Lawes, Daniel; (2004) The role of microsatellite instability in the development of multiple colorectal cancers. Doctoral thesis (M.D), UCL (University College London).

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Abstract

There are 30,000 new cases of colorectal cancer in the United Kingdom annually with 10% of patients developing a second, primary colorectal malignancy. Although a small number of patients with multiple cancers are caused by inherited conditions the majority are not. However cancers from these patients may demonstrate a higher incidence of microsatellite instability (MSI), a genetic phenomenon caused by loss of function of the DNA mismatch repair (MMR) system that is strongly associated with hereditary non polyposis colon cancer (HNPCC). This study examines the incidence of MSI and the underlying genetic cause in patients who develop multiple colorectal cancers. Archival paraffin embedded cancer tissue was obtained for 134 malignancies taken from 90 patients who developed multiple colorectal cancers, and 102 patients who developed a single cancer were used as a control group. MSI was analysed by polymerase chain reaction (PCR) and single stranded conformational polymorphism and expression of the hMLH1, hMSH2 and hMSH6 MMR proteins by immunohistochemistry. Methylation of the hMLH1 promoter region was assessed by bisulphite conversion and methylation specific PCR. High-level MSI (MSI-H) was detected in 59/111 (53%) of the multiple cancer samples compared to 10/74 (13%) of the single cancers. Loss MLH1 or MSH2 expression was seen in 7/9 single and 20/43 multiple MSI-H cancers, 4 of which also demonstrated loss of MSH6 expression. MSH6 expression was lost in 1 other sample. Methylation was identified in 25/48 MSI-H cancers compared to 5/26 control samples, and was more common in older, female patients. MSI-H and loss of expression of the same MMR gene was identified in 6/19 paired cancers taken from individual patients, the remaining 13 demonstrated various genetic abnormalities. Patients with multiple colorectal cancers have an increased incidence of MSI-H, although some cases may be due to HNPCC, the majority may have no single underlying cause.

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