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UV biomarker genes for classification and risk stratification of cutaneous actinic keratoses and squamous cell carcinoma subtypes.

ABSTRACT: 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.

SUBMITTER: Queen D

PROVIDER: S-EPMC8323755 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:Cutaneous squamous cell carcinoma (SCC) is the second-most-common cancer in Australia. The majority of SCCs progress from premalignant actinic keratosis (AK) lesions that form on chronically sun-exposed skin. The role of skin microbiota in this progression is not well understood; therefore, we performed a longitudinal microbiome analysis of AKs and SCCs using a cohort of 13 SCC-prone immunocompetent men. The majority of variability in microbial profiles was attributable to subject, followed by time and lesion type. Propionibacterium and Malassezia organisms were relatively more abundant in nonlesional photodamaged skin than in AKs and SCCs. Staphylococcus was most commonly associated with lesional skin, in particular, sequences most closely related to Staphylococcus aureus Of 11 S. aureus-like operational taxonomic units (OTUs), six were significantly associated with SCC lesions across seven subjects, suggesting their specific involvement with AK-to-SCC progression. If a causative link exists between certain S. aureus-like OTUs and SCC etiology, therapeutic approaches specifically targeting these bacteria could be used to reduce SCC.IMPORTANCE Actinic keratosis (AK) and cutaneous squamous cell carcinoma (SCC) are two of the most common dermatologic conditions in Western countries and cause substantial morbidity worldwide. The role of human papillomaviruses under these conditions has been well studied yet remains inconclusive. One PCR-based study has investigated bacteria in the etiology of these conditions; however, no study has investigated the microbiomes of AK and SCC more broadly. We longitudinally profiled the microbiomes of 112 AK lesions, profiled cross sections of 32 spontaneously arising SCC lesions, and compared these to matching nonlesional photodamaged control skin sites. We identified commonly occurring strains of Propionibacterium and Malassezia at higher relative abundances on nonlesional skin than in AK and SCC lesions, and strains of Staphylococcus aureus were relatively more abundant in lesional than nonlesional skin. These findings may aid in the prevention of SCC.

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UV biomarker genes for classification and risk stratification of cutaneous actinic keratoses and squamous cell carcinoma subtypes.

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