Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Malignant Melanoma, familial form type2 (CMM2) [C43.9]

OMIM numbers: 155601, 600160 (CDKN2A)

Dr. rer. nat. Christoph Marschall

Scientific Background

Melanomas are among the most common tumor diseases. Among the Western population, the incidence is 1:2,500–25,000. The risk of developing a melanoma increases significantly after the 20th year of life. Light-skinned people with severe UV exposure as well as individuals with numerous or dysplastic naevi are at a higher risk than others.

In association with familial melanomas, a tumor suppressor gene (CDKN2A) was identified and characterized in its function. The protein encoded by CDKN2A (p16) interacts with the cyclin-dependant kinase 4 (CdK4) and thus causes the progression of the cells into the G1 phase of the cell cycle to be inhibited. Mutations in the CDKN2A gene reduce the interaction between p16 with Cdk4 and accelerate the cell cycle. Absence of the controlling step may lead to malignant cell transformation. The protein p16 seems to compete with p53 regarding its universal function in the tumor genesis. CDKN2A is frequently homozygously mutated or deleted in both various primary tumor cells and in tumor cell lines. In cases of familial melanomas, 25–50% of all families have a mutated CDKN2A allele in the germ line. Loss of heterozygosity (LOH) or homozygous deletions in tumor cells was detected in CDKN2A, similar to other tumor suppressor genes.

In predictive genetic testing, at-risk, asymptomatic individuals are tested, usually first-degree relatives of affected patients. According to the Genetic Diagnosis Act (GenDG) genetic counseling should be offered along with any genetic diagnostic procedure. In the case of predictive genetic testing genetic counseling must be carried out prior to testing as well as after having received the result, unless there exists a written waiver of the at-risk person after having received written information on the content of the counseling. According to the recommendations of medical societies genetic testing should be accompanied by psychotherapeutic counseling prior to, during and after the genetic diagnostic procedure.