Abstract
Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary cancer syndrome that results from mutations in several genes, including the CDKN2A gene. In addition to melanoma, certain other malignancies such as pancreatic cancer are known to occur more frequently in family members who carry the mutation. However, as these families have been followed over time, additional cancers have been observed in both carriers and noncarriers. We sought to determine whether these additional cancers occur at higher frequencies in carriers than noncarriers. We performed survival analyses using 10 FAMMM syndrome families (N ¼ 1,085 individuals) as well as a mixed effects Cox regression, with age at last visit to the clinic or age at cancer diagnosis as our time variable. This analysis was done separately for the known FAMMM-related cancers and "other" cancer groups. The survival curves showed a significant age effect with carriers having a younger age at cancer onset than noncarriers for FAMMM-related cancers (as expected) as well as for newly associated cancers. The Cox regression reflected what was seen in the survival curves, with all models being highly significant (P ¼ 7.15E20 and P ¼ 5.00E13 for the FAMMM-related and other cancers, respectively). These analyses support the hypothesis that CDKN2A mutation carriers in FAMMM syndrome families have increased risk for early onset of several cancer types beyond the known cancers. Therefore, these individuals should be screened for additional cancers, and mutation screening should be extended to more than first-degree relatives of an index carrier patient. Significance: This study shows that carriers of mutations in the CDKN2A gene in FAMMM syndrome are at increased risk for early onset of several cancer types beyond the known cancers.