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Updated: Jan 18, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Targeted germline sequencing of patients with three or more primary melanomas reveals high rate of pathogenic
Christopher Li1, Tong Liu1, Sean V Tavtigian1,2
1Huntsman Cancer Institute, University of Utah Health Sciences Center.
Abstract:
Individuals with multiple primary melanomas have rates of germline CDKN2A pathogenic variants of 3%-18%, and are also frequent carriers of variants in the melanocortin-1 receptor. Few patients with numerous (≥3) primary melanomas have been studied with respect to these or other potential germline pathogenic variants. We investigated 46 patients with ≥3 primary melanomas (3, n = 17; 4, n = 14; 5-14, n = 15) to determine if higher rates of germline pathogenic variants of CDKN2A, MC1R, or other cancer genes could explain their extreme melanoma phenotype. Most (43/46, 93%) patients had variants in MC1R and 11/46 (24%) had CDKN2A pathogenic variants, but only male sex and having two variants in MC1R correlated with increasing number of melanomas. Panel screening of 56 other cancer predisposition genes did not reveal other germline pathogenic variants associated with melanoma (CDK4, BAP1, POT1), although pathogenic variants in TP53, CHEK2, and BRCA2 were present in three separate patients and some patients had variants of uncertain significance. In summary, targeted germline sequencing of patients with ≥3 primary melanomas revealed a high rate of pathogenic variants in CDKN2A and other known cancer genes. Although further investigation of these pathogenic variants and variants of uncertain significance is needed, these results support cancer gene panel testing in individuals diagnosed with ≥3 melanomas.
Insights
Individuals with multiple primary melanomas often carry genetic variants. This study found high rates of CDKN2A and melanocortin-1 receptor (MC1R) variants in patients with numerous melanomas, supporting genetic panel testing.
Area of Science:
- Genetics
- Oncology
- Dermatology
Background:
- Multiple primary melanomas are associated with germline variants in CDKN2A and MC1R.
- Few studies have investigated germline variants in individuals with a high number (≥3) of primary melanomas.
Purpose of the Study:
- To determine if higher rates of germline pathogenic variants in CDKN2A, MC1R, or other cancer genes explain the extreme melanoma phenotype in patients with ≥3 primary melanomas.
Main Methods:
- Targeted germline sequencing was performed on 46 patients with ≥3 primary melanomas.
- Analysis included CDKN2A, MC1R, and a panel of 56 other cancer predisposition genes.
- Correlations between genetic variants, sex, and number of melanomas were assessed.
Main Results:
- 93% of patients had MC1R variants, and 24% had CDKN2A pathogenic variants.
- Male sex and having two MC1R variants correlated with an increased number of melanomas.
- No other germline pathogenic variants strongly associated with melanoma were identified, though TP53, CHEK2, and BRCA2 variants were found in three patients.
Conclusions:
- Patients with ≥3 primary melanomas exhibit high rates of pathogenic variants in CDKN2A and MC1R.
- These findings support the utility of cancer gene panel testing for individuals diagnosed with multiple primary melanomas.
- Further investigation into variants of uncertain significance is warranted.
