Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma

Hervás‐Marín, David; Higgins, Faatiemah; Sanmartín, O.; Löpez‐Guerrero, José Antonio; Bañó, M. Carmen; Igual, J. Carlos; Quilis, Inma; Sandoval, Juan

doi:10.1371/journal.pone.0223341

Cited by 36 publications

(31 citation statements)

References 54 publications

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“…Recently, a global-scale approach to investigate the DNA-methylation profile in patients at different stages (i.e., AK, low-risk invasive, high-risk nonmetastatic, and metastatic cSCC) identified a minimal methylation signature to discriminate different stages, especially distinguishing low-risk vs. high-risk stages. Moreover, a prognostic prediction model in cSCC patients identified a methylation signature able to predict the overall survival of patients [ 119 ].…”

Section: Pathogenesis Of Csccmentioning

confidence: 99%

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

et al. 2021

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Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ (e.g., Bowen’s disease) or an invasive form. A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses. Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death. cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. Thus, cSCC development is a gradual process with several histological- and pathological-defined stages. Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC. Surgical excision is the first-line treatment for invasive cSCC. Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery. Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC. Furthermore, the implementation of prevention measures has been useful in patient management.

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Section: Pathogenesis Of Csccmentioning

confidence: 99%

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

et al. 2021

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“…In cutaneous melanoma, it was demonstrated that promoter hypomethylation and intragenic hypermethylation of specific genes are associated with tumor aggressiveness due to the alteration of extracellular matrix components and the upregulation of matrix metalloproteinases [98][99][100]. This highlights the clinical potential of deregulated methylation status as a hallmark for carcinogenesis, allowing the recognition of various methylation patterns as biomarkers for diagnosis and prognosis [101] (Table 1). Methylation studies focusing on cSCC, have demonstrated various patterns.…”

Section: Cpg Island Methylation (Cim)mentioning

confidence: 99%

“…In detail, they demonstrated a differential methylation status between the two pathological stages, with low-risk SCCs being hypomethylated and high-risk SCCs hypermethylated. According to the authors, this finding may suggest a sequential approach of SCC formation, where UV-exposure leads to hypomethylation and thus foretells the premalignant and low-risk stages of cSCC, while advanced stages of SCC present a hypermethylated status [101]. As regards the evaluation of the methylation status of BCC, Goldberg et al presented the FHIT promoter to be hypomethylated [114], while Heitzer et al found the hypermethylated PTCH promoter only in a small number of cases [115].…”

Section: Cpg Island Methylation (Cim)mentioning

confidence: 99%

Current and Future Trends in Molecular Biomarkers for Diagnostic, Prognostic, and Predictive Purposes in Non-Melanoma Skin Cancer

Νikolouzakis

Falzone

Lasithiotakis

et al. 2020

JCM

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Skin cancer represents the most common type of cancer among Caucasians and presents in two main forms: melanoma and non-melanoma skin cancer (NMSC). NMSC is an umbrella term, under which basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC) are found along with the pre-neoplastic lesions, Bowen disease (BD) and actinic keratosis (AK). Due to the mild nature of the majority of NMSC cases, research regarding their biology has attracted much less attention. Nonetheless, NMSC can bear unfavorable characteristics for the patient, such as invasiveness, local recurrence and distant metastases. In addition, late diagnosis is relatively common for a number of cases of NMSC due to the inability to recognize such cases. Recognizing the need for clinically and economically efficient modes of diagnosis, staging, and prognosis, the present review discusses the main etiological and pathological features of NMSC as well as the new and promising molecular biomarkers available including telomere length (TL), telomerase activity (TA), CpG island methylation (CIM), histone methylation and acetylation, microRNAs (miRNAs), and micronuclei frequency (MNf). The evaluation of all these aspects is important for the correct management of NMSC; therefore, the current review aims to assist future studies interested in exploring the diagnostic and prognostic potential of molecular biomarkers for these entities.

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“…Having confirmed that differential FILIP1L methylation and expression is also present in human cSCC, we evaluated its clinical relevance in humans using Infininium MethylationEPIC data provided by Herv as-Marín et al for 10 low (initial invasive carcinoma) and 8 high-risk (high-risk non-metastatic carcinoma and metastatic carcinoma) samples [33]. Note that a high-risk assessment is associated with a higher frequency of local recurrence, lymph node metastasis and significant morbidity and mortality and thus helps identifying patients with poor outcomes.…”

Section: Differential Methylation At the Filip1l Locus Affects Filip1l Expressionmentioning

confidence: 96%

Clinically relevant aberrant Filip1l DNA methylation detected in a murine model of cutaneous squamous cell carcinoma

et al. 2021

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Background: Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Understanding the impact of DNA methylation in cSCC may provide avenues for new therapeutic strategies. Methods: We used reduced-representation bisulfite sequencing for DNA methylation analysis of murine cSCC. Differential methylation was assessed at the CpG level using limma. Next, we compared with human cSCC Infinium HumanMethylation BeadArray data. Genes were considered to be of major relevance when they featured at least one significantly differentially methylated CpGs (RRBS) / probes (Infinium) with at least a 30% difference between tumour vs. control in both a murine gene and its human orthologue. The human EPIC Infinium data were used to distinguish two cSCC subtypes, stem-cell-like and keratinocyte-like tumours. Findings: We found increased average methylation in mouse cSCC (by 12.8%, p = 0.0011) as well as in stemcell like (by 3.1%, p=0.002), but not keratinocyte-like (0.2%, p = 0.98), human cSCC. Comparison of differentially methylated genes revealed striking similarities between human and mouse cSCC. Locus specific methylation changes in mouse cSCC often occurred in regions of potential regulatory function, including enhancers and promoters. A key differentially methylated region was located in a potential enhancer of the tumour suppressor gene Filip1l and its expression was reduced in mouse tumours. Moreover, the FILIP1L locus showed hypermethylation in human cSCC and lower expression in human cSCC cell lines. Interpretation: Deregulation of DNA methylation is an important feature of murine and human cSCC that likely contributes to silencing of tumour suppressor genes, as shown for Filip1l. Funding: British Skin Foundation, Cancer Research UK

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Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma

Cited by 36 publications

References 54 publications

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

Current and Future Trends in Molecular Biomarkers for Diagnostic, Prognostic, and Predictive Purposes in Non-Melanoma Skin Cancer

Clinically relevant aberrant Filip1l DNA methylation detected in a murine model of cutaneous squamous cell carcinoma

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