This cohort study compares the clinical characteristics of first and second melanomas and estimates the relative risks of developing 1 vs multiple melanomas associated with demographic, phenotypic, sun exposure, and genetic factors. Key PointsQuestionDo second melanomas develop in people who have a risk factor profile different from that of people who develop only 1 melanoma during a defined period of follow-up? FindingsIn this cohort study of 38845 patients, after 7.4 years of follow-up, people who had a second primary melanoma diagnosis were significantly more likely than people with a first primary melanoma diagnosis to have a nevus-prone phenotype (self-reported) and to have higher genetic predisposition for melanoma (as determined by polygenic risk scores). Only limited evidence supported that higher levels of personal sun exposure were associated with multiplicity. MeaningFindings suggest that people who develop second primary melanomas have more nevi and greater genetic risk than people who develop only 1 melanoma. ImportanceAn increasing number of people develop more than 1 primary melanoma, yet to date, no population-based prospective cohort studies have reported on risk factors for developing first vs second primary melanomas. ObjectiveTo compare the clinical characteristics of first and second melanomas and then to estimate the relative risks of developing 1 vs multiple melanomas associated with demographic, phenotypic, sun exposure, and genetic factors. Design, Setting, and ParticipantsThis population-based prospective cohort study included men and women aged 40 to 69 years recruited in 2011 and followed up until December 2018 in Queensland, Australia. Data analysis was performed from February to July 2022. ExposuresSelf-reported information about demographic, phenotypic, and sun exposure measures captured using a survey completed at baseline, and polygenic risk score for melanoma. Main Outcomes and MeasuresIncident first or second primary melanoma diagnosis, and histologic and clinical characteristics thereof. The Wei-Lin-Weissfeld model for recurrent events was used to estimate the association of each factor with the risks of first and second primary melanoma. ResultsA total of 38845 patients (mean [SD] age at baseline, 56.1 [8.2] years; 17775 men and 21070 women) were included in the study. During a median follow-up period of 7.4 years, 1212 (3.1%) participants had a single primary melanoma diagnosis, and 245 (0.6%) had a second primary melanoma diagnosis. Second melanomas were more likely than first melanomas to be in situ; for invasive tumors, second melanomas were more likely to be thin (ie, <= 1 mm) than first melanomas. Having many moles at age 21 years (self-reported using visual scoring tool) was more strongly associated with second (hazard ratio [HR], 6.36; 95% CI, 3.77-10.75) than first primary melanoma (HR, 3.46; 95% CI, 2.72-4.40) (P value for difference between the HRs=.01). A high genetic predisposition (ie, polygenic risk score in tertile 3) was also more strongly associated with second (HR, 3.28; 95% CI, 2.06-5.23) than first melanoma (HR, 2.06; 95% CI, 1.71-2.49; P=.03). Second melanomas were more strongly associated with a history of multiple skin cancer excisions (HR, 2.63; 95% CI, 1.80-3.83) than first melanomas (HR, 1.86; 95% CI, 1.61-2.16; P=.05). For all other phenotypic characteristics and sun exposure measures, similarly elevated associations with first vs second melanomas were observed. Conclusions and RelevanceFindings of this cohort study suggest that within the general population, the presence of many nevi and having a high genetic predisposition to melanoma were associated with the highest risks of developing second primary melanomas.
