Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although most cSCCs have good prognosis, a subgroup of high-risk cSCC has a higher frequency of recurrence and mortality. Therefore, the identification of molecular risk factors associated with this aggressive subtype is of major interest. In this work we carried out a global-scale approach to investigate the DNA-methylation profile in patients at different stages, from premalignant actinic keratosis to low-risk invasive and high-risk non-metastatic and metastatic cSCC. The results showed massive non-sequential changes in DNA-methylome and identified a minimal methylation signature that discriminates between stages. Importantly, a direct comparison of low-risk and high-risk stages revealed epigenetic traits characteristic of high-risk tumours. Finally, a prognostic prediction model in cSCC patients identified a methylation signature able to predict the overall survival of patients. Thus, the analysis of DNA-methylation in cSCC revealed changes during the evolution of the disease through the different stages that can be of great value not only in the diagnosis but also in the prognosis of the disease.
Highlights
Nonmelanoma skin cancer (NMSC) is the most common cancer in humans and its incidence has risen dramatically [1]
In this work the classification is based on the Cancer Staging Manual 8th Edition of the American Joint Committee on Cancer (AJCC) [41], which distinguishes cutaneous squamous cell carcinomas (cSCC) stages based on the presence or absence of several high risk-features such as the presence of significant perineural invasion, invasion of the tumour beyond subcutaneous fat or depth greater than 6mm and presence of bone involvement
We distinguish between carcinomas in the early stages of the disease defined by the absence of high risk features (T1 and T2 stages of AJCC-8) and cases at more advanced stages of the disease defined by the presence of high risk features (T3 and T4 stages of AJCC-8), differentiating those without nodal metastasis at the time of diagnosis from those with nodal metastasis
Summary
Nonmelanoma skin cancer (NMSC) is the most common cancer in humans and its incidence has risen dramatically [1]. 20% of nonmelanoma skin cancers are cutaneous squamous cell carcinomas (cSCC). CSCC is by far the most common cancer with metastatic potential in white populations and there is a progressive increase of cSCC incidence with no tendency for levelling off [2,3,4]. Following the classical model of multistage carcinogenesis, cSCC is usually manifested as a spectrum of lesions of progressive malignancy.
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