Biomarkers and Lymph Node Morphology in Early-stage Colon Cancer
New Zealand has one of the highest rates of colorectal cancer (CRC) in the world, resulting in approximately 1200 deaths per year. Optimising the use of adjuvant chemotherapy is one key area to reduce CRC-related mortalities. Stage II colon cancer patients are clinically and biologically heterogenous. Despite 60-80% of these patients being cured from surgery alone, a subset of these patients have a recurrence risk approximating stage III disease. Current risk stratification for the administration of adjuvant chemotherapy fails to accurately detect subgroups with different prognostic and treatment sensitivities. The discovery and use of molecular biomarkers could be used to improve the power of this risk stratification. The aim of this exploratory, pilot study was to characterise the expression of potential prognostic biomarkers, CD147, microRNA-29a and microRNA-21, in a small pilot cohort of stage II colon cancer patients. These markers are strongly associated with aggressiveness and progression in later-stage CRC. However, their prognostic potential in early stage colon cancer has not been well defined. Additionally, these markers are expressed on tumour-derived extracellular vesicles (tEVs) which can home to nearby lymph nodes and promote the spread of cancer. Considering the lymph nodes are the first site for dissemination of tumour cells in CRC, tEVs may be particularly relevant to stage II colon cancer patients who undergo recurrence. Therefore, the overexpression of these markers could be risk-factors in the tumour and draining lymph nodes of these patients. Tumour, normal mucosa, and the draining lymph nodes were collected from 13 stage II colon cancer patients at the time of surgical resection. Immunohistochemical and quantitative reverse transcription PCR techniques were optimised for the detection of CD147, miR-21 and miR-29a in all tissue types. The histological morphology of the lymph nodes was also explored. We found CD147 was overexpressed in 60% of tumours while miR-21 was overexpressed in 50% of tumours. When combined, CD147 and miR-21 potentially highlight specific subsets of patients. Tumour-associated expression of miR-21 was dysregulated in the lymph nodes, while tumour-specific CD147 expression was not detectable due to immunological-associated expression. Instead, histomorphological findings suggested a large variation in the number, size and shape of lymph node B cell compartments. Specifically, changes in follicle and germinal centre size density and size were associated with pathological risk factors such as, the presence of lymphatic invasion and T stage. CD147 and miR-21 are considerably dysregulated in stage II colon tumours and combined with our knowledge of their functionality in preclinical and clinical studies, they represent potential prognostic biomarkers for this population. We have also demonstrated how the heterogenous histomorphology of B cell compartments, within the lymph nodes, could be a reflection of the observed clinical heterogeneity in these patients. Altogether, these potential biomarkers could be used to strengthen the current risk stratification in stage II colon cancer patients. While our preliminary data warrants validation in a future, larger cohort, our findings demonstrate the clinical feasibility of detecting potential biomarkers and direct the research design of future studies.
Advisor: Danielson, Kirsty
Degree Name: Bachelor of Biomedical Sciences with Honours
Degree Discipline: Surgery and Anaesthesia
Publisher: University of Otago
Keywords: colorectal cancer; colon cancer; biomarkers; lymph node morphology; stage II; CD147; miRNA
Research Type: Thesis