Molecular Mechanisms and Biomarkers of Skin Photocarcinogenesis

Abstract

Skin cancer is the most commonly diagnosed malignancy in the United States and worldwide. While melanoma is the deadliest form of skin cancer, non-melanoma skin cancers, which include basal cell carcinoma and squamous cell carcinoma, are responsible for significant morbidity in millions of Americans each year. While numerous attempts have been made to reduce skin cancer risk factors related to ultraviolet radiation exposure, skin cancer incidence continues to rise. Improved understanding of the molecular pathways underlying skin cancer pathogenesis has led to the investigation of new approaches to skin cancer prevention. In particular, the search for ultraviolet radiation associated biomarkers of skin cancer has become a rapidly expanding and promising area of research. Advances in genetic sequencing have facilitated the discovery of novel biomarkers, which have the potential to profoundly improve patient care. Here we will review the molecular genetics of skin cancer and analyze the existing literature of proposed biomarkers for potential use in skin cancer diagnosis and prevention.

Deciphering the Molecular Landscape of Cutaneous Squamous Cell Carcinoma for Better Diagnosis and Treatment

“…UV-B rays directly induce DNA lesions (misbonding of two pyrimidines, either thymine or cytosine, within the same DNA strand), because the wavelength of this specific radiation corresponds to the absorption spectrum of the genetic material. As such, UV-B photons are directly absorbed and lead to formation of cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts, which left unrepaired become mutagenic [ 5 , 19 ]. In contrast to UV-B, the exact role of UV-A in cutaneous carcinogenesis is not clearly understood.…”

“…Epidemiologic studies also seem to support these harmful effects, and it has been reported that a single indoor tanning session, during which UV-A radiation emission is substantially higher than from natural sun [ 21 ], can increase the risk of developing cSCC by 67% [ 22 ]. In light of these findings, alternative pathways that lead to skin carcinogenesis are currently being searched for, to understand the mechanisms behind UV-A induced mutations [ 5 ].…”

“…Instead, p53 alleles present UV signature mutations identified as ‘hot spots’ along their sequences, which cause the gene to become inactive and give rise to a p53 mutant protein, also inactive. The p53 alterations are primarily believed to bestow resistance to apoptosis upon the cells, in response to UV radiation ( Figure 2 B), thereby leading to positive selection of p53 mutant cells and clonal expansion [ 5 ]. Across different studies the mutational frequency of TP53 ranges from 42% to ~95% ( Table 1 ) [ 27 , 28 , 29 , 30 , 31 , 33 ], with a statistically higher rate of mutation in metastatic tumors relative to primary non-metastatic cSCC.…”

“…Similarly, alterations in tumor suppressor genes, which have the function to inhibit cell growth, can easily lead to unregulated cell proliferation as a result of the loss of negative control. As such, any dysregulation of the proto-oncogenes and tumor suppressors represents the basic mechanism behind tumor development and growth [ 5 ]. Research for a pathway of similar significance to SCC as the Hedgehog signaling cascade for BCC, meaning that mutations appearing in that pathway lead to oncogenesis, is ongoing.…”

The Non-Coding Landscape of Cutaneous Malignant Melanoma: A Possible Route to Efficient Targeted Therapy

“…Exposure to ultraviolet (UV) radiation induces the proliferation of melanocytes and the synthesis of melanin, the photoprotective pigment that is distributed to neighbouring keratinocytes via large specific vesicles termed melanosomes. Prolonged and intense exposure to UV is thought to be the main factor that determines melanomagenesis, as UV radiations can trigger oxidative stress and induce point mutations haphazardly across the genome, which can lead to loss of cell cycle control and apoptosis escape [ 4 , 5 ]. Extensive data from The Cancer Genome Atlas (TCGA) project partly defined the complex genetic landscape of melanoma, disclosing the high occurrence of somatic mutations and the prevalent activation of the mitogen-activated protein kinase (MAPK) pathway [ 6 ].…”