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Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility |
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| Authors: | James S. Wilmott Peter A. Johansson Felicity Newell Nicola Waddell Peter Ferguson Camelia Quek Ann-Marie Patch Katia Nones Ping Shang Antonia L. Pritchard Stephen Kazakoff Oliver Holmes Conrad Leonard Scott Wood Qinying Xu Robyn P. M. Saw Andrew J. Spillane Jonathan R. Stretch Kerwin F. Shannon Richard F. Kefford Alexander M. Menzies Georgina V. Long John F. Thompson John V. Pearson Graham J. Mann Nicholas K. Hayward Richard A. Scolyer |
| Affiliation: | 1. Melanoma Institute Australia, The University of Sydney, Sydney, Australia;2. QIMR Berghofer Medical Research Institute, Brisbane, Australia Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia;3. Melanoma Institute Australia, The University of Sydney, Sydney, Australia Sydney Medical School, The University of Sydney, Sydney, Australia Charles Perkins Centre, The University of Sydney, Sydney, Australia Royal Prince Alfred Hospital, Camperdown, Australia;4. Melanoma Institute Australia, The University of Sydney, Sydney, Australia Sydney Medical School, The University of Sydney, Sydney, Australia Charles Perkins Centre, The University of Sydney, Sydney, Australia;5. QIMR Berghofer Medical Research Institute, Brisbane, Australia;6. QIMR Berghofer Medical Research Institute, Brisbane, Australia The University of the Highlands and Islands, Inverness, United Kingdom;7. Melanoma Institute Australia, The University of Sydney, Sydney, Australia Sydney Medical School, The University of Sydney, Sydney, Australia Royal Prince Alfred Hospital, Camperdown, Australia;8. Melanoma Institute Australia, The University of Sydney, Sydney, Australia Sydney Medical School, The University of Sydney, Sydney, Australia Royal North Shore Hospital, New South Wales, Australia;9. Melanoma Institute Australia, The University of Sydney, Sydney, Australia Sydney Medical School, The University of Sydney, Sydney, Australia;10. Melanoma Institute Australia, The University of Sydney, Sydney, Australia Sydney Medical School, The University of Sydney, Sydney, Australia Royal Prince Alfred Hospital, Camperdown, Australia Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Camperdown, Australia;11. Melanoma Institute Australia, The University of Sydney, Sydney, Australia Macquarie University, North Ryde, Australia;12. Melanoma Institute Australia, The University of Sydney, Sydney, Australia Sydney Medical School, The University of Sydney, Sydney, Australia Charles Perkins Centre, The University of Sydney, Sydney, Australia Royal North Shore Hospital, New South Wales, Australia |
| Abstract: | Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15–30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10–30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10−6 and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10−4). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas. |
| Keywords: | adolescent and young adult melanoma whole genome sequencing mutation signature germline variant |