FAMILIAL CUTANEOUS MELANOMA AND 2-MUTATIONAL-EVENT MODELING

Background. According to the Knudson two-mutational-event theory, two mutations at a genetic locus may be required for the development of so me cancers. Persons who have inherited a defect in one chromosome and therefore require only one more mutation for cancer development are at a higher risk of manifesting cancer at a younger age than persons wit hout an inherited mutation, who need two acquired ''hits.'' This diffe rence allows one to distinguish familial and sporadic types of the sam e malignancy by evaluating age of disease onset. Methods. To study the role of inheritance in the etiology of familial cutaneous melanoma, c haracteristics of patients with familial versus nonfamilial melanoma w ere analyzed according to the Knudson two-mutational-event model. Resu lts. The familial versus nonfamilial graphs, based on age of diagnosis , did not support this model. However, there was a statistically signi ficant earlier age of diagnosis for patients with familial melanoma. M elanoma thickness was less (i.e., earlier cancer at possibly younger a ge) for patients with a positive versus a negative family history. Con versely, linear regression, after adjusting for tumor thickness, showe d that patients with hereditary melanoma still manifested earlier ages of diagnosis of melanoma compared with sporadic patients. Conclusions . Genetic patterns other than the two-step model, additional family-re lated factors, patient-physician sensitization due to a family history , or a combination of these factors might explain this age difference. More complex multistep modeling of the data may be helpful in better characterizing the genetic patterns of cutaneous melanoma.