Characterization of Microsatellite Instability in Young Patients with Mucinous Colorectal Cancer

Nitty Skariah Mathews, (2014) Characterization of Microsatellite Instability in Young Patients with Mucinous Colorectal Cancer. Masters thesis, Christian Medical College, Vellore.


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INTRODUCTION: Cancer therapeutics today has come to incorporate the fast emerging personalized medicine wherein knowledge of the molecular basis of cancer development and progression is taken advantage of to optimize treatment and to direct preventive resources at high risk population. Cancers of the colon and rectum provide excellent examples where molecular diagnostics can play a major role in therapeutics and determine the final outcome of the patient. Colorectal cancers (CRC) are the 3rd most common cancers in both males (after prostate and lung) and females (after breast and lung) worldwide. They are also the 3rd most common causes of cancer deaths in both genders globally. OBJECTIVES: To ascertain the microsatellite instability (MSI) status of mucinous colorectal cancers (CRCs) in patients aged 40 years of age by molecular testing using 2 mononucleotide markers and to correlate this with immunohistochemical (IHC) analysis for mismatch repair protein expression using 3 antibodies, with histology, and with available clinical information. METHODS: Thirty cases of mucinous CRCs in patients 40 years of age treated at Christian Medical College Hospital, Vellore between 2003 and 2012 were included in the study. Archived formalin-fixed paraffin embedded tissue blocks of these patients were used. Molecular testing for MSI was done using a panel of 2 mononucleotide repeat markers- BAT26 and NR24 and the PCR-based Fluorescence Capillary Electrophoresis technique. A panel of 3 antibodies to the mismatch repair proteins MLH1, MSH2 and MSH6 was used for IHC analysis. The staining pattern of tumour was compared with that of the normal adjacent tissue. Histological features of all tumours were also studied. The results of MSI testing were correlated with that of IHC analysis, histological features and clinical data including stage at presentation, recurrence/metastasis, effect of 5FU chemotherapy and death. Data was analysed using SPSS software and the Pearson's Chi square test and Fisher's exact test. Kaplan Meier estimation was used to plot the survival curve and determine the time to recurrence. RESULTS: Eight out of 30 cases (26.7%) showed MSI on molecular testing. IHC picked up 7 of these MSI cases and missed 1 case rendering a sensitivity, specificity and positive predictive value of 87.5%, 100% and 100% respectively when compared to MSI testing. Among the 6 surgically resected tumours, the histologic features that showed statistically significant association with MSI were the presence of a well-differentiated adenocarcinoma component (4 out of 6 cases; p = 0.003), peritumoural lymphocytes (all 6 cases; p = 0.002) and tumour budding (4 out of 6 cases; p = 0.021). None of the clinical parameters studied showed a significant association with MSI. CONCLUSION: The detection of defective MMR proteins using IHC for MLH1, MSH2 and MSH6 and molecular testing using 2 markers, BAT26 and NR24, appears to be a good protocol to detect CRCs with MSI. Histology could be useful in identifying cases that require screening for presence of MMR protein defects.

Item Type: Thesis (Masters)
Additional Information: Reg.No.20111954
Uncontrolled Keywords: Colorectal cancer, microsatellite instability, BAT26, NR24, MLH1, MSH2, MSH6.
Subjects: MEDICAL > Pathology
Depositing User: Subramani R
Date Deposited: 23 Mar 2020 16:47
Last Modified: 17 Aug 2020 05:58

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