Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Shih Ching Chang, Jen Kou Lin, Shung Haur Yang, Huann Sheng Wang, Anna Fen Yau Li, Chin Wen Chi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

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 χ2 test (Yates' correction). Kaplan-Meier survival curves were compared using log-rank 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 carcinoembryqnic 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 = 0.003). The same trend was found in patients with MSS-aneuploid CRC(wild p53 vs. mutant p53, 64% vs. 41%, p = 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.

Original languageEnglish
Pages (from-to)1721-1727
Number of pages7
JournalInternational Journal of Cancer
Volume118
Issue number7
DOIs
StatePublished - 1 Apr 2006

Keywords

  • Aneuploidy
  • Colorectal cancer
  • Microsatellite instability
  • p53
  • Prognosis

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