Identification of tumour anitgens that may facilitate effective cancer detection and treatment

Mohamed, Eithar

Abstract

Tumour antigens (TAs) play a crucial role in terms of cancer diagnosis and targets for therapy. As TAs are normally expressed in restricted tissues such as testis, sensitivity and specificity may not be ideal, but they could still represent good biomarkers in combination with other diagnostic tools and could become targets for the treatment, with tolerable safety profiles. Thus, search of TAs continues to improve diagnostic performance when combined in panels rather than used as single antigens as carcinogenesis is a complex and heterogenous with single cancer types. This thesis aims to identify TAs acting as biomarkers and targets for cancer focusing on lung cancer that has developed from incidental lung nodules and B-acute lymphoblastic leukaemia (B-ALL). The malignancy of lung nodules is challenging to be identified with only 5% of these nodules developing into lung carcinoma within 2-years and significant overlap between the features of benign and malignant nodules and requires follow-up and invasive procedures in some cases of indeterminate nodules with high growth rate. A systematic review was performed to characterise the known antigens that could act as biomarkers for early lung cancer detection. Verification of biomarkers with high sensitivities (Ciz1, exoGCC2, ITGA2B), high specificities (CYFRA21-1, antiHE4, OPNV), or both (HSP90α, CEA) along with miR-15b and miR-27b were indicated as promising biomarkers for early lung cancer detection. COL11A1 was identified from RNAseq data using different algorithms such as linear regression and logistic regression with elastic net regularization, and presented an aggregated score calculated as the cumulative rank of variable importance.
Regarding B-ALL, we identified a number of antigenic targets for the treatment of adult B-ALL, based on serological analysis of recombinant cDNA expression libraries (SEREX), previous protoarray analysis, transcriptional (from GSE13204), epigenetic profiling (GSE38403) and cancer testis antigens (http://www.cta.lncc.br/). Pathways that were enriched included Wnt, Hippo, and TGFβ. Their expression in B-ALL versus healthy bone marrow were examined and associated with survival, using the BloodSpot database as well as literature searches. Prioritising the TAs using the pre-defined criteria described by Cheever et al. identified a panel of genes (SOX4, ROCK1, YAP1, TEAD4, SMAD3, and TCF4) that had a high cumulative score for 0.89, 0.41, 0.36, 0.34, 0.33, and 0.32 respectively. Upon examining the expression of the above genes in primary B-ALL samples by qPCR, TEAD4 and SOX4 were found to be significantly upregulated in adult B-ALL samples compared to healthy donors with p<0.01 and p<0.05 respectively. Immunocytochemistry identified high expression of TEAD4 in the cell nucleus of B-ALL samples and moderate to high expression of SMAD3 both in cell nuclei and cytoplasm. Future studies will examine how these antigens and/or their pathways can be targeted by immunotherapeutic strategies.

Citation

Mohamed, E. Identification of tumour anitgens that may facilitate effective cancer detection and treatment. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4866442

• Thesis Type: Thesis
• Deposit Date: Oct 15, 2024
• Publicly Available Date: Oct 25, 2024
• Keywords: Biomedicine
• Public URL: https://hull-repository.worktribe.com/output/4866442
• Additional Information: Centre for Biomedicine; University of Hull
• Award Date: Mar 8, 2024