Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility

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 KeffordAlexander M Menzies, Georgina V Long, John F Thompson, John V Pearson, Graham J Mann, Nicholas K Hayward, Richard A Scolyer

Research output: Contribution to journalArticle

7 Citations (Scopus)
11 Downloads (Pure)

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 tumour and germline DNA, exome data was 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< 6.0x10-6 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=2.0x10-4 ). 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 harbour 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)1049-1060
Number of pages12
JournalInternational Journal of Cancer. Journal International du Cancer
Volume144
Issue number5
Early online date4 Sep 2018
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • adolescent and young adult
  • germline variant
  • melanoma
  • mutation signature
  • whole genome sequencing

Fingerprint Dive into the research topics of 'Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility'. Together they form a unique fingerprint.

  • Cite this

    Wilmott, J. S., Johansson, P. A., Newell, F., Waddell, N., Ferguson, P., Quek, C., Patch, A-M., Nones, K., Shang, P., Pritchard, A. L., Kazakoff, S., Holmes, O., Leonard, C., Wood, S., Xu, Q., Saw, R. P. M., Spillane, A. J., Stretch, J. R., Shannon, K. F., ... Scolyer, R. A. (2019). Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility. International Journal of Cancer. Journal International du Cancer, 144(5), 1049-1060. https://doi.org/10.1002/ijc.31791