Mismatch repair deficiency in colorectal cancer : prognosis and prediction for basic treatment strategies

Abstract: Colorectal cancer (CRC) remains a significant healthcare problem worldwide, being the third most common cancer and the fourth most frequent cause of cancer death. Environmental and dietary factors such as alcohol abuse, cigarette smoking, and genetic predisposition seem to constitute the main aetiologies.Two major distinct molecular genetic pathways have been recognised as models of transition from normal epithelium to adenoma and carcinoma. The first involves chromosomal instability (CIN) and the second involves microsatellite instability (MSI). The MSI pathway constitutes 2-4% of CRCs with a hereditary Mismatch Repair (MMR) defect (dMMR) and approximately 15% of sporadic MMR defects due to epigenetic silencing of the MutL homologue 1 (MLH1) promoter. Extracellular factors and spontaneous copy errors necessitate molecular systems to survey and repair human genetic information, and to protect it from chemical disruption. A complicated and entangled network of DNA damage response mechanisms, including multiple DNA repair pathways, damage tolerance processes, and cell cycle checkpoints safeguard genomic integrity. It has recently become apparent that key proteins contributing tocellular survival by taking part in DNA repair become executioners in the face of excess DNA damage. All prokaryotic and eukaryotic organisms have major DNA repair pathways. In each of these DNA repair pathways there are key proteins that have dual functions in DNA damage sensing/repair and apoptosis, taking advantage of the fact that DNA is a double helix with the same information present on both strands. Damages that affect one strand can easily be repaired by excision and replacement with newly synthesised DNA using the complementary strand as a template. MMR plays a critical role in the repair of errors that occur spontaneously during DNA replication, such as single base mismatches. dMMR increases the mutation frequency in an affected cell by approximately 1000 times, leading to MSI through the accumulation of short repetitive DNA sequences called microsatellites. Carcinogenesis in dMMR cases can present as hereditary cases (Lynch syndrome) due to germline mutation inin one of the main MMR genes – MLH1, MSH2, MSH6, and PMS2 or somatic/sporadic cases (epigenetic silencing or somatic inactivation of MLH1promoter. dMMR seems to have a favourable prognosis as these CRCs seems to be less prone to metastasising. This phenomenon is much more obvious for tumour stages II and III, while in advanced disease dMMR seems to lose its positive prognostic effect. Even if the underlying mechanism is not fully understood, some studies attribute the positive effect of dMMR tumours to their increased immunogenicity leading to a stronger more effective immune response. On the other hand, the predictive value of the dMMR mechanism isless well understood and has only gained attention in recent years. In general, dMMR seems to predict a poor response to 5-FU, the basis of gastrointestinal chemotherapy.The aims of this thesis were: 1. To review the latest publications on the role of MSI status as prognostic factor in stage II colon cancer (CC) patients (Study I); 2. To validate MMR status as a prognostic factor in patients with CC Stage II (Study II); 3. To verify MMR status as a predictive factor in relation to the administration of adjuvant chemotherapy in patients with stage II CC (Study III); 4. To investigate the potential role of MMR status as a risk factor for acute CC surgery (Study IV); and finally 5. To investigate the association between CRC with sporadic dMMR and non-colorectal malignancy (Study V).Study I, a meta-analysis reviewing recently published papers, revealed that MSI status in stage II CC patients does not seem to affect overall survival (OS)and disease-free survival (DFS). This lack of impact could be explained by selection bias and the extremely high proportion of patients receiving adjuvant chemotherapy in the studies included. This was the first meta-analysis specifically evaluating patients with colon cancer stage II. The optimal treatment algorithm for these patients remains unclear, and approximately 20% experience relapse and finally die from disseminated disease.Study II verified the prognostic role of MMR status in patients with stage II CC. Patients with a dMMR tumour have a significantly lower risk for cancer recurrence, a finding that is particularly important for CC treatment. This relationship does not correlate to a better OS since these patients are older and often die from other causes. Debate on the best postoperative strategy in stage II CC continues. What this study contributes is the idea that determination of MMR status can have prognostic value in these patients.Study III also verified the predictive role of MMR status in patients with stageII CC, only this time in relation to treatment with adjuvant chemotherapy. Patients with proficient MMR (pMMR) status receiving adjuvant chemotherapy have a significantly better OS than those not receiving adjuvant treatment. This relationship was not seen in patients with a dMMR tumour. Furthermore, patients with a pMMR tumour receiving adjuvant treatment have a significantly longer survival time after the first relapse compared to those not receiving adjuvant treatment.Study IV revealed the higher probability of dMMR tumours to present as a surgical emergency. Stage III and IV tumours were also associated with acute surgery. This association was significant regardless of the potential bias due toretrospective methodology and possible heterogeneity between the differentcohorts. Further research is required before our conclusions can be applied in clinical practice due to the multicomplex relationship and interactions between variables that influence the oncologic outcome of acute CC surgery.Study V revealed that patients with sporadic, non-hereditary dMMR CRC run a greater risk for having non-colorectal cancer prior to or after the diagnosis ofCRC. This implies that patients with a dMMR tumour should be screened for other non-colorectal cancer, more so than in the the general population.Conclusion: CRC continues to be a significant healthcare problem worldwide, and treatment algorithms for patients with different genomic backgrounds can vary significantly. This thesis supports the idea of using MMR status as a prognostic and predictive factor in everyday clinical practice, especially in stage II CC and acute cases.