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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

Authors :
James S. Wilmott
Peter Johansson
Oliver Holmes
Qinying Xu
Peter M. Ferguson
Kerwin F. Shannon
Ann-Marie Patch
Richard F. Kefford
John V. Pearson
Andrew J. Spillane
Nicholas K. Hayward
Conrad Leonard
Graham J. Mann
Felicity Newell
Stephen H. Kazakoff
Katia Nones
Camelia Quek
Nicola Waddell
Ping Shang
Jonathan R. Stretch
Richard A. Scolyer
Alexander M. Menzies
John F. Thompson
Scott Wood
Georgina V. Long
Robyn P. M. Saw
Antonia L. Pritchard
Source :
International Journal of Cancer. 144:1049-1060
Publication Year :
2018
Publisher :
Wiley, 2018.

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 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). 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.

Details

ISSN :
00207136
Volume :
144
Database :
OpenAIRE
Journal :
International Journal of Cancer
Accession number :
edsair.doi...........71995c3cc981b98d02ec5899e222b7b4
Full Text :
https://doi.org/10.1002/ijc.31791