Prediction of biological behavior and prognosis of colorectal cancer patients by tumor MSI/MMR in the Chinese population

Abstract

Colorectal cancers (CRCs) exhibiting microsatellite instability (MSI) have special biological behavior. The clinical predictors for MSI and its survival relevance for the Chinese population were still unclear. Seven hundred ninety-five CRC patients were retrospectively assessed. Mismatch repair (MMR) proteins (MSH2, MSH6, PMS1, and MLH1) expression was detected by immunohistochemistry using tumor tissues of all patients. DNA MSI status was analyzed by polymerase chain reaction in 182 samples randomly selected from the 795 cases. Among all CRC tumor tissues, 97 cases (12.2%) were with an MMR protein-deficient (MMR-D) phenotype, whereas 698 cases (87.8%) were with an MMR proteins intact (MMR-I) phenotype. A total of 21 (11.5%) CRCs were identified as having high microsatellite instability, 156 (85.7%) tumors were having microsatellite stability (MSS), and five (2.7%) were having low microsatellite instability. Importantly, MMR status was demonstrated to be moderately consistent with MSI status (κ=0.845, 95% confidence interval [CI] 0.721, 0.969). Unconditional logistic regression analysis revealed age, number of lymph node, tumor diameter, and tumor site as predictors for MSI with a substantial ability to discriminate different MSI status by area under curve of 80.62% using receiver operation curve. Compared with MMR-I, MMR-D was an independent prognostic factor for longer overall survival (hazard ratio =0.340, 95% CI 0.126, 0.919; P=0.034). MMR-D is an independent prognostic factor for better outcome. Our results may provide evidence for individualized diagnosis and treatment of CRC, but this will require further validation in larger sample studies.

Keywords: clinicopatho-logical features; microsatellite instability; mismatch repair; prognosis; sporadic colorectal cancer.

Figure 1

Immunohistochemical profile of mismatch repair gene protein. Notes: (A) MLH1 negative (×200). (B) PMS2 negative (×200).

Figure 2

Images of separation of multiplex-amplified Bethesda loci (BAT25, BAT26, D2S123, D5S346, and D17S250). Notes: (A) Normal amplification of all the five loci. (B) Representative image showing MSI-L. (C) Representative image showing MSI-H with arrows indicating instability. Abbreviations: MSI-H, microsatellite instability high; MSI-L, microsatellite instability low; MSS, microsatellite stable.

Figure 3

ROC curves for the predictive ability of clinical factors for microsatellite instability status. Abbreviation: ROC, receiver operating characteristic curve.

Figure 4

PFS and OS in all patients. Notes: (A and B) PFS and OS according to MSI status in all patients. The red line is MSI-H. The blue line is MSS/MSI-L. (C and D) PFS and OS according to MMR proteins expression in overall patients. The red line is MMR-D. The blue line is MMR-I. Abbreviations: MMR, mismatch repair gene; MMR-D, mismatch repair proteins deficient; MMR-I, mismatch repair proteins intact; MSI, microsatellite instability; MSI-H, microsatellite instability high; MSI-L, microsatellite instability low; MSS, microsatellite stable; PFS, progression-free survival; OS, overall survival.

Figure 5

PFS and OS in patients with stages II–III. Notes: (A and B) PFS and OS according to MSI status in patients with stages II–III. The red line is MSI-H. The blue line is MSS/MSI-L. (C and D) PFS and OS according to mismatch repair gene proteins expression in patients with stages II–III. The red line is MMR-D. The blue line is MMR-I. Abbreviations: MMR-D, mismatch repair proteins deficient; MMR-I, mismatch repair proteins intact; MSI, microsatellite instability; MSI-H, microsatellite instability high; MSI-L, microsatellite instability low; MSS, microsatellite stable; PFS, progression-free survival; OS, overall survival.