The Genomic Landscape of Actinic Keratosis

Jason Thomson,Findlay Bewicke-Copley,Chinedu Anthony Anene,Abha Gulati,Ai Nagano,Karin Purdie,Gareth J Inman,Charlotte M Proby,Irene M Leigh,Catherine A Harwood,Jun Wang

doi:10.1016/j.jid.2020.12.024

Abstract

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.

Highlights

Actinic keratoses (AKs) are dysplastic epidermal keratinocyte lesions resulting from chronic UVR exposure
Mutational burden and mutational signatures whole-exome sequencing (WES) targeted 334,378 exons from 20,965 genes and yielded a mean coverage of Â53 with 83% of targeted bases covered by Â20 and 94% of them covered by Â10
49,853 were nonsynonymous with a median of 1,676 total and 1,071 nonsynonymous mutations per AK (Figure 1a and Supplementary Tables S4 and S5). This corresponds to a mean tumor mutational burden (TMB) of 43.5 mutations per megabase DNA, similar to the TMB of 50 mutations per megabase DNA we previously reported in cutaneous squamous cell carcinoma (cSCC) (Inman et al, 2018)

Summary

Introduction

Actinic keratoses (AKs) are dysplastic epidermal keratinocyte lesions resulting from chronic UVR exposure. Identifying genomic alterations driving AK‒cSCC progression is challenging because of the high level of background mutations in keratinocytes associated with UV exposure. Several molecular genetic studies have examined AK and cSCC at the levels of gene expression, chromosomal instability, and mutations in known cancer genes. These studies generally show that AK and cSCC possess similar genetic alterations with some conflict on whether AKs are more or less genomically unstable (summarized in Supplementary Table S1). Three previous studies have used whole-exome sequencing (WES) to study AK; these studies have included 10 samples and reported similar mutational spectra in AK and cSCC with frequent mutations in known cSCC tumor suppressor genes TP53, NOTCH1, NOTCH2, and FAT1 (Albibas et al, 2018; Chitsazzadeh et al, 2016; Rodrıguez-Paredes et al, 2018) (Supplementary Table S2)

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Results

Conclusion