Epigenetic alterations in sporadic basal cell carcinomas

Abstract

Basal cell carcinoma (BCC) is the most common malignant human neoplasm characterized by slow growth and virtual absence of metastases. Recently, it has become evident that along with genetic mutations epigenetic alterations play a key role in the pathogenesis of human cancer. We searched for promoter methylation of hMLH1, RASSF1A, DAPK, APC, DCR1 and DCR2 genes and BRAF mutations in BCCs in association with the clinicopathological parameters and the histological subtypes of the tumours. Fifty-two BCCs, 17 FFPE along with 35 fresh tissue samples with matching normal tissues for 26 cases were analyzed by methylation-specific PCR to assess the methylation status of hMLH1, RASSF1A, DAPK, APC, DCR1 and DCR2 genes after sodium bisulfite treatment of the tumour and normal DNA. hMLH1 and DCR1 gene expression was investigated by immunohistochemistry. BRAF mutations were studied by high resolution melting analysis. Methylation was detected at a variable frequency of 44, 33, 32.5, 32 and 14 % of DCR2, APC, DCR1, RASSF1 and DAPK promoters, respectively, whereas methylation of hMLH1 promoter was absent. No BRAF mutations were found. There was no correlation between the frequency of the promoter methylation of the above-mentioned genes and the clinicopathological features or the histological subtypes of the tumours. The relatively high frequency of RASSF1A, DCR1, DCR2 and APC promoter methylation may imply that methylation constitutes an important pathway in the tumourigenesis of BCC that could provide new opportunities in developing epigenetic therapies for BCC patients. Nevertheless, further studies are needed to establish the above-mentioned hypothesis.

DNA Methylation in Epidermal Differentiation, Aging, and Cancer

“…therapy (Berdasco and Esteller, 2019). Cancer-related genes found silenced in basal cell carcinoma are CDH13, SFN, TNFRSF10C, FHIT, SHH, APC, SFRP5, and RASSF1 (Brinkhuizen et al, 2012;Goldberg et al, 2006;Lodygin et al, 2003;Stamatelli et al, 2014;Takeuchi et al, 2002). Genes inactivated in cSCC are, for instance, the tumor suppressors CDKN2A, RB1, and CDH1 (Brown et al, 2004;Murao et al, 2006), and silencing of MIR204 appears to be involved in the progression from AK to cSCC (Toll et al, 2016).…”

Chemopreventive opportunities to control basal cell carcinoma: Current perspectives

“…Importantly, they found Shh, adenomatous polyposis coli (APC), secreted frizzled‐related protein 5 (SFRP5), and Ras association domain family 1A (RASSFIA) to be more methylated in BCC versus normal skin . Another study found similar results in which they analyzed 52 sporadic BCCs and found five genes to show variable frequency of methylation (14–44%), those include DCR2, DCR1, RASSFIA, APC, and death associated‐protein kinase (DAPK) promoter . However, another group irradiated human keratinocytes several times with UVB radiation and analyzed the DNA methylation of the irradiated cells versus non‐irradiated cells; and found no difference of DNA methylation between the two groups .…”

Epigenetics in Oral Pathology

“…Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/ MEK/ERK, PI3K/AKT/mTOR, Wnt/b-catenin, and several others. 34 Hypermethylation of specific tumor suppressor genes, as well as those involved in cell-cycle regulation, DNA repair, cell signaling, transcription, and apoptosis, have been reproducibly described in cutaneous melanoma. The CDKN2A promoter has been shown to be hypermethylated in a substantial fraction of primary cutaneous melanoma samples and is associated with both increased Ki-67 index and reduced patient survival.…”

“…The expression of aVb3 integrin, which, in addition to E-cadherin loss and N-cadherin expression, also tightly associates with the transition from the radial-to vertical-growth phase in melanoma. 34…”