Overexpression of MutL homolog 1 and MutS homolog 2 proteins have reversed prognostic implications for stage I-II colon cancer patients

Abstract

Background: The outcome of colon cancer patients without lymph node metastasis is heterogeneous. Searching for new prognostic markers is warranted.

Methods: One hundred twenty stage I-II colon cancer patients who received complete surgical excision during 1995-2004 were selected for this biomarker study. Immunohistochemical method was used to assess p53, epidermal growth factor receptor, MLH1, and MSH2 status. KRAS mutation was examined by direct sequencing.

Results: Thirty three patients (27.5%) developed metachronous metastasis during follow up. By multivariate analysis, only female gender (p = 0.03), high serum carcinoembryonic antigen (CEA) level (≧5 ng/ml) (p = 0.04), and MLH1 overexpression (p = 0.003) were associated with the metastasis group. The 5-year-survival rate were also significantly lower for female gender (71.7% versus 88.9%, p = 0.025), high CEA level (64.9% versus 92.4%, p < 0.001), and MLH1 overexpression (77.5% versus 94.4%, p = 0.039). In contrast, MSH2 overexpression was associated with better survival, 95.1% versus 75.5% (p = 0.024).

Conclusions: The reversed prognostic implications in the overexpression of MLH1 and MSH2 for stage I-II colon cancer patients is a novel finding and worthy of further confirmation.

Keywords: CEA; Colon cancer; MLH1; MSH2; Mismatch repair.

Fig. 1

Immunohistochemical satin for MLH1 protein expression in the colon adenocarcinoma: (A) Intermediate expression (200×), (B) Overexpression (400×), (C) Negative expression (400×); for MSH2 protein expression: (D) Intermediate expression (200×), (E) Overexpression (400×), (F) Negative expression (400×).

Fig. 2

Kaplan–Meier overall survival curve of the 120 colon adenocarcinoma patients according to different variables: (A) gender, (B) carcinoembryonic antigen (CEA) level, (C) MLH1 expression, and (D) MSH2 expression.

Fig. 3

Kaplan–Meier overall survival curve of the 120 colon adenocarcinoma patients based on the three different expression levels of A: MLH1 protein, and B: MSH2 protein.