Cutaneous squamous cell carcinomas and actinic keratoses from organ transplant recipients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32979 | GEO | 2013/02/06
SECONDARY ACCESSION(S): PRJNA146429
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-06 | E-GEOD-32979 | biostudies-arrayexpress
Project description:BackgroundThe 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 and genomic alterations that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs).MethodsTo perform the analysis in an isogenic background, RNA and DNA were isolated from SCC, AK and normal (unexposed) epidermis (NS) from each of 13 OTRs. Samples were subjected to genome-wide expression analysis and genome SNP analysis using Illumina's HumanWG-6 BeadChips and Infinium II HumanHap550 Genotyping BeadChips, respectively. mRNA expression results were verified by quantitative PCR.ResultsHierarchical cluster analysis of mRNA expression profiles showed SCC, AK and NS samples to separate into three distinct groups. Several thousand genes were differentially expressed between epidermis, AK and SCC; most upregulated in SCCs were hyperproliferation related genes 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 NFκB and TNF already in AKs. In contrast to what has been reported previously, genome-wide SNP analysis showed very few copy number variations in AKs and SCCs, and these variations had no apparent relationship with observed changes in mRNA expression profiles.ConclusionVast differences in gene expression profiles exist between SCC, AK and NS from immunosuppressed OTRs. Moreover, several pathways activated in SCCs were already activated in AKs, confirming the assumption that AKs are the precursor lesions of SCCs. Since the drastic changes in gene expression appeared unlinked to specific genomic gains or losses, the causal events driving SCC development require further investigation. Other molecular mechanisms, such as DNA methylation or miRNA alterations, may affect gene expression in SCCs of OTRs. Further study is required to identify the mechanisms of early activation of NFκB and TNF, and to establish whether these pathways offer a feasible target for preventive intervention among OTRs.
| S-EPMC3570297 | biostudies-literature
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.
2013-02-06 | GSE32628 | GEO
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
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 SCC development in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. CDKN2A loss, RAS amplification) have been found in SCCs. The aim of this study was to identify genomic alterations that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs). To perform the analysis in an isogenic background, DNA was isolated from SCC and AK from each of 13 OTRs. Tumor samples and their matching normal control (peripheral blood) were analyzed on the Illumina HumanHap550V3_duo genotyping beadchips. In contrast to previous studies, genome-wide SNP analysis showed very few copy number variations in AKs and SCCs, and these variations had no apparent relationship with observed changes in mRNA expression profiles (GSE32628). Other molecular mechanisms, such as DNA methylation or miRNA alterations, may affect gene expression in SCCs of OTRs.
2013-02-06 | GSE32969 | GEO
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 SCC development in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. CDKN2A loss, RAS amplification) have been found in SCCs. The aim of this study was to identify genomic alterations that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs). To perform the analysis in an isogenic background, DNA was isolated from SCC and AK from each of 13 OTRs. Tumor samples and their matching normal control (peripheral blood) were analyzed on the Illumina HumanHap550V3_duo genotyping beadchips. In contrast to previous studies, genome-wide SNP analysis showed very few copy number variations in AKs and SCCs, and these variations had no apparent relationship with observed changes in mRNA expression profiles (GSE32628). Other molecular mechanisms, such as DNA methylation or miRNA alterations, may affect gene expression in SCCs of OTRs. 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, including 2 repeats) and AKs (n=11). Peripheral blood was taken as normal control. DNA was isolated and SNP profiles were obtained using HumanHap550V3_duo Genotyping BeadChips (Illumina). Both the log R ratio and the B allele frequency (BAF) were investigated to identify copy number alterations and loss of heterozygosity (LOH) The tumor DNA samples are from the same tumor samples as the RNA samples in GSE32628.
2013-02-06 | E-GEOD-32969 | biostudies-arrayexpress
Project description:Importance:Solid organ transplant recipients (SOTRs) have a 100-fold increased risk of squamous cell carcinoma (SCC), and they may develop more aggressive SCCs compared with immunocompetent individuals. Objective:To compare outcomes associated with aggressive behavior of SCC in SOTRs and high-risk immunocompetent patients. Design, Setting, and Participants:A retrospective cohort study of 58 SOTRs and 40 immunocompetent patients evaluated at the Yale Transplant Dermatology Clinic in New Haven, Connecticut, who had at least 1 SCC confirmed histopathologically between January 1, 2008, and December 31, 2015. Cumulative follow-up time for this study was 369 patient-years. Exposure:Immunosuppressive medication regimen for SOTRs. Main Outcomes and Measures:The primary outcome measure was tumor depth of SCC. Secondary outcome measures that reflected tumor aggressiveness included perineural invasion, regional metastases, nodal metastases, disease-specific death, and overall death. Results:Of the 58 SOTR study participants, 14 were women and 44 were men; the mean (SD) age was 61.3 (8.4) years. Of the 40 immunocompetent study participants, 16 were women and 24 were men; the mean (SD) age was 69.8 (10.9) years, resulting in a statistically significant difference from the SOTR group. The mean (SD) number of years that SOTRs were immunosuppressed was 14.6 (9.2) years (range, 2-37 years). The SOTR and immunocompetent groups were statistically comparable regarding race and sex, patient care, follow-up time, numbers of skin lesions, and field cancerization and chemopreventive therapies. The SOTR group had a significantly higher annual frequency of visits (mean [SD], 4 [2] vs 3 [2] office visits per patient per year, P = .02) and annual biopsy rates (mean [SD], 6 [4] vs 5 [3] biopsies per patient per year, P = .04). The SOTRs developed SCCs that did not appear to be significantly more aggressive than those found in the immunocompetent control group. These SOTRs also did not develop significantly thicker tumors than the immunocompetent control group (median [IQR] tumor depth, 1.30 [0.90-1.60] mm in 35 SOTRs vs 1.22 [1.10-1.60] mm in 20 immunocompetent patients). Conclusions and Relevance:The increased risk and the potential for aggressive behavior of SCCs in SOTRs may be successfully managed at a level comparable to that in high-risk immunocompetent individuals through close adherence to current dermatologic surveillance recommendations and a marginally lower threshold for biopsy of suspicious lesions for SOTRs.
| S-EPMC5833573 | biostudies-literature
Project description:A low percentage of actinic keratoses progress to develop into cutaneous squamous cell carcinoma. The immune mechanisms that successfully control or eliminate the majority of actinic keratoses and the mechanisms of immune escape by invasive squamous cell carcinoma are not well-understood. Here, we took a systematic approach to evaluate the neoantigens present in actinic keratosis and cutaneous squamous cell carcinoma specimens. We compared the number of mutations, the number of neoantigens predicted to bind MHC class I, and the number of neoantigens that are predicted to bind MHC class I and be recognized by a T cell receptor in actinic keratoses and cutaneous squamous cell carcinomas. We also considered the relative binding strengths to both MHC class I and the T cell receptor in a fitness cost model that allows for a comparison of the immune recognition potential of the neoantigens in actinic keratosis and cutaneous squamous cell carcinoma samples. The fitness cost was subsequently adjusted by the expression rates of the neoantigens to examine the role of neoantigen expression in tumor immune evasion. Our analyses indicate that, while the number of mutations and neoantigens are not significantly different between actinic keratoses and cutaneous squamous cell carcinomas, the predicted immune recognition of the neoantigen with the highest expression-adjusted fitness cost is lower for cutaneous squamous cell carcinomas compared with actinic keratoses. These findings suggest a role for the down-regulation of expression of highly immunogenic neoantigens in the immune escape of cutaneous squamous cell carcinomas. Furthermore, these findings highlight the importance of incorporating additional factors, such as the quality and expression of the neoantigens, rather than focusing solely on tumor mutational burden, in assessing immune recognition potential.
| S-EPMC6896054 | biostudies-literature
Project description:Micro RNAs (miRNAs) are considered as promising biomarkers for skin cancer. By next generation sequencing (NGS), we measured and compared miRNA expression profiles of tumor, peri-lesional, and control tissue of immunosuppressed organ transplant recipients (OTR), suffering from localized cutaneous squamous cell carcinoma (cSCC). Out of 490 miRNAs detected in cSCC tissue, 23 significantly regulated miRNAs were selected for quantitative targeted analysis in serum samples of our patients and control sera from OTR without cSCC. Two onco-miRNAs (mir-1290, mir-1246), previously identified as crucial drivers for tumor initiation and cancer progression, were significantly and exclusively upregulated in both tumor tissue and serum. This finding suggests that miRNA dysregulation in cSCC tissue is reflected in serum even in patients without advanced disease and highly differentiated cSCCs.
| S-EPMC7676459 | biostudies-literature
Project description:Currently, there is no sensitive molecular test for identifying transformation-prone actinic keratoses (AKs) and aggressive squamous cell carcinoma (SCC) subtypes. Biomarker-based molecular testing represents a promising tool for risk stratifying these lesions. We evaluated the utility of a panel of ultraviolet (UV) radiation-biomarker genes in distinguishing between benign and transformation-prone AKs and SCCs. The expression of the UV-biomarker genes in 31 SCC and normal skin (NS) pairs and 10 AK/NS pairs was quantified using the NanoString nCounter system. Biomarker testing models were built using logistic regression models with leave-one-out cross validation in the training set. The best model to classify AKs versus SCCs (area under curve (AUC) 0.814, precision score 0.833, recall 0.714) was constructed using a top-ranked set of 13 UV-biomarker genes. Another model based on a 15-gene panel was developed to differentiate histologically concerning from less concerning SCCs (AUC 1, precision score 1, recall 0.714). Finally, 12 of the UV-biomarker genes were differentially expressed between AKs and SCCs, while 10 genes were uniquely expressed in the more concerning SCCs. UV-biomarker gene subsets demonstrate dynamic utility as molecular tools to classify and risk stratify AK and SCC lesions, which will complement histopathologic diagnosis to guide treatment of high-risk patients.
| S-EPMC8323755 | biostudies-literature