Tsamiya, Isah Rilwanu (2025) The role of foxp3 in relation to BRAFV600E and MMR protein status in early-onset colorectal cancer. PhD thesis, Universiti Sains Malaysia.
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Abstract
The global rise in EOCRC is concerning, as its pathogenesis is still under investigation. In Malaysia, EOCRCs in CRC patients below the age of 50 are typically diagnosed in advanced stages, often exhibiting aggressive histologic features like poor differentiation and mucinous or signet histology. EOCRC progression is influenced by the immune suppression of host cells, with T regulatory cells (Tregs) playing a crucial role. Forkhead box protein 3 (FOXP3) is a transcriptional factor and a critical marker for CD4+ and CD25+ Tregs. The study examined FOXP3 protein and gene expression in conjunction with v-raf murine sarcoma viral oncogene homolog B1 (BRAF), specifically the BRAFV600E mutation that replaces valine (V) with glutamic acid (E) at position 600, and mismatch repair (MMR) protein status among EOCRC patients. The study analyzed EOCRC patients under 50 at HUSM between 2013 and 2021, based on age parameters from medical records and the Laboratory Information System (LIS). The study utilised monoclonal antibodies to immunohistochemically stain FOXP3, BRAFV600E, and MMR proteins, which were then scored using immunoreactive scoring (IRS). FFPE tissues' total RNA was converted to cDNA, and FOXP3 mRNA expression was measured using RT-qPCR for FOXP3 full length (FOXFL) and FOXP3 with exon 2 deleted (FOXP3△2). Between 2013 and 2021, HUSM diagnosed 65 EOCRC patients, with a 20.4% prevalence, primarily found on the left colon and frequently in individuals without a family history of CRC. Moderately differentiated adenocarcinoma (81.5%) was the most common histology diagnosed at the advanced stage, followed by mucinous adenocarcinoma (15.38%) and signet ring carcinoma (6.2%). The study found a significant association (p = 0.02) in the infiltration of tumour lymphocytes stained with haematoxylin and eosin (H&E) across different age groups. The tumour-infiltrating lymphocytes were recognized by their dark blue-stained, small, and round nuclei with a small amount of cytoplasm stained pink within the tumour stroma of the EOCRC. 53.8% of the EOCRC patients had proficient MMR (pMMR), with positivity in all four MMR proteins tested, while 46.2% had deficient MMR (dMMR), with negativity in one or more of the four MMR proteins tested. The BRAFV600E protein was overexpressed in 69.2% of the EOCRC cases. The FOXP3 protein was expressed by 93.8% of EOCRC patients, while 6.2% were negative. Patients with pMMR and BRAFV600E positive showed higher FOXP3 protein expression (54.2%) than those with dMMR and BRAFV600E positive (22.9%). The study revealed a significant correlation between high FOXP3 protein expression, histological types, tumour grade, MMR, and BRAFV600E status (p ≤0.05). FOXP3FL was the major expressed variant of the FOXP3, with a mean relative expression of 14.86±6.5. In contrast, FOXP3△2 was less expressed, with a mean relative expression of 1.03±0.66. The two variants of the FOXP3 were observed to be expressed by the EOCRC. The FOXPFL variant expression by the EOCRC was significantly increased (p = 0.034), as most patients have sporadic rather than hereditary CRC. In conclusion, the study provided valuable insights into the characteristics and molecular mechanisms of EOCRC in HUSM patients. The findings highlight the importance of FOXP3 protein and gene expression, as well as BRAFV600E and MMR protein status, in understanding EOCRC and its potential prognostic implications. This study recommends further research using other molecular techniques to elucidate the anti-tumour and immunosuppressive roles of FOXP3 in EOCRC.
| Item Type: | Thesis (PhD) |
|---|---|
| Uncontrolled Keywords: | colorectal cancer |
| Subjects: | R Medicine R Medicine > RC Internal medicine > RC254-282 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Kampus Kesihatan (Health Campus) > Pusat Pengajian Sains Perubatan (School of Medical Sciences) > Thesis |
| Depositing User: | Mr Abdul Hadi Mohammad |
| Date Deposited: | 16 Nov 2025 03:49 |
| Last Modified: | 19 Jan 2026 04:22 |
| URI: | http://eprints.usm.my/id/eprint/62982 |
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