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Melanoma Genes and Multiple Primary Melanomas

Transformation of a normal cell into one that is malignant can result from either uncontrolled activation of an oncogene or loss of function of both copies of a tumor suppressor (TS) gene. An analogy would be the loss of control of an automobile due to a "stuck" gas pedal (oncogene) or the failure of both sets of brakes (TS gene). It is thought that in most cancer-prone families affected individuals inherit one abnormal copy of a TS gene (a germ-line mutation) and then receive a second hit, e.g., loss of a portion of a chromosome or exposure to an environmental mutagen such as UV light. This results in loss of function of both copies of a particular TS gene, which sets the stage for uncontrolled cellular proliferation.

Germ-line mutations in the CDKN2A TS gene (also known as p16) have been described in affected members of several melanoma-prone families. The name of the gene reflects the function of its protein product: inhibition of cyclin dependent kinases (CDK) 4 and 6. Because an active CDK allows cell division, an uninhibited CDK can result in uncontrolled proliferation. This study searched for germ-line mutations in the CDKN2A gene in a group of 33 unrelated patients with multiple primary cutaneous melanomas (at least one was invasive) and no known family history of melanoma.

Five patients (15%) had germ-line mutations in the CDKN2A gene. On further investigation, two of the five patients were found to have family members with melanoma, and in three families, CDKN2A mutations identical to those in the probands were found in other family members. These findings point to the need for surveillance of relatives of patients with multiple primary melanomas.

Comment: To date, two definite melanoma genes have been described -- CDKN2A and CDK4, a TS gene and an oncogene, respectively -- and there are clearly more to come. Although genetic screening can be done on family members when a relative with melanoma has a known mutation in one of these genes, negative results from random screenings of at-risk individuals are meaningless at this time.

— J Bolognia

Published in Journal Watch Dermatology July 1, 1998

Citation(s):

Monzon J et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med 1998 338 879-887.

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