Risks of Melanoma and Other Cancers in Melanoma-Prone Families over 4 Decades

Abstract

Since 1976, melanoma-prone families have been followed at the National Cancer Institute to identify etiologic factors for melanoma. We compared risks of melanoma and other cancers in 1,226 members of 56 families followed for up to 4 decades with population rates in the Surveillance, Epidemiology, and End Results program. All families were tested for mutations in CDKN2A and CDK4; 29 were mutation-positive and 27 mutation-negative. We compared rates of invasive melanomas, both first and second, by family mutation status, with Surveillance, Epidemiology, and End Results program. Comparing three calendar periods of the study, risk of first primary melanoma decreased slightly. Risks of melanoma after first examination, however, were approximately one-third the risks prior to the first examination in both mutation-positive and mutation-negative families. Among patients with melanoma, risk of a second melanoma was increased 10-fold in all families; risk was somewhat higher in mutation-positive families. Risks of other second cancers were increased only for pancreatic cancer after melanoma in mutation-positive families. Over 4 decades, prospective risk of melanoma has decreased substantially in both mutation-positive and mutation-negative families, when melanoma has greatly increased in the general population.

Trial registration: NCI 02-C-0211, ClinicalTrials.gov ID NCT00040352.

Figure 1.

Invasive, multiple primary, and in situ melanomas in all cases. Total number of melanomas in probands (n = 136, left), retrospective cases (n = 97, middle), and prospective cases (n = 30, right). Each circle shows the distribution of invasive single primary, invasive multiple primary, and in situ melanomas for each case group, comprising all melanomas with tumor data available, including cases not clinically examined. Most cases were either probands (defining their families as eligible for study) or retrospective cases (individuals with first melanoma prior to study participation). There were many fewer prospective cases, individuals who developed their first melanoma after first study examination. The distribution of invasive single primary, invasive multiple primary, and in situ melanomas across the three case groups was significantly different (P < 0.0001).

Figure 2.

Age, gender, and calendar-period specific melanoma incidence in Seer9 (1975–2013), mutation-positive families, and mutation-negative families. The numbers under the x-axis reflect the number of individuals in mutation-negative families in red and mutation-positive families in blue. The orange dashed line represents the age-specific first primary melanoma incidence in SEER; the red solid line represents the age-specific risk of first melanoma in the mutation-negative families; and the blue dashed line represents the age-specific incidence in mutation-positive families; overall log-rank P < 0.0001. The log-rank P value for the comparison of the families is 0.0112. The blue and red shading represent the 95% Hall-Wellner bands for the familial data. Seer, Surveillance, Epidemiology, and End Results program.