Suanno, Cristina
(2021)
Expression of β-catenin, Ki67 and stroma percentage in colorectal cancer.
MRes thesis, University of Nottingham.
Abstract
AIMS. The purpose of this study was to explore the expression of β-catenin, Ki67 and stroma percentage in colorectal cancer and investigate their role as biological and prognostic biomarkers.
METHODS. Colorectal cancer samples of approximately 1000 patients were collected, together with the corresponding clinicopathological data. Tissue microarrays were constructed, immunohistochemically stained for β-catenin and Ki67 and scanned into digital images. Nuclear, cytoplasmic and membranous β-catenin staining intensities were manually scored; Ki67 expression was analysed using the Qu Path platform. H-scores and Ki67LI were computed for β-catenin and Ki67 respectively; the stroma percentage was estimated from the content of the TMAs. The statistical analyses were performed using IBM SPSS Statistics version 26. Different cut-offs were used to distinguish population subgroups (i.e. low/high expression), depending on the biological characteristics of the biomarkers and the characteristics of the distributions. A χ2 test was carried out to investigate the correlation between the biomarkers and clinicopathological parameters. Kaplan-Meier’s curves and Log-rank tests were performed to analyse the correlation with survival. The Cox proportional hazard model was used to evaluate the independent effect of the variables on survival. Further analyses were carried out after patients stratification for MMR status, tumour location and final stage. Different parametric and non-parametric tests and relative effect sizes were used to evaluate the correlation between the biomarkers, between the biomarkers in CRC and normal tissue and between the biomarkers in luminal, central and peripheral portions of the tumour. Results were considered significant when showed a p-value less than 0.05.
RESULTS. Nuclear and cytoplasmic β-catenin were found associated with distal CRCs and MMR proficiency, whereas membranous expression was associated with proximal CRCs. Ki67 was significantly correlated with deficient MMR status, conspicuous peritumoral lymphocytes and pushing tumour edge. Stroma-rich tumours displayed advanced T stage, lymph nodes involvement and presence of metastases; they are also associated with recurrence, vascular and perineural invasion and characterized by poor differentiation and infiltrative tumour edge. Survival analyses revealed that nuclear β-catenin is an independent prognostic factor and predictive of good prognosis in stage III CRCs and that high Ki67 is associated with better outcome in dMMR and stage III CRCs but worse outcome in stage II patients. Finally, tumours with high stroma content were associated with poor prognosis. β-catenin changed sub-cellular localization in CRC compared to normal intestinal epithelium, shifting from a predominant membranous localization to a higher nuclear expression; likewise, Ki67 was higher in tumour than normal tissue. Ki67 and β-catenin and β-catenin and stroma were found significantly correlated. Stroma-rich tumours were found associated with low proliferative rate and high nuclear β-catenin. Lastly, we couldn’t establish a significant differential expression of these biomarkers between luminal, central and peripheral portions of tumours.
CONCLUSION. In summary, our data show that high β-catenin is a feature of left-sided CRCs, that Ki67 is associated with dMMR tumours and their histological characteristics and that stroma-rich tumours display aspects of advanced disease. High nuclear β-catenin and high Ki67 are associated with good prognosis in stage III CRCs, whereas stroma percentage is predictive of shorter survival.
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