Prognosis in DNA mismatch repair deficient colorectal cancer: are all MSI tumours equivalent? A. J. Clark, R. Barnetson, S. M. Farrington and M. G. Dunlop Colon Cancer Genetics Group, Academic Coloproctology, Division of Oncology, University of Edinburgh, Western General Hospital, Edinburgh, UK Received 23 April 2004; accepted 11 May 2004 Key words: colorectal cancer, DNA mismatch repair, genetics, microsatellite instability, prognosis Abstract Microsatellite instability (MSI) in colorectal tumours is the hallmark of defective DNA mismatch repair (MMR) and high level MSI can be detected in up to 15% of incident colorectal cancers. MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1 while MSI is almost universal in tumours from HNPCC family members due to germline MMR gene mutation with loss or mutational inactivation of the second copy as a somatic event. There is evidence that tumour MSI is associated with a better outcome than the generality of large bowel malignancy. However, although MSI occurs in both sporadic colorectal cancer and in tumours arising in patients with germline MMR gene mutations, cancer survival should not be considered to be equivalent for these two groups with MSI tumours simply because both exhibit similarities in molecular phenotype. Here, we review the evidence on prognosis in patients with sporadic MSI tumours compared to those who have inherited a germline DNA MMR repair gene defect. In addition, we explore whether there are variables that afford opportunity to distinguish three groups on the basis of MSI status, namely: sporadic MSI tumours; MSI tumours in carriers of germline MMR gene defects; microsatellite stable (MSS) tumours. Differences in prognosis between these three groups is important because it underpins the rationale for surveillance and early identification of tumours in MMR gene carriers, as well as refining understanding of the influence of MSI on cancer progression. Furthermore, we discuss the effect of MSI on the effectiveness of chemotherapy regimens. Introduction Cancer prognosis has important clinical, public health and biological implications. Prediction of survival is of pivotal importance for patients in planning their indi- vidual future, as well as that of their dependents. Prognosis also impacts on clinical decision making in guiding the nature and intensity of intervention, such as surgery and chemotherapy. Ideally, the intervention should be tailored to predicted outcome. It is also important to define biological variables associated with poor, or adverse, response to particular therapies such as adjuvant chemotherapy, in order to avoid unneces- sary harm. In addition to the clinical implications of prognosis, outcome for a given tumour type also has important public health relevance in determining resource allocation at the population level. Understand- ing differences in the natural history of tumours arising from the same tissue of origin also provides important opportunity to understand molecular and cell biological influences on tumour initiation and progression. Colorectal cancer has proven to be an excellent paradigm for investigating molecular determinants of prognosis, being a high incidence disease associated with relatively high mortality (40–50% overall 5-year sur- vival). Furthermore, it has been the subject of consid- erable research activity aimed at understanding the molecular basis of cancer causation, providing a wealth of data on clinical and molecular parameters with potential prognostic value. This review focuses on the prognostic implications of MSI, the hallmark of defec- tive DNA MMR, which can be detected in up to 15% of incident colorectal cancers. Tumour MSI is observed in patients with sporadic colorectal cancer due to somatic molecular events but is also observed in patients with germline mutations in one of the MMR genes, most frequently MSH2, MLH1 or MSH6. Hence, we focus on the controversial area of differences in outcome between Correspondence to: Prof M.G. Dunlop, Colon Cancer Genetics Group, Academic Coloproctology, Division of Oncology, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. E-mail: oncology@ed.ac.uk Familial Cancer 3: 85–91, 2004. Ó 2004 Kluwer Academic Publishers. Printed in the Netherlands.