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

## TL;DR

This study finds that children and adolescents with melanoma have rare genetic mutations in genes related to telomeres, pigmentation, and DNA repair, but fewer MC1R R-alleles compared to adults.

## Contribution

The study identifies rare germline variants in CDKN2A-negative early-onset melanoma patients, emphasizing the role of telomere biology and pigmentation genes.

## Key findings

- Potentially pathogenic variants in shelterin complex genes were found in 3% of early-onset melanoma cases.
- Eleven individuals (7%) had pathogenic variants in pigmentation genes linked to albinism.
- Two patients carried truncating MBD4 variants, suggesting a role in early-onset melanoma.

## Abstract

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.

This study examined exonic variants in 154 individuals diagnosed with cutaneous melanoma in Australia before the age of 20 years.
MC1R R‐alleles, which are associated with melanoma risk in adults, were less frequent in this early‐onset cohort.Several variants were identified in shelterin complex genes involved in telomere biology.Eleven participants carried variants in pigmentation genes associated with albinism, highlighting the importance of pigmentation pathways in early‐onset melanoma susceptibility.Two individuals carried truncating MBD4 variants, suggesting that monoallelic loss of MBD4 may contribute to early‐onset cutaneous melanoma.

This study examined exonic variants in 154 individuals diagnosed with cutaneous melanoma in Australia before the age of 20 years.

MC1R R‐alleles, which are associated with melanoma risk in adults, were less frequent in this early‐onset cohort.

Several variants were identified in shelterin complex genes involved in telomere biology.

Eleven participants carried variants in pigmentation genes associated with albinism, highlighting the importance of pigmentation pathways in early‐onset melanoma susceptibility.

Two individuals carried truncating MBD4 variants, suggesting that monoallelic loss of MBD4 may contribute to early‐onset cutaneous melanoma.

Individuals with childhood and adolescent melanoma carry inherited mutations in shelterin complex genes, pigmentation genes and MBD4, but have fewer MC1R R‐alleles than adults with melanoma. Created with BioRender.com.