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A molecular signature for rejuvenation characterizes lesional and non lesional skin following Metvix treatment in Actinic Keratosis patients.

ABSTRACT: Actinic keratoses (AK) are proliferations of pre-neoplastic keratinocytes in the epidermis that are the result of cumulative ultraviolet (UV) radiations from sun exposure. Lesions are commonly found on sites of sun-exposed skin such as the face, balding scalp, and back of the hand. AKs may present on a patient as a few detectable lesions and 5-10% of them are susceptible to transform into SCC. In contrast, Organ Transplant Recipients (OTR) are of increasing risk at developing cancers as a consequence of long-term immunosuppressive therapy. The molecular changes that occur in lesional and perilesional skin of OTR patients 18 weeks following of PDT with topical MAL treatment were investigated to better understand the effect of the therapeutic intervention on the AK lesions. Our data show the complete normalization of the skin biology in the treated areas, i. e restoration of normal proliferation related gene profiles, and correction of aberrantly expressed cancer associated genes. We were also able to uncover a transcriptional signature of a rejuvenation effect induced by MAL-PDT in photodamaged skin opening new avenues in the use of PTD for treating photodamaged skin and field cancerized areas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90643 | GEO | 2018/06/15

REPOSITORIES: GEO

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Characterizing dermal transcriptional change in the progression from sun-protected skin to actinic keratosis. II[

Project description:Here we used a pan-cytokeratin antibody to differentiate the epidermal from dermal compartment and assayed over 18,000 RNA probes from multiple regions of interest (ROI) comparing sun protected skin, and two regions (edge and center) from AK/sun damaged skin. This allows for a trajectory from sun protected to sun damaged within an individual. Traditionally, cancer biology focusses on change within the tumor compartment for diagnosis and staging and current genetic profiling of actinic keratosis (the precursor lesion for cutaneous squamous cell carcinoma) has focused on analysis limited to whole skin or the epidermal compartment alone. Here we use spatial transcriptomics to compare and contrast the epidermal and stromal compartments from different regions of actinic keratosis and matched sun protected skin from six individuals. Our data show that the major changes in AK at the transcriptional level are evident in the dermal compartment. Sun protected skin (n=5-6 from 6 individuals for a total of 34 ROI), the center of an AK lesion (n=3 for a total of 18 ROI) and edge of the AK lesion (n=2-3 for a total of 17 ROI) representing sun-damaged skin, from six unrelated individuals, the center of an AK lesion (n=3 for a total of 18 ROI) and edge of the AK lesion (n=2-3 for a total of 17 ROI) representing sun-damaged skin, from six unrelated individuals.

2022-12-19 | GSE221000 | GEO

Characterizing dermal transcriptional change in the progression from sun-protected skin to actinic keratosis. [I]

2022-12-19 | GSE220998 | GEO

Molecular profiling of cutaneous squamous cell carcinomas and actinic keratoses from organ transplant recipients

2013-02-06 | GSE32628 | GEO

Molecular profiling of cutaneous squamous cell carcinomas and actinic keratoses from organ transplant recipients

Project description:The risk of developing cutaneous squamous cell carcinoma (SCC) is markedly increased in organ transplant recipients (OTRs) compared to the normal population. Next to sun exposure, the immunosuppressive regimen is an important risk factor for the development of SCC in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. loss of CDKN2A, amplification of RAS) have been found in SCCs. The aim of this genome-wide study was to identify pathways that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs). To perform the analysis in an isogenic background, RNA and DNA were isolated from normal (unexposed) epidermis, benign AK, and SCC from each of 15 OTRs. Hierarchical cluster analysis of mRNA expression profiles showed SCC, AK and epidermal samples to separate into three distinct groups. Several thousand genes were differentially expressed between epidermis, AK and SCC; most upregulated in SCCs were genes related to hyperproliferation and stress markers, such as keratin 6 (KRT6), KRT16 and KRT17. Matching to oncogenic pathways revealed activation of downstream targets of RAS and cMYC in SCCs and of NFkappaB and TNF already in AKs. Patients were selected from the group of OTRs that are regularly seen at the dermatology clinic of the Leiden University Medical Center. Patients with clinically suspected SCC were informed on the study and after informed consent was obtained, fresh frozen samples were obtained from SCCs (n=15), AKs (n=14) and NS (n=13). RNA was isolated and gene expression profiles were obtained using HumanWG-6 v2 Expression BeadChips (Illumina). The normalized expression data was analyzed for differences in expression between SCC, AK and NS, at single-gene level but also at geneset level.

2013-02-06 | E-GEOD-32628 | biostudies-arrayexpress

RNA-seq of human skin lesions diagnosed as actinic keratosis, intraepidermal carcinoma or squamous cell carcinoma

Project description:We report whole tissue RNA-seq data captured from 25 AK, IEC or SCC lesions obtained from the skin of 17 individuals. We used RNA-seq to detect and measure HPV E7 transcription.

2018-07-09 | E-MTAB-6430 | biostudies-arrayexpress

Ingenol mebutate induces profound inflammatory and wound healing responses in uninvolved and actinic keratosis skin

Project description:We studied the transcriptomic profile of actinic keratosis (AK) skin compared to matched samples from uninvolved skin (US) before and after treatment with ingenol mebutate gel. We found that AK has a distinct mRNA profile that separates it from uninvolved skin. In particular, numerous genes associated with epidermal development and keratinocyte differentiation, such as LCE3D, SPRR1A, PI3 and several genes in the keratin family were highly expressed in AK0 skin, but not in US0, in line with the hyperkeratosis characteristic for AK. Topical application of ingenol mebutate had a profound effect on the gene expression profile, and interestingly, many more genes were affected in US than in AK. Enrichment analysis revealed that the main responses to ingenol mebutate treatment of both US and AK were inflammatory response, response to wounding, and wound healing. 30 skin biopsies were analysed; 5 from each of 6 AK patients. Before initiation of treatment, baseline biopsies were taken from one AK lesion (AK0) and from uninvolved skin (US0). A third biopsy was taken after day 1 application of ingenol mebutate from one AK lesion (AK1). The fourth and fifth biopsies were obtained one day after the second topical application with ingenol mebutate from an AK lesion (AK2) and from uninvolved skin (US2), respectively.

2016-03-31 | E-GEOD-63107 | biostudies-arrayexpress

Ingenol mebutate induces profound inflammatory and wound healing responses in uninvolved and actinic keratosis skin

2016-03-31 | GSE63107 | GEO

Genome-wide SNP analysis of cutaneous squamous cell carcinomas and actinic keratoses from organ transplant recipients

2013-02-06 | GSE32969 | GEO

Transcription profiling of human normal skin, actinic keratosis and squamous cell carcinoma

Project description:normal skin (no), actinic keratosis (ak), and squamous cell carcinoma (scc) of the skin were examined:; BACKGROUND: Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. This study examined and identified differentially expressed genes in cutaneous squamous cell carcinoma (SCC). RESULTS: Three different biopsies of 5 immunosuppressed organ-transplanted recipients each normal skin (all were pooled), actinic keratosis (AK) (two were pooled), and invasive SCC and additionally 5 normal skin tissues from immunocompetent patients were analyzed. Thus, total RNA of 15 specimens were used for hybridization with Affymetrix HG-U133A microarray technology containing 22,283 genes. Data analyses were performed by prediction analysis of microarrays using nearest shrunken centroids with the threshold 3.5 and ANOVA analysis was independently performed in order to identify differentially expressed genes (p < 0.05). Verification of 13 up- or down-regulated genes was performed by quantitative real-time reverse transcription (RT)-PCR and genes were additionally confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes. CONCLUSION: The majority of identified differentially expressed genes in cutaneous SCC were previously not described.

2007-10-02 | E-GEOD-2503 | biostudies-arrayexpress

THE GENOMIC LANDSCAPE OF ACTINIC KERATOSIS

Project description:Actinic keratoses (AK) are lesions of epidermal keratinocyte dysplasia and are pre-cursor lesions to invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression of normal skin to AK and invasive cSCC is challenging due to the massive, ultraviolet radiation-induced mutational burden characteristic to these lesions. Here, we present the largest whole exome sequencing study to date on AK with matched cSCC and demonstrate that AK and cSCC are almost indistinguishable at the genomic level, in terms of mutational burden, patterns of driver gene mutations and copy number alterations. We identified 44 significantly mutated AK driver genes through our established bioinformatics pipeline and demonstrate these genes are similarly mutated in cSCC. We also identified mutational signature-32 exclusively in AK from patients exposed to azathioprine, providing further, compelling evidence for this drugÃ¢Â€Â™s role in keratinocyte carcinogenesis, likely through its blocking of transcription coupled repair. We demonstrated that cSCC had higher levels of intra-sample heterogeneity than AK and that several signaling pathways, including immune-related signaling and TGF-beta signaling were significantly more mutated in cSCC. Integrating our findings with independent gene expression data confirms that dysregulated TGF-beta signaling may represent the critical pathway in the progression from AK to cSCC.

| EGAS00001004243 | EGA

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