Basal cell carcinoma is the most common form of human malignancy, and as such there are varied methods for treating its various forms. Its more advanced and aggressive forms have required both the use of and advent of therapies which offer differing safety profiles, cost, and efficacy. Two therapies which differ substantially in these respects but have overlap in their recommended use are Mohs micrographic surgery and the pharmaceutical drug vismodegib. Few studies have sought to compare the two methods using these criteria, and as vismodegib has only received FDA approval in the past ten years, it is worthwhile to explore the limitations and advantages of each therapy. In exploring previous clinical trials and retrospective studies, the two therapies are put side by side to contrast their results with their shared intended use. The general findings were that Mohs micrographic surgery remains the gold standard for the treatment of locally advanced basal cell carcinoma, and there are few demonstrable instances in which vismodegib could be deemed a more appropriate therapy. The future of vismodegib appears to be in its use as a neoadjuvant therapy for locally advanced basal cell carcinomas for which a decrease in size by vismodegib would allow for better treatment outcomes.

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with rising global incidence. Merkel cell polyomavirus (MCV) was discovered in 2008 in 80% of MCC samples and since then a causal link between MCV and the majority of MCC cases has been established. microRNAs (miRNA, miR) are a family of small non-coding RNAs which play a key role in post-transcriptional regulation of gene expression and are considered significant players in disease and development in many species. Whilst the focus of MCV research has thus far been on the oncogenic MCV early proteins, large tumour (LT) and small tumour (sT) antigens, there is a knowledge gap regarding MCV miRNA and its functional significance in MCV pathogenesis. Given the emerging importance of viral miRNAs in virus-host interaction and pathogenesis, the aim of this doctoral research project was to investigate alterations in host cell transcripts induced by MCV miRNA and determine any functional significance these might have on virus-host cell interaction. RNA sequencing (RNA-Seq) in the presence and absence of MCV miRNA uncovered a multitude of downregulated cellular transcripts. Gene ontology analysis revealed that MCV miRNA targets transcripts associated with multiple cellular processes, however, regulation of immune response was overrepresented in our datasets. Validation of RNA-Seq data using MCV miRNA mimics and a synthetic, fully replicative MCV genome (MCVSyn) confirmed RNA-Seq data at mRNA and protein expression level for several targets, including the cytokine stimulating gene, SP100, and the neutrophil stimulator chemokine, CXCL8. Moreover, dual luciferase assays revealed that SP100 and MAPK10 (a member of mitogen-activated protein kinases (MAPK) family which is involved in regulation of CXCL8 expression) are directly and specifically targeted and downregulated by MCV miRNA. The MCV miRNA-dependent dysregulation of CXCL8 secretion is associated with impaired neutrophil migration, suggesting that the virus miRNA may be implicated in evasion of the host immune response.

PET/CT with prostate-specific membrane antigen (PSMA)-targeted tracers has been used in the diagnosis and staging of patients with clear cell renal cell carcinoma (ccRCC). For ccRCC primary tumors, PET parameters were shown to predict histologic grade and features. The aim of this study was to correlate PSMA PET/CT with histopathological findings in patients with metastatic recurrence of ccRCC. Patients with ccRCC who underwent PSMA-targeted PET/CT and subsequent histopathological evaluation of suspicious lesions were included. Specimens underwent immunohistochemical marking. Lesion diameter, volume and tracer uptake were correlated with the extent and intensity of molecular PSMA expression and with clinical findings. Twelve PET-positive lesions of nine patients were evaluated. Eleven ccRCC metastases and one prostate carcinoma were detected histopathologically. Molecular PSMA expression was detected in all lesions, which intensity and distribution did not correlate with PET parameters. PSMA-targeted PET/CT is a feasible tool for the evaluation of patients with ccRCC but cannot reliably predict histologic features of metastases. PSMA may also be expressed in malignant lesions other than ccRCC, leading to incidental detection of these tumors.

Despite considerable development in the therapeutic repertoire for managing cancer-related malignancies, head and neck cancer mortality has not significantly improved. The burden of HNSCC fluctuates across countries and has been associated with exposure to tobacco-derived carcinogens, excessive alcohol consumption or combinations. Due to late detection, patients often present with oral pre-malignant lesions which have progressed to an advanced stage of HNSCC. In this study, the samples were from a male cohort as generally, men are at two to four-fold higher risk than women with over 90% of HNSCCs arising in the upper aerodigestive tract. Therefore, the purpose of this thesis was to identify HNSCC biomarkers in males associated within defined anatomical region (tongue) and causative agents, specific to smoking. An iTRAQ proteomic approach was used to profile protein changes in matched normal and tumour samples from male non-smoking (n=6) and smoking patients (n=6) with tongue carcinomas revealing identification of potential targets specific to cancer. Samples were subjected to liquid nitrogen cryo-pulverisation and protein determination. Protein extracts from the same category were pooled, trypsin digested and iTRAQ 4-plex labelled. Data was generated by 2D-LC/MS on an Orbitrap Fusion and significantly changed proteins (median ± SD) were subject to bioinformatics appraisal. A total of 3426 proteins were identified and quantified by proteomic analysis. Comparison of non-smoker tumour (NS:T) with smoker tumour (S:T) distinguished 64 proteins that were upregulated and 62 downregulated, S:T vs S:N categorised 349 proteins up- and 395 down-regulated respectively and NS:T vs NS:N identified 469 proteins up- and 431 down-regulated, respectively. Arginase-1 (ARG1), Keratin Type-2 Cytoskeletal 8 (KRT8), Lipocalin-1 (LCN1) and DNA replication licensing factor MCM2 (MCM2) were identified as biologically associated with smoking compared to non-smoking, providing viable targets for verification by immunochemical methods which further supported the proteomic data. Overall, the project demonstrated the importance of using matched biopsies with good clinicopathological data for experimental design and provided a set of unique targets for a more expanded verification study.

p63, a homologue of the transcription factor p53, is essential for maintaining the proliferative capacity of epithelial stem cells. The p63 gene yields two major isoforms transcribed from dual promoters at its N-terminus and at least three different splice variants at its C-terminus. The TAp63 isoform functions as a p53-like tumor suppressor and transactivates p53 gene targets. In contrast, ΔNp63α predominates in epithelial stem cells and regulates their proliferative potential, whilst also acting as an oncogene by suppressing the function of both p53 and TAp63 in a dominant-negative manner. ΔNp63α is frequently upregulated in human epithelial cancers and has been theorized to play a role in tumorigenesis. Our prior studies found that an aberrantly spliced ΔNp63α isoform heterozygous for a lack of exon 4-coded sequences (hereafter referred to as Δ4) appeared to be specifically expressed in squamous cell carcinomas, suggesting a potential link between this new isoform and a specific type of cancer. Our study aimed to elucidate the involvement of this aberrantly spliced p63 isoform in the initiation and/or development of epithelial cancer. We established a p63+/Δ4 mouse model to obtain a baseline for the effect of one aberrant allele on both embryonic and adult mouse development. We found that p63+/Δ4 mouse embryos developed normally and that over a period of 74 weeks, the p63+/Δ4 mice developed normally and lived lifespans equivalent to their wildtype counterparts, though a small proportion of the p63+/Δ4 colony showed minor issues with inflammation. After our initial observations, we established an experimental mouse model to test the effect of oncogenic stimulation on p63+/Δ4 mice. In the first model, we administered the oral carcinogen 4-nitroquinoline 1-oxide to mirror the histological and molecular changes seen in human oral carcinogenesis. We observed significant dysplasia in the tongue epithelia of p63+/Δ4 mice compared to that of wildtype. With this data, we developed the hypothesis that expression of Δ4 accelerates tumorigenesis in the presence of oncogenic stimulation. To further test this possibility, we generated a second mouse model: a triple transgenic Cre-inducible mouse model under the control of epithelial cell-specific promotor gene, keratin 14 (K14). This cross introduced a mutated Kras gene to the p63+/Δ4 lineage, as well as to control wildtype mice bred with the same Cre elements. Upon administration of tamoxifen, genetic recombination caused expression of both mutant Kras G12D and Δ4 in K14-positive tissues and subsequent malignant transformation. Among these K14-positive tissues were the oral epithelia, which presented with dysplasia more severe than that of control mice expressing either Kras or Δ4 alone and which matched the phenotype-genotype associations observed in our 4NQO experiment. Lastly, we attempted to create an antibody specific to Δ4 that could eliminate the need for our current two-antibody identification strategy. Though we did not succeed, we found value in elucidating the genetic sequence requirements to create the artificial peptide that we used for mouse immunization. We attempted to optimize established hybridoma protocols and developed a Δ4-specific screening process to determine viable candidates for expansion. In conclusion, this study is the first characterization of a hitherto unknown mutant splice variant of a gene vital to stem cell maintenance and epithelial development. It is the first demonstration of this gene mutation’s responsibility for the acceleration of squamous cell carcinoma, which carries implications for potential therapeutic treatments. / 2026-02-12T00:00:00Z

Background: The mechanisms through which immunosuppressed patients bear increased risk and worse survival in oral squamous cell carcinoma (OSCC) are unclear. Here, we used deep learning to investigate the genetic mechanisms underlying immunosuppression in the survival of OSCC patients, especially from the aspect of various survival-related subtypes. Materials and methods: OSCC samples data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and OSCCrelated genetic datasets with survival data in the National Center for Biotechnology Information (NCBI). Immunosuppression genes (ISGs) were obtained from the HisgAtlas and DisGeNET databases. Survival analyses were performed to identify the ISGs with significant prognostic values in OSCC. A deep learning (DL)-based model was established for robustly differentiating the survival subpopulations of OSCC samples. In order to understand the characteristics of the different survival-risk subtypes of OSCC samples, differential expression analysis and functional enrichment analysis were performed. Results: A total of 317 OSCC samples were divided into one inferring cohort (TCGA) and four confirmation cohorts (ICGC set, GSE41613, GSE42743, and GSE75538). Eleven ISGs (i.e., BGLAP, CALCA, CTLA4, CXCL8, FGFR3, HPRT1, IL22, ORMDL3, TLR3, SPHK1, and INHBB) showed prognostic value in OSCC. The DL-based model provided two optimal subgroups of TCGA-OSCC samples with significant differences (p = 4.91E-22) and good model fitness [concordance index (C-index) = 0.77]. The DL model was validated by using four external confirmation cohorts: ICGC cohort (n = 40, C-index = 0.39), GSE41613 dataset (n = 97, C-index = 0.86), GSE42743 dataset (n = 71, C-index = 0.87), and GSE75538 dataset (n = 14, C-index = 0.48). Importantly, subtype Sub1 demonstrated a lower probability of survival and thus a more aggressive nature compared with subtype Sub2. ISGs in subtype Sub1 were enriched in the tumorinfiltrating immune cells-related pathways and cancer progression-related pathways, while those in subtype Sub2 were enriched in the metabolism-related pathways. Conclusion: The two survival subtypes of OSCC identified by deep learning can benefit clinical practitioners to divide immunocompromised patients with oral cancer into two subpopulations and give them target drugs and thus might be helpful for improving the survival of these patients and providing novel therapeutic strategies in the precision medicine area.

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