Rare Germline Variants in CDKN2A-Negative Children and Adolescents With Cutaneous Melanoma

Cutaneous melanoma is a complex disease influenced by both environmental and genetic factors. Inherited susceptibility plays a significant role, involving a combination of high-, intermediate- and low-penetrance genes. Melanoma in children and adolescents has been speculated to have a stronger genetic component due to the early onset. This study investigates germline variants in early-onset melanoma through exome sequencing of 154 patients in Australia diagnosed with cutaneous melanoma before the age of 20. Potentially pathogenic variants in shelterin complex genes were identified in 3% of the cases, consistent with a role for telomere dysregulation in early-onset melanoma. MC1R R-alleles, associated with red hair, fair skin and increased melanoma risk, were less frequent than in adult cases (0.46 vs. 0.64). Pathogenic germline variants in pigmentation genes linked to albinism were identified in 11 individuals (7%), including three truncating variants in PMEL, reinforcing the role of pigmentation pathways in cutaneous melanoma susceptibility. Two patients carried mutations in MBD4, suggesting it may contribute to early-onset disease. The high frequency of rare variants in high- or intermediate-risk genes highlights the importance of including such genes in genetic tests, as they may have implications for future risk in the adolescent patients and their at-risk relatives.