TY - JOUR
T1 - The Genomic Landscape of Actinic Keratosis
AU - Thomson, Jason
AU - Bewicke-Copley, Findlay
AU - Anene, Chinedu Anthony
AU - Gulati, Abha
AU - Nagano, Ai
AU - Purdie, Karin
AU - Inman, Gareth J.
AU - Proby, Charlotte M.
AU - Leigh, Irene M.
AU - Harwood, Catherine A.
AU - Wang, Jun
N1 - Funding Information:
This work was supported by Cancer Research UK program grant (reference 13044) and a Barts Charity small project grant (reference MGU0394, awarded to JT). CAA is funded by the Barts Charity project grant (reference MRD&U0003). JW, FBC, and CAA also acknowledge support from the Cancer Research UK Centre of Excellence Award to Barts Cancer Centre (London, United Kingdom) (reference C16420/A18066). GJI acknowledges support from Cancer Research UK Beatson Institute (Glasgow, United Kingdom) core grant.
Publisher Copyright:
© 2021 The Authors
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Actinic keratoses (AKs) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression from normal skin to skin with AK to skin with invasive cSCC is challenging because of the massive UVR-induced mutational burden characteristic at all stages of this progression. In this study, we report the largest AK whole-exome sequencing study to date and perform a mutational signature and candidate driver gene analysis on these lesions. We demonstrate in 37 AKs from both immunosuppressed and immunocompetent patients that there are significant similarities between AKs and cSCC in terms of mutational burden, copy number alterations, mutational signatures, and patterns of driver gene mutations. We identify 44 significantly mutated AK driver genes and confirm that these genes are similarly altered in cSCC. We identify azathioprine mutational signature in all AKs from patients exposed to the drug, providing further evidence for its role in keratinocyte carcinogenesis. cSCCs differ from AKs in having higher levels of intrasample heterogeneity. Alterations in signaling pathways also differ, with immune-related signaling and TGFβ signaling significantly more mutated in cSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGFβ signaling may represent an important event in AK‒cSCC progression.
AB - Actinic keratoses (AKs) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression from normal skin to skin with AK to skin with invasive cSCC is challenging because of the massive UVR-induced mutational burden characteristic at all stages of this progression. In this study, we report the largest AK whole-exome sequencing study to date and perform a mutational signature and candidate driver gene analysis on these lesions. We demonstrate in 37 AKs from both immunosuppressed and immunocompetent patients that there are significant similarities between AKs and cSCC in terms of mutational burden, copy number alterations, mutational signatures, and patterns of driver gene mutations. We identify 44 significantly mutated AK driver genes and confirm that these genes are similarly altered in cSCC. We identify azathioprine mutational signature in all AKs from patients exposed to the drug, providing further evidence for its role in keratinocyte carcinogenesis. cSCCs differ from AKs in having higher levels of intrasample heterogeneity. Alterations in signaling pathways also differ, with immune-related signaling and TGFβ signaling significantly more mutated in cSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGFβ signaling may represent an important event in AK‒cSCC progression.
UR - http://www.scopus.com/inward/record.url?scp=85101373607&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2020.12.024
DO - 10.1016/j.jid.2020.12.024
M3 - Article
C2 - 33482222
SN - 0022-202X
VL - 141
SP - 1664-1674.e7
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 7
ER -