Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Abstract

Because chromosomal chromosomal instability (CIN) and microsatellite instability (MSI) are important genetic alterations in colorectal cancers, we classified the sporadic colorectal cancers (CRC) on the status of the CIN and MSI and explored their molecular profiles. A total of 213 colorectal tumors were collected for analysis of DNA ploidy, MSI, loss of heterozygosity (LOH), mutation of p53 (exons 5 to 9), Ki-ras (exons 1 and 2) and BRAF (V599E). Relationships between clinicopathological variables and molecular analyses were analyzed with the v 2 test (Yates' correction). Kaplan-Meier survival curves were compared using logrank test. Variables with p < 0.1 were entered into the Cox regression hazard model for multivariate analysis. High microsatellite instability (MSI-H) existed in 19 tumors (8.9%), which were more likely to be right-sided (31.6%) with poor differentiation (26.3%). Seventy-one (33.3%) tumors were diploid and 142 (66.7%) were aneuploid. Mutations in p53, Ki-ras and BRAF were found in 45.1%, 41.8% and 4.2% of tumors, respectively. Based on MSI, and CIN, 3 classes were defined: (i) High microsatellite instability MSI-H tumors: young age, high carcinoembryonic antigen (CEA) level, right colon, poorly differentiated, mucin production, high BRAF mutation, lower allelic loss and relatively good prognosis; (ii) Microsatellite stability (MSS) diploid tumors: right colon, poorly differentiated, less infiltrative tumor, mucin production, lower allelic loss and low p53, BRAF mutation; (iii) MSS aneuploid tumors: more infiltrative invasion, greater allelic loss and high p53 mutation. According to multivariate analysis, tumor stage and p53 mutation were significantly associated with disease progression. The MSS diploid and MSS aneuploid CRCs could be subtyped with p53 mutation and had different prognostic outcome and molecular profiles. The 4-year disease-free survival (DFS) of patients with MSS-diploid, wild-type p53 tumors was 67% and significantly higher than those of patients with MSS-diploid, mutant p53 CRC (30%, p 5 0.003). The same trend was found in patients with MSS-aneuploid CRC(wild p53 vs. mutant p53, 64% vs. 41%, p 5 0.009). We concluded that CIN, MSI and p53 mutation status might be used as a multiple parameter profile for the prognosis of sporadic colorectal cancer. ' 2005 Wiley-Liss, Inc.Key words: p53; aneuploidy; microsatellite instability; colorectal cancer; prognosis Colorectal cancer is the third most common cancer followed behind cervix cancer and breast cancer in women and lung cancer and hepatoma in men, in Taiwan. 1 The development of most colorectal carcinomas is associated with allelic losses of tumor suppressor genes 17p (p53 gene), 5q (adenomatous polyposis coli, APC) and 18q (deleted in colorectal cancer, DCC), as well as a mutation-based dysregulation of the Ki-ras proto-oncogene. 2,3

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

“…Several studies have reported a link between somatic mutations in components of the EGFR-RAS-RAF pathway and evidence of mucinous differentiation in colorectal carcinomas, [59][60][61][62][63] but the inclusion of microsatelliteunstable carcinomas in many of these studies is likely to have confounded the association because of previous observations that microsatellite-unstable tumors are associated with overexpression of MUC2 and MUC5AC 19 and a mucinous phenotype. 11,12,64 KRAS mutations have been identified in 65% of mucinous colorectal carcinoma, 65 and associations between mutations in the EGFR-RAS-RAF pathway and other types of malignancy have been made, 66 including mucinous ovarian cancers, half or more of which possess somatic KRAS mutations.…”

Clinical and molecular characterization of colorectal cancer in young Moroccan patients

“…Several studies report that MSI is significantly related to improved prognosis independent of the other prognostic factors such as the stage and site of the tumor. The mortality is decreased in MSI+ patients (19)(20)(21). Many studies have found that Lynch patients have a more favorable prognosis than MSI+ patients with sporadic CRC (21)(22)(23).…”

“…The mortality is decreased in MSI+ patients (19)(20)(21). Many studies have found that Lynch patients have a more favorable prognosis than MSI+ patients with sporadic CRC (21)(22)(23). The MSI status is also related to sensitivity to the chemotherapy.…”

Cell Lineage Analysis of a Mouse Tumor

“…The TP53 mutation is not likely to have caused elevated MS mutation rates because mutations in P53 have been shown to be unassociated with MS instability in a variety of human cancers such as prostate (33), gastric (34), and esophageal (35) carcinomas. In human colorectal cancer, mutations in P53 have been shown to be inversely correlated with MS instability (36)(37)(38). However, this negative correlation is not likely to be due to decreased MS mutation rates in tumors with P53 mutations but, rather, is likely to reflect the fact that in colorectal cancer, mutations in TP53 and in MMR genes represent two independent pathways to cancer pathogenesis (i.e., the ''chromosomal instability'' versus the ''microsatellite instability'' pathways; ref.…”