RESUMO
BACKGROUND: Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. METHODS: This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. RESULTS: We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results. CONCLUSION: This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.
Assuntos
Melanoma , Análise da Randomização Mendeliana , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Melanoma/genética , Melanoma/imunologia , Carcinoma Basocelular/genética , Carcinoma Basocelular/imunologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Ceratose Actínica/genética , Ceratose Actínica/imunologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We aimed to unveil the underlying pathogenic mechanisms of skin cancer in relation to metabolic factors and pathway mechanisms. This study utilized the TwoSample Mendelian randomization (MR) method to investigate the causal relationship between 1400 plasma metabolites and skin cancer. The primary method employed was the inverse variance weighting (IVW). Through IVW analysis, we found 105 plasma metabolites associated with Basal Cell Carcinoma (BCC), with the highest association observed for Prolylglycine levels (OR [95% CI]: 1.1902 [1.0274, 1.3788]). For Malignant Melanoma of Skin (MSS), 68 plasma metabolites were linked, with the highest causal relationship seen for 3-Hydroxybutyrate levels (OR [95% CI]: 1.0030 [1.0013, 1.0048]). Regarding actinic keratosis (AK), and the highest association observed for Hexadecadienoate (16:2n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.7125]). Glycerol to palmitoylcarnitine (16: n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.125]) were found to be significant for BCC and AK. Palmitoylcarnitine (C16) had the most positive causal effect for BCC (OR [95% CI]: 1.1777 [1.0493, 1.3218]), while 5-hydroxy-2-methylpyridine sulfate levels had the highest effect for AK (OR [95% CI]: 1.1788 [1.0295, 1.3498]). And 4-guanidinobutanoate levels had the largest positive causal effect (OR [95% CI]: 1.0857 [1.0417, 1.1317]) for BCC, and X-11880 levels for MSS (OR [95% CI]: 1.0013 [1.0000, 1.0025]). The study revealed a positive association between hereditary Glycerol to palmitoylcarnitine (C16) and 5-hydroxy-2-methylpyridine sulfate levels with the risk of developing BCC and AK. Additionally, 4-guanidinobutanoate levels and X 11880 levels were found to be positively associated with the risk of BCC and MMS.
Assuntos
Carcinoma Basocelular , Análise da Randomização Mendeliana , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/epidemiologia , Carcinoma Basocelular/sangue , Carcinoma Basocelular/genética , Carcinoma Basocelular/epidemiologia , Melanoma/sangue , Melanoma/genética , Melanoma/epidemiologia , Ceratose Actínica/sangue , Ceratose Actínica/genética , Ácido 3-Hidroxibutírico/sangue , Predisposição Genética para Doença , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Chronic inflammation has been shown to promote cancer progression. Rosacea is indeed a long-term inflammatory skin condition and had been reported to link with increased risk for several types of malignancies, but evidence for causality is lacking. OBJECTIVES: To systematically estimate the causal relationship between rosacea and several types of cancer, including cutaneous malignant melanoma (CMM), cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), actinic keratosis (AK), thyroid cancer, breast cancer, glioma and hepatic cancer, as well as explore the potential underlying pathogenesis. METHODS: We conducted a bidirectional two-sample Mendelian randomization study to probe the potential causal relationships between rosacea and several types of cancer. Instrumental variables were established using genome-wide significant single nucleotide polymorphisms associated with rosacea and cancers. The assessment of causality was carried out through multiple methods, and the robustness of the results was evaluated via sensitivity analyses. RESULTS: There was no significant indication of causal effects of rosacea on CMM (pivw = 0.71), cSCC (pivw = 0.45), BCC (pivw = 0.90), AK (pivw = 0.73), thyroid cancer (pivw = 0.59), glioma (pivw = 0.15), and hepatic cancer (pivw = 0.07), but the genetic risk of rosacea was associated with an increased susceptibility to human epidermal growth factor receptor (HER)-negative malignant neoplasm of breast (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18; pivw = 0.01). TANK (TRAF family member associated nuclear factor kappa B (NFKB) activator) was identified as a common protective gene for both rosacea (OR, 0.90; 95% CI, 0.82-0.99; pivw = 0.048) and HER-negative malignant neoplasm of the breast (OR, 0.86; 95% CI, 0.75-0.98; pivw = 0.032), which was primarily enriched in the negative regulation of NF-κB signal transduction and may contribute to the genetic links between rosacea and this subtype of breast cancer. CONCLUSIONS: Our findings provide suggestive evidence for causal links between rosacea and HER-negative malignant neoplasm of the breast risk.
Assuntos
Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Rosácea , Neoplasias Cutâneas , Humanos , Rosácea/genética , Neoplasias Cutâneas/genética , Feminino , Melanoma/genética , Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Fatores de Risco , Predisposição Genética para Doença/genética , Neoplasias da Mama/genética , Ceratose Actínica/genética , Neoplasias da Glândula Tireoide/genética , Glioma/genética , Neoplasias Hepáticas/genética , MasculinoRESUMO
BACKGROUND: Observational and epidemiological studies show conflicting results on the relationship between atopic dermatitis and skin cancer. Additionally, observational studies are susceptible to the reverse causation and confounders, thus, may not interpret true causal relationships. The causal effects of atopic dermatitis on the risk of skin cancers remains unclear. OBJECTIVES: To investigate the causal relationship between atopic dermatitis and skin cancer including cutaneous malignant melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma and actinic keratosis. METHODS: We performed a two-sample Mendelian randomization analysis based on summary datasets of public genome-wide association studies of European ancestry. The inverse variance-weighted approach was applied as the main analysis. MR-Egger and weighted median methods were used to complement the inverse variance-weighted results. A series of sensitivity analyses were used to ensure the robustness of the causality estimates. RESULTS: Inverse variance-weighted method showed that genetically predicted dermatitis patients were significantly associated with an increased incidence of basal cell carcinoma (OR, 1.20; 95% CI, 1.10-1.31; p = 4.07E-05) and cutaneous squamous cell carcinoma (OR, 1.14; 95% CI, 1.10-1.19; p = 1.05E-11). However, we did not find a significant causality for atopic dermatitis on melanoma neither did we find actinic keratosis. Subsequent sensitive analyses supported these results. CONCLUSIONS: Our study identified the causality between atopic dermatitis basal cell carcinoma and squamous cell carcinoma. Accordingly, regular skin cancer screening is recommended for patients with atopic dermatitis.
Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Dermatite Atópica , Ceratose Actínica , Melanoma , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/genética , Carcinoma de Células Escamosas/genética , Ceratose Actínica/complicações , Ceratose Actínica/genética , Dermatite Atópica/complicações , Dermatite Atópica/epidemiologia , Dermatite Atópica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Carcinoma Basocelular/epidemiologia , Carcinoma Basocelular/genéticaRESUMO
Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To comprehensively delineate the underlying mechanisms for the whole progression from normal skin to AK to invasive cSCC, we performed single-cell RNA sequencing (scRNA-seq) to acquire the transcriptomes of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC, and their matched normal tissues, covering comprehensive clinical courses of cSCC. We identified diverse cell types, including important subtypes with different gene expression profiles and functions in major keratinocytes. In SCCIS, we discovered the malignant subtypes of basal cells with differential proliferative and migration potential. Differentially expressed genes (DEGs) analysis screened out multiple key driver genes including transcription factors along AK to cSCC progression. Immunohistochemistry (IHC)/immunofluorescence (IF) experiments and single-cell ATAC sequencing (scATAC-seq) data verified the expression changes of these genes. The functional experiments confirmed the important roles of these genes in regulating cell proliferation, apoptosis, migration, and invasion in cSCC tumor. Furthermore, we comprehensively described the tumor microenvironment (TME) landscape and potential keratinocyte-TME crosstalk in cSCC providing theoretical basis for immunotherapy. Together, our findings provide a valuable resource for deciphering the progression from AK to cSCC and identifying potential targets for anticancer treatment of cSCC.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/metabolismo , Ceratose Actínica/genética , Ceratose Actínica/metabolismo , Ceratose Actínica/patologia , Neoplasias Cutâneas/patologia , Queratinócitos/metabolismo , Transcriptoma , Microambiente Tumoral/genéticaRESUMO
IMPORTANCE: Actinic keratosis (AK) is a premalignant lesion that has a1% to 10% potential of progression to squamous cell carcinoma (SCC), but it is not possible to determine which lesions are at higher risk. OBJECTIVE: This study examined the epidermal genetic profiles of actinic keratosis and SCC through non-invasive techniques seeking to develop a biopsy-free method for AK monitoring and aid in the early diagnosis of developing SCC. DESIGN: Ribonucleic acid (RNA) was collected from adhesive tape strips and gene expression levels were measured. A threshold fold change >2 and adjusted P-value <0.05 were used to determine differentially expressed genes. SETTING: Single center dermatology clinic. PARTICIPANTS: Patients who presented to the clinic with lesions suspicious of non-melanoma skin cancer that had never been previously biopsied. MAIN OUTCOME AND MEASURE: RNA was extracted via non-invasive biopsy and sequenced. Low quality samples were filtered out and the remaining samples underwent differential gene expression analysis by DESeq2 in R package. A threshold of fold change >2 and adjusted P-value <0.05 was used for determination of differentially expressed genes. The differentially expressed genes that overlapped between the corrected and uncorrected groups were the most significant for analysis. RESULTS: From 47 lesions, 6 significant differentially expressed genes were found between AK and SCC, and 25 significant differentially expressed genes between in-situ SCC and invasive SCC. Individual samples showed similarities based on diagnosis, suggesting mutations were specific to the disease and not the individual. CONCLUSIONS AND RELEVANCE: These findings highlight which genes may play a role in AK progression to SCC. The genomic differences between in-situ and invasive squamous cell carcinoma open an opportunity for early diagnosis of squamous cell carcinoma and risk prediction of actinic keratosis. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7097.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Humanos , Ceratose Actínica/diagnóstico , Ceratose Actínica/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Epiderme/patologia , RNARESUMO
Actinic keratoses (AKs) are sun-damaged skin areas that affect 20% of the European adult population and more than 50% of people aged 70 years and over. There are currently no clinical or histological features allowing us to identify to which clinical class (i.e., regression or progression) an AK belongs. A transcriptomic approach seems to be a robust tool for AK characterization, but there is a need for additional studies, including more patients and elucidating the molecular signature of an AK. In this context, the present study, including the largest number of patients to date, is the first aiming at identifying biological features to objectively distinguish different AK signatures. We highlight two distinct molecular profiles: AKs featuring a molecular profile similar to squamous cell carcinomas (SCCs), which are called "lesional AKs" (AK_Ls), and AKs featuring a molecular profile similar to normal skin tissue, which are called "non-lesional AKs" (AK_NLs). The molecular profiles of both AK subclasses were studied, and 316 differentially expressed genes (DEGs) were identified between the two classes. The 103 upregulated genes in AK_L were related to the inflammatory response. Interestingly, downregulated genes were associated with keratinization. Finally, based on a connectivity map approach, our data highlight that the VEGF pathway could be a promising therapeutic target for high-risk lesions.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Adulto , Humanos , Idoso , Idoso de 80 Anos ou mais , Ceratose Actínica/genética , Ceratose Actínica/patologia , Transcriptoma , Neoplasias Cutâneas/patologia , Pele/patologia , Carcinoma de Células Escamosas/patologiaRESUMO
Vitamin D3, a prohormone, is converted to circulating calcidiol and then to calcitriol, the hormone that binds to the vitamin D receptor (VDR) (a nuclear transcription factor). Polymorphic genetic sequence variants of the VDR are associated with an increased risk of breast cancer and melanoma. However, the relationship between VDR allelic variants and the risk of squamous cell carcinoma and actinic keratosis remains unclear. We examined the associations between two VDR polymorphic sites, Fok1 and Poly-A, and serum calcidiol levels, actinic keratosis lesion incidence, and the history of cutaneous squamous cell carcinoma in 137 serially enrolled patients. By evaluating the Fok1 (F) and (f) alleles and the Poly-A long (L) and short (S) alleles together, a strong association between genotypes FFSS or FfSS and high calcidiol serum levels (50.0 ng/ml) was found; conversely, ffLL patients showed very low calcidiol levels (29.1 ng/ml). Interestingly, the FFSS and FfSS genotypes were also associated with reduced actinic keratosis incidence. For Poly-A, additive modeling showed that Poly-A (L) is a risk allele for squamous cell carcinoma, with an OR of 1.55 per copy of the L allele. We conclude that actinic keratosis and squamous cell carcinoma should be added to the list of squamous neoplasias that are differentially regulated by the VDR Poly-A allele.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Humanos , Vitamina D , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Alelos , Calcifediol , Incidência , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/genética , Ceratose Actínica/epidemiologia , Ceratose Actínica/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Vitaminas , GenótipoRESUMO
BACKGROUND: Actinic keratosis (AK) is considered as precursor lesion of invasive squamous cell carcinoma. Molecular studies on AK are limited because of too small size of the biopsy specimen to obtain enough DNA or RNA. METHODS: Twenty biopsy cases of AK, followed by second same-sited biopsies, were included. Ten cases were diagnosed with total regression (regression group), while the other 10 were diagnosed with invasive carcinoma (progression group) in the follow-up biopsies. Using digital spatial profiling (DSP) technology, whole-gene expression analysis defined by specific regions of interest was performed for all 20 cases. After the clinicopathological features were assessed, separate and integrated analyses of these features and gene expression patterns were performed using machine-learning technology. All analyses were performed on both lesion keratinocytes (KT) and infiltrated stromal lymphocytes (LC). RESULTS: Among the 18,667 genes assessed, 33 and 72 differentially expressed genes (DEGs) between the regression and progression groups were found in KT and LC respectively. The primary genes distinguishing the two groups were KRT10 for KT and CARD18 for LC. Clinicopathological features were weaker in risk stratification of AK progression than the gene expression patterns. Pathways associated with various cancers were upregulated in the progression group of KT, whereas the nucleotide-binding oligomerization domain (NOD)-like receptor signalling pathway was upregulated in the progression of LC. CONCLUSION: Gene expression patterns were effective for risk stratification of AK progression, and their distinguishing power was higher than that of clinicopathological features.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Humanos , Ceratose Actínica/genética , Ceratose Actínica/patologia , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Expressão Gênica , Medição de RiscoRESUMO
Actinic keratosis (AK) and cutaneous squamous cell carcinoma in situ (CIS) are two of the most common precursors of cutaneous squamous cell carcinoma (cSCC). However, the genomic landscape of AK/CIS and the drivers of cSCC progression remain to be elucidated. The aim of our study was to investigate the genomic alterations between AK/CIS and cSCC in terms of somatic mutations and copy number alterations (CNAs). We performed targeted deep sequencing of 160 cancer-related genes with a median coverage of 515× for AK (N = 9), CIS (N = 9), cSCC lesions (N = 13), and matched germline controls from 17 patients. cSCC harboured higher abundance of total mutations, driver mutations and CNAs than AK/CIS. Driver mutations were found in TP53 (81%), NOTCH1 (32%), RB1 (26%) and CDKN2A (19%). All AK/CIS and cSCC lesions (93.5%), except two, harboured TP53 or NOTCH1 mutations, some of which were known oncogenic mutations or reported mutations in normal skin. RB1 driver mutations were found in CIS/cSCC (36.4%) but not in AK. CDKN2A driver mutations were found more frequently in cSCC (30.8%) than in AK/CIS (11.1%). Among recurrent (≥3 samples) CNAs (gain in MYC and PIK3CA/SOX2/TP63; loss in CDKN2A and RB1), MYC (8q) gain and CDKN2A (9p) loss were more frequently detected in cSCC (30.8%) than in AK/CIS (11.1%). Ultraviolet was responsible for the majority of somatic mutations in both AK/CIS and cSCC. Our study revealed that AK/CIS lesions harbour prevalent TP53 or NOTCH1 mutations and that additional somatic mutations and CNAs may lead to cSCC progression in AK/CIS lesions.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Ceratose Actínica/genética , Ceratose Actínica/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Genômica , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Actinic keratosis (AK) is a common precancerous cutaneous neoplasm that arises on chronically sun-exposed skin. AK susceptibility has a moderate genetic component, and although a few susceptibility loci have been identified, including IRF4, TYR, and MC1R, additional loci have yet to be discovered. We conducted a genome-wide association study of AK in non-Hispanic white participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (n = 63,110, discovery cohort), with validation in the Mass-General Brigham (MGB) Biobank cohort (n = 29,130). We identified eleven loci (P < 5 × 10-8), including seven novel loci, of which four novel loci were validated. In a meta-analysis (GERA + MGB), one additional novel locus, TRPS1, was identified. Genes within the identified loci are implicated in pigmentation (SLC45A2, IRF4, BNC2, TYR, DEF8, RALY, HERC2, and TRPS1), immune regulation (FOXP1 and HLA-DQA1), and cell signaling and tissue remodeling (MMP24) pathways. Our findings provide novel insight into the genetics and pathogenesis of AK susceptibility.
Assuntos
Ceratose Actínica , Neoplasias Cutâneas , Adulto , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Humanos , Ceratose Actínica/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Neoplasias Cutâneas/genéticaRESUMO
The mechanism underlying the progression of actinic keratosis (AK) and cutaneous squamous cell carcinoma (SCC) in situ (SCCIS) to SCC remains unclear. To investigate this, we performed regional microdissection and targeted deep sequencing in SCC (n = 10) and paired adjacent sun-damaged epidermis (SE)/AK/SCCIS (n = 13) samples to detect mutations and copy number alterations. Most (11/13) SE/AK/SCCIS tissues harbored ≥1 driver alterations, indicating their precancerous nature. All pairs except one showed genome architectures representing the genomic progression of SE/AK/SCCIS to SCC with common trunks and unique branches (seven parallel and five linear progression cases). SE/AK/SCCIS tissues tended to harbor lower mutation/copy number alteration burdens than SCC tissues, but most of them had driver mutations, including NOTCH1 and TP53 mutations. SCC-specific genomic alterations included TP53, PIK3CA, FBXW7, and CDKN2A mutations and an MYC copy number gain, but they were heterogeneous among cases, suggesting that a single gene or pathway does not explain the progression of AK to SCC. In multiregion analyses of AK lesions, only some AK samples were related to SCC. In conclusion, the SE/AK/SCCIS genomes may have previously acquired truncal driver alterations, such as NOTCH1 and TP53 mutations, which promote parallel or linear progression to SCC on an acquisition of additional genomic alterations.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Carcinoma de Células Escamosas/patologia , Genômica , Humanos , Ceratose Actínica/genética , Ceratose Actínica/patologia , Mutação , Neoplasias Cutâneas/patologiaRESUMO
Most cutaneous squamous cell carcinomas (cSCCs) arise from actinic keratoses (AKs), making these premalignant lesions attractive targets for therapeutic intervention before transformation. In a new article of the Journal of Investigative Dermatology, Thomson et al. (2021) characterize the genetic alterations in AKs and identify significantly mutated drivers associated with risk factors such as UVR or azathioprine along with signaling pathways that may regulate the progression from AK to cSCC.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Carcinoma de Células Escamosas/genética , Genômica , Humanos , Ceratose Actínica/genética , Neoplasias Cutâneas/genéticaRESUMO
The presence of actinic keratoses (AKs) increases a patient's risk of developing squamous cell carcinoma by greater than six-fold. We evaluated the effect of topical treatment with imiquimod on the tumor microenvironment by measuring transcriptomic differences in AKs before and after treatment with imiquimod 3.75%. Biopsies were collected prospectively from 21 patients and examined histologically. RNA was extracted and transcriptomic analyses of 788 genes were performed using the nanoString assay. Imiquimod decreased number of AKs by study endpoint at week 14 (p < 0.0001). Post-imiquimod therapy, levels of CDK1, CXCL13, IL1B, GADPH, TTK, ILF3, EWSR1, BIRC5, PLAUR, ISG20, and C1QBP were significantly lower (adjusted p < 0.05). Complete responders (CR) exhibited a distinct pattern of inflammatory gene expression pre-treatment relative to incomplete responders (IR), with alterations in 15 inflammatory pathways (p < 0.05) reflecting differential expression of 103 genes (p < 0.05). Presence of adverse effects was associated with improved treatment response. Differences in gene expression were found between pre-treatment samples in CR versus IR, suggesting that higher levels of inflammation pre-treament may play a part in regression of AKs. Further characterization of the immune micro-environment in AKs may help develop biomarkers predictive of response to topical immune modulators and may guide therapy.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Expressão Gênica , Imiquimode/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Ceratose Actínica/genética , Transcriptoma , Adjuvantes Imunológicos/administração & dosagem , Administração Tópica , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Imiquimode/administração & dosagem , Ceratose Actínica/patologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Cutaneous squamous cell carcinoma (cSCC) is a malignant neoplasm of the skin resulting from the accumulation of somatic mutations due to solar radiation. cSCC is one of the fastest increasing malignancies, and it represents a particular problem among immunosuppressed individuals. MicroRNAs are short noncoding RNAs that regulate the expression of protein-coding genes at the post-transcriptional level. In this study, we identify miR-130a to be downregulated in cSCC compared to healthy skin and precancerous lesions (actinic keratosis). Moreoever, we show that its expression is regulated at the transcriptional level by HRAS and MAPK signaling pathway. We demonstrate that overexpession of miR-130a suppresses long-term capacity of growth, cell motility and invasion ability of human cSCC cell lines. We report that miR-130a suppresses the growth of cSCC xenografts in mice. Mechanistically, miR-130a directly targets ACVR1 (ALK2), and changes in miR-130a levels result in the decreased activity of the BMP/SMAD pathway through ACVR1. These data reveal a link between activated MAPK signaling and decreased expression of miR-130a, which acts as a tumor-suppressor microRNA in cSCC and contribute to a better understanding of the molecular processes during malignant transformation of epidermal keratinocytes.
Assuntos
Receptores de Ativinas Tipo I/genética , Carcinoma de Células Escamosas/genética , Ceratose Actínica/genética , MicroRNAs/metabolismo , Neoplasias Cutâneas/genética , Animais , Biópsia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Queratinócitos/patologia , Ceratose Actínica/patologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Neoplasias Cutâneas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer. Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK). However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet. To identify genes involved in this progression trajectory and possible therapeutic targets for cSCC, here we constructed a UV-induced cSCC mouse model covering the progression from normal skin to AK to cSCC, which mimicked the solar UV radiation perfectly using the solar-like ratio of UVA and UVB, firstly. Then, transcriptome analysis and a series of bioinformatics analyses and cell experiments proved that Rorα is a key transcript factor during cSCC progression. Rorα could downregulate the expressions of S100a9 and Sprr2f in cSCC cells, which can inhibit the proliferation and migration in cSCC cells, but not the normal keratinocyte. Finally, further animal experiments confirmed the inhibitory effect of cSCC growth by Rorα in vivo. Our findings showed that Rorα would serve as a potential novel target for cSCC, which will facilitate the treatment of cSCC in the future.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Transformação Celular Neoplásica/metabolismo , Ceratose Actínica/metabolismo , Neoplasias Induzidas por Radiação/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/deficiência , Neoplasias Cutâneas/metabolismo , Animais , Calgranulina B/genética , Calgranulina B/metabolismo , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Proteínas Ricas em Prolina do Estrato Córneo/genética , Proteínas Ricas em Prolina do Estrato Córneo/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ceratose Actínica/etiologia , Ceratose Actínica/genética , Ceratose Actínica/patologia , Camundongos Pelados , Invasividade Neoplásica , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/patologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fatores de Transcrição de Octâmero/genética , Fatores de Transcrição de Octâmero/metabolismo , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Transcriptoma , Raios UltravioletaRESUMO
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 TGFß signaling significantly more mutated in cSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGFß signaling may represent an important event in AKâcSCC progression.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Ceratose Actínica/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma de Células Escamosas/patologia , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Queratinócitos/patologia , Ceratose Actínica/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Transdução de Sinais/genética , Pele/patologia , Neoplasias Cutâneas/patologia , Fator de Crescimento Transformador beta/metabolismo , Sequenciamento do ExomaRESUMO
This Perspective briefly reviews the relationship between UV-induced mutations in habitually sun-exposed human skin and subsequent development of actinic keratoses (AKs) and skin cancers. It argues that field therapy rather than AK-selective therapy is the more logical approach to cancer prevention and hypothesizes that treatment early in the process of field cancerization, even prior to the appearance of AKs, may be more effective in preventing cancer as well as more beneficial for and better tolerated by at-risk individuals. Finally, the Perspective encourages use of rapidly advancing DNA analysis techniques to quantify mutational burden in sun-damaged skin and its reduction by various therapies.
Assuntos
Carcinoma Basocelular/prevenção & controle , Carcinoma de Células Escamosas/prevenção & controle , Dermatologia/tendências , Ceratose Actínica/terapia , Neoplasias Cutâneas/prevenção & controle , Administração Cutânea , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Transformação Celular Neoplásica/efeitos da radiação , Abrasão Química/métodos , Abrasão Química/tendências , Terapia Combinada/métodos , Terapia Combinada/tendências , Criocirurgia/métodos , Criocirurgia/tendências , Curetagem/métodos , Curetagem/tendências , Dano ao DNA/efeitos da radiação , Análise Mutacional de DNA , Dermatologia/métodos , Progressão da Doença , Eletrocoagulação/métodos , Eletrocoagulação/tendências , Fluoruracila/administração & dosagem , Humanos , Queratinócitos/patologia , Queratinócitos/efeitos da radiação , Ceratose Actínica/etiologia , Ceratose Actínica/genética , Ceratose Actínica/patologia , Mutação/efeitos da radiação , Fotoquimioterapia/métodos , Fotoquimioterapia/tendências , Pele/efeitos dos fármacos , Pele/patologia , Pele/efeitos da radiação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Protetores Solares/administração & dosagem , Raios Ultravioleta/efeitos adversosRESUMO
Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer with an increasing incidence. As a pre-cancerous condition, actinic keratosis (AK) has an up to 20% risk of progression to cSCC. This study aims to define the potential genes that associated with genesis and progression of cSCC, thereby further identify critical biomarkers for the prevention, early diagnosis, and effective treatment of cSCC.Two datasets GSE42677 and GSE45216 were downloaded from the GEO. Microarray data analysis was applied to explore the differentially expressed genes (DEGs) between cSCC samples and AK samples. Then functional enrichment analysis, protein-protein interaction (PPI) network, and drug-gene interaction analysis were performed to screen key genes.A total of 711 DEGs, including 238 upregulated genes and 473 downregulated genes, were screened out. DEGs mainly involved in pathways as extracellular matrix (ECM)-receptor interaction, hematopoietic cell lineage, phosphatidylinositol 3-kinase (PI3K-Akt) signaling pathway, and focal adhesion. Candidate genes, including upregulated genes as JUN, filamin A (FLNA), casein kinase 1 delta (CSNK1D), and histone cluster 1 H3 family member f (HIST1H3F), and downregulated genes as androgen receptor (AR), heat shock protein family H member 1 (HSPH1), tropomyosin 1 (TPM1), pyruvate kinase, muscle (PKM), LIM domain and actin binding 1 (LIMA1), and synaptopodin (SYNPO) were screened out. In drug-gene interaction analysis, 13 genes and 44 drugs were identified.This study demonstrates that genes JUN, FLNA, AR, HSPH1, and CSNK1D have the potential to function as targets for diagnosis and treatment of cSCC.