasms." Annu. Rev. Pathol. Mech. Dis. 4:551-579. PubMed ID: 19400696
  • Lin JY, Fisher DE. 2007. Melanocyte biology and skin pigmentation. Nature 445: 843–850. PubMed ID: 17314970
  • Mehnert and Kluger. (2012). "Driver mutations in melanoma: lessons learned from bench-to-bedside studies." Curr Oncol Rep 14:449–457. PubMed ID: 22723080
  • Meyle at al. (2009). "Genetic risk factors for melanoma." Hum Genet 126:499–510. PubMed ID: 19585149
  • Nelson AA, Tsao H. 2009. Melanoma and genetics. Clinics in Dermatology 27: 46–52. PubMed ID: 19095153

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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