Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel.

Sonia Segura,Agustí Toll,Alejandra Gadea,Lara Nonell,Ramon Pujol,Inmaculada Hernández-Muñoz,Evelyn Andrades,Silvia Sánchez

doi:10.1371/journal.pone.0232146

Sonia Segura, Agustí Toll + Show 6 more

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https://doi.org/10.1371/journal.pone.0232146

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Journal: PloS one	Publication Date: May 15, 2020
Citations: 4	License type: CC BY 4.0

Affiliation: Hospital Del Mar, University of Barcelona

Abstract

Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma if left untreated. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood. In this study, we evaluated the gene expression profiles of actinic keratosis lesions before and after treatment with ingenol mebutate using microarray technology. Actinic keratoses on face/scalp of 15 immunocompetent patients were identified and evaluated after treatment with topical ingenol mebutate gel 0.015%, applied once daily for 3 consecutive days. Diagnostic and clearance of lesions was determined by clinical, dermoscopic, and reflectance confocal microscopy criteria. Lesional and non-lesional skin biopsies were subjected to gene expression analysis profiled by Affymetrix microarray. Differentially expressed genes were identified, and enrichment analyses were performed using STRING database. At 8 weeks post-treatment, 60% of patients responded to ingenol mebutate therapy, achieving complete clearance in 40% of cases. A total of 128 differentially expressed genes were identified following treatment, and downregulated genes (114 of 128) revealed changes in pathways important to epidermal development, keratinocyte differentiation and cornification. In responder patients, 388 downregulated genes (of 450 differentially expressed genes) were also involved in development/differentiation of the epidermis, and immune system-related pathways, such as cytokine and interleukin signaling. Cluster analysis revealed two relevant clusters showing upregulated profile patterns in pre-treatment actinic keratoses of responders, as compared to non-responders. Again, differentially expressed genes were mainly associated with cornification, keratinization and keratinocyte differentiation. Overall, the present study provides insight into the gene expression profile of actinic keratoses after treatment with ingenol mebutate, as well as identification of genetic signatures that could predict treatment response.

Highlights

Actinic keratosis (AK) is a common skin disease characterized by thick, scaly, cutaneous lesions on chronic sun-exposed areas, and histologically by atypical keratinocytes extending to the basal layer of the epidermis, that may progress to invasive squamous cell carcinoma (SCC) if left untreated [1,2]
Similar results were obtained when analyzing samples responsive to treatment with ingenol mebutate (IM): we identified 388 downregulated genes associated with epidermis development, keratinocyte differentiation, cornification, keratinization, epidermal cell differentiation and formation of the cornified envelope
The results presented provide insight into the gene expression profile of AK samples after treatment with topical IM, as well as the biological processes involved. This is the first comparison of untreated skin samples and AK lesions treated with IM between responder and non-responder patients, leading to the identification of genetic signatures that could be correlated with the treatment response

Summary

Introduction

Actinic keratosis (AK) is a common skin disease characterized by thick, scaly, cutaneous lesions on chronic sun-exposed areas, and histologically by atypical keratinocytes extending to the basal layer of the epidermis, that may progress to invasive squamous cell carcinoma (SCC) if left untreated [1,2]. The risk to develop a cutaneous SCC is approximately 0.03–20% per year for any single lesion [3,4,5,6], and the risk of malignant progression for a patient affected by multiple AK lesions has been estimated within a wide range between 0.15% and 80% [7]. Despite the advances in the recognition of clinic, dermoscopic and histologic patterns, it is not yet possible to predict which lesions will advance to SCC [11]. For this reason, an early diagnosis and effective treatment are recommended. Since AKs are usually multiple and often subclinical, a field-directed approach is suggested to remove clinically visible as well as non-visible lesions within the treatment area to prevent the development to invasive SCC [12]

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