Variation in Cutaneous Patterns of Melanomagenesis According to Germline CDKN2A/CDK4 Status in Melanoma-Prone Families

Abstract

CDKN2A and CDK4 are well-established melanoma susceptibility genes, but their effect on tumor location and distribution is unknown. We used a case-case study design to assess for differences in tumor location between mutation carriers (CDKN2A = 141 patients, 348 melanomas; CDK4 = 15 patients, 54 melanomas) and noncarriers (104 patients, 157 melanomas) in US melanoma-prone families. Associations between groups were assessed with chi-square tests. Odds ratios (ORs) for tumor location were adjusted for diagnosis age, gender, and superficial spreading subtype. Models included random effects to account for within individual and family correlations. Compared with having a truncal melanoma, CDK4 (vs. noncarriers: lower extremities OR = 14.5, 95% confidence interval [CI] = 5.02-42.0, P < 0.001; upper extremities OR = 6.88, 95% CI = 2.37-19.9, P < 0.001; head and neck OR = 18.6, 95% CI = 4.04-85.2, P < 0.001) and CDKN2A (vs. noncarriers: lower extremities OR = 3.01, 95% CI = 1.56-5.82, P < 0.05; upper extremities OR = 1.91, 95% CI = 1.03-3.52, P < 0.05; head and neck OR = 5.40, 95% CI = 2.10-13.9, P < 0.001) carriers had higher odds of developing melanoma at all other sites. Similar findings were observed for analyses stratified by gender, age, and first versus subsequent melanoma diagnoses. Further studies are needed to understand the biology underlying these genotype-associated patterns of tumor development, which could provide new insights into melanoma treatment and prevention.

Trial registration: ClinicalTrials.gov NCT00040352.

Figure 1:. Cutaneous patterns of melanomagenesis in U.S. melanoma-prone families with and without germline CDKN2A and CDK4 mutations.

The above figure illustrates the regional distribution (column “a”) and specific biopsy sites (column “b”) for melanomas diagnosed in individuals from U.S. melanoma-prone families according to genotype. Global p-values comparing differences in melanoma distribution between mutation carriers (CDKN2A or CDK4) and non-carriers (individuals without a CDKN2A or CDK4 mutation) with adjustments for within individual and within family correlations, age at diagnosis, gender, and superficial spreading melanoma subtype are provided in column “a”.

Figure 2:. Body surface area and melanoma distribution.

The above figure illustrates the observed and expected number of melanomas for each anatomic region according to genotype. In column “a”, the total number of melanomas (N) for each group (non-carriers, CDKN2A carriers, CDK4 carriers) was multiplied by the body surface area of each anatomic region to calculate the expected number of melanomas. Differences between the observed and expected melanoma distribution were assessed by chi-square test (column “a”). The ratio of observed to expected number of melanomas for each anatomic region is presented in column “b”.