Molecular subtype, biological sex and age shape melanoma tumour evolution
Open Access
- 8 June 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in British Journal of Dermatology
- Vol. 184 (2), 328-337
- https://doi.org/10.1111/bjd.19128
Abstract
Background Many cancer types display sex and age disparity in incidence and outcome. The mutational load of tumours, including melanoma, varies according to sex and age. However, there are no tools to systematically explore if clinical variables such as age and sex determine the genomic landscape of cancer. Objectives To establish a mathematical approach using melanoma mutational data to analyze how sex and age shape the tumour genome. Methods We model how age‐related (clock‐like) somatic mutations that arise during cell division, and extrinsic (environmental ultraviolet light) mutations accumulate in cancer genomes. Results Melanoma is primarily driven by cell‐intrinsic age‐related mutations and extrinsic ultraviolet light‐induced mutations, and we show these mutation types differ in magnitude, chronology and by sex in the distinct molecular melanoma subtypes. Our model confirms age and sex are determinants of cellular mutation rate, shaping the final mutation composition. We show mathematically for the first time how, similar to non‐cancer tissues, melanoma genomes reflect a decline in cell division during ageing. We find clock‐like mutations strongly correlate with the acquisition of ultraviolet light‐induced mutations, but critically, males present a higher number and rate of cell division‐linked mutations. Conclusions These data indicate the contribution of environmental damage to melanoma likely extends beyond genetic damage to affect cell division. Sex and age determine the final mutational composition of melanoma.Funding Information
- Cancer Research UK (A27412)
- Wellcome (110078/Z/15/Z)
- European Commission (FP7‐PEOPLE‐2013-IEF – 6270270)
This publication has 34 references indexed in Scilit:
- Older Age is Associated with a Higher Incidence of Melanoma Death but a Lower Incidence of Sentinel Lymph Node Metastasis in the SEER Databases (2003–2011)Annals of Surgical Oncology, 2015
- Variation in cancer risk among tissues can be explained by the number of stem cell divisionsScience, 2015
- Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53Nature, 2014
- Signatures of mutational processes in human cancerNature, 2013
- The Life History of 21 Breast CancersCell, 2012
- Interferon-γ links ultraviolet radiation to melanomagenesis in miceNature, 2011
- The cancer genomeNature, 2009
- Improving Melanoma Classification by Integrating Genetic and Morphologic FeaturesPLoS Medicine, 2008
- MC1R Germline Variants Confer Risk for BRAF -Mutant MelanomaScience, 2006
- Distinct Sets of Genetic Alterations in MelanomaThe New England Journal of Medicine, 2005