Melanoma-Pancreatic Cancer: CDKN2A Gene Sequencing

Condition Description

Members offamilies with melanoma-pancreatic cancer syndrome (also known as familialatypical multiple-mole melanoma (FAMMM) syndrome) inherit a predisposition todevelop multiple atypical cutaneous nevi (> 50), although not all patientswith melanoma in these families display this phenotype. These families alsoappear to be at increased risk of other malignancies, particularlyadenocarcinoma of the pancreas. A melanoma family apparently predisposed to pancreaticcancer was reported first in 1968, and a number of additional families havebeen identified subsequently. Several studies of melanoma-pancreatic cancersyndrome families have found an excess of nonmelanoma malignancies comparedwith the expected frequency of these malignancies in the general population.The risk of developing malignant disease in these families appears to beincreased 10-fold to 40-fold, and the cumulative risk of pancreatic cancer, thesecond most common cancer in the syndrome, has been estimated at 17% by age 75years. In addition, these families may be at increased risk of developing othercarcinomas, including breast tumors, lung tumors, sarcoma, and digestive tracttumors.

The mostcommon known mutation in these melanoma-prone families involves the CDKN2A gene on chromosome 9p21. CDKN2A encodes p16, a low-molecular-weight protein that inhibits the cyclinD1-cyclin dependent kinase complex (CDK4).If it is not inhibited, the CDK4 complex, in turn, phosphorylates the retinoblastoma protein, allowing a cell toprogress through the G1 phase of the cell cycle. Thus, p16 acts as a tumor suppressor protein, and mutations in CDKN2A can result in unregulated cell growth and neoplastic progression. Germ line CDKN2A mutations have been detected in up to 25% of melanoma-prone families worldwide.

For patients with suspected melanoma-pancreatic cancer syndrome, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.


Rulyak, S, Brentnall, T, Lynch, H, Austin, M.Characterization of the neoplastic phenotype in the familial atypicalmultiple-mole melanoma-pancreatic carcinoma syndrome. 2003. Cancer 98(4):798-804.

Genes (1)

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This test is indicated for:

  • Confirmation of a clinical diagnosis of melanoma-pancreatic cancer syndrome
  • Individuals at-risk for melanoma-pancreatic cancer syndrome due to family history


PCR amplification of 3 exons contained in the CDKN2A gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.


Clinical Sensitivity: Germ line CDKN2A mutations have been detected in up to 25% of melanoma-prone families worldwide. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (
Submit only 1 of the following specimen types
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the CDKN2A gene by CGH array is available for those individuals in whom sequence analysis is negative (VO).
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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