Prognostic Impact of Deficient DNA Mismatch Repair and KRAS and BRAF V600E Mutations in Patients with Lymph-Node-Positive Colon Cancer

Abstract

While tumor stage remains the key determinant of colorectal cancer (CRC) prognosis and treatment, there is considerable stage-independent variability in clinical outcome. Molecular markers hold promise for explaining variations in clinical behavior, and may identify patient subsets with differential efficacy and survival after adjuvant chemotherapy which is standard of care for patients with lymph node-positive, i.e., stage III, colon cancer. An increased understanding of the molecular evolution and progression of CRC has identified two major pathways of tumorigenesis that are characterized by chromosomal instability or microsatellite instability (MSI). MSI is a consequence of deficient DNA mismatch repair (MMR) that is generally due to epigenetic inactivation of MLH1 in tumors that often carry mutations in oncogenic BRAFV600E. Activating BRAFV600E and KRAS mutations are mutually exclusive and in this article, we review the current status of these mutations and MMR status as prognostic biomarkers in stage III colon cancers.

Systematic immunohistochemical screening for mismatch repair and ERCC1 gene expression from colorectal cancers in China: Clinicopathological characteristics and effects on survival

“…Compared to stage III CRCs, more stage II CRCs were with dMMR, especially the stage IIA tumors that had a higher dMMR rate of 16.6%. In our study, MMR status appeared to act as an independent prognostic biomarker for DFS in patients with stage III colon cancer that had received adjuvant FOLFOX chemotherapy a result that is consistent with other recent studies[ 6 , 23 ]. In metastatic CRC (mCRC), we found that the prevalence of dMMR was low (4.9%).…”

“…Multiple studies have shown that CRCs with dMMRhave a better stage-adjusted survival compared with pMMR cancers. However, these data are largely from retrospective studies or focused on Lynch syndrome [ 6 , 7 , 8 ]. Molecular studies comparing CRCs with early and advanced stages have been rare.…”

Prognostic relevance of microsatellite instability in pT3N0M0 colon cancer: a population-based study

“…For Stage II colon cancer, 5-year survival is reported approximately varying from 75 to 87.5 % [1,14,18] and only 3.5-5 % of these patients receive a benefit from post-surgical oncological treatments [19,20]. In addition to the traditional tumor stage, which remains the key determinant of CC prognosis and treatment, there are considerable stage-independent clinical-pathological and molecular prognostic markers identifying subsets of patients with high risk of progression and suitable for postsurgical treatment [21]. Different molecular pathways of tumorigenesis involving microsatellite (MSI) have been identified [21].…”

“…In addition to the traditional tumor stage, which remains the key determinant of CC prognosis and treatment, there are considerable stage-independent clinical-pathological and molecular prognostic markers identifying subsets of patients with high risk of progression and suitable for postsurgical treatment [21]. Different molecular pathways of tumorigenesis involving microsatellite (MSI) have been identified [21]. In the literature, it is reported that about 10-20 % of colorectal cancers display microsatellite instability [6-13, 19, 22].…”

Recent Advances in the Use of Molecular Biomarkers in Colorectal Cancer

“…Indeed, among patients with resected stage II and stage III CRC, MSI-H disease is associated with favourable prognosis and predicts limited benefit from adjuvant 5-fluorouracil (5-FU) monotherapy [30,31]. Additionally, approximately one-quarter of MSI-H tumours occur as a result of a germline mutation (Lynch syndrome, also known as hereditary nonpolyposis CRC) [32].…”