title: Impact of microsatellite status on chemotherapy for colorectal cancer patients withKRASorBRAFmutation.
abstract: KRASandBRAFmutations are frequently detected in cases of colorectal cancer (CRC). The microsatellite status of patients with CRC and mutatedKRAS/BRAFis important when determining cancer therapy. In the present study, the microsatellite status and genetic polymorphisms ofKRAS(codons 12 and 13) andBRAF(V600E) were characterized in CRC tissue. The mismatch repair activity and oncogenic potential ofKRASwere assessed by immunoblots from twoKRAS-mutated CRC cell lines, SW480 and HCT116, with different microsatellite statuses, following treatment with 5-fluorouracil (5-FU) and oxaliplatin. Of all the 205 patients with CRC enrolled in the present study, 31.2% (64 of 205) had aKRASorBRAFmutation, and 79.7% (51 of 64) of these patients with aKRAS/BRAFmutation exhibited microsatellite stability (MSS), indicating that microsatellite status is correlated withKRAS/BRAFmutation (P=0.027). A higher proportion (39.0%, 41 of 105) of elderly patients (≥62.6 years) had mutatedKRASorBRAFthan younger patients (<62.6 years; 23.0%, 23 of 100; P=0.013). In the subgroup of 154 patients with MSS, patients without theKRASorBRAFmutation (n=110) had longer disease-specific survival rates (58.8±9.4%) than patients withKRASorBRAFmutations (n=44; 50.6±11.0%; P=0.043). Cytoplasmic KRAS levels decreased whereas nuclear MutS protein homolog 2 (MSH2) levels increased slightly in CRC HCT116 cells that were microsatellite instable, following treatment with 76.9 µM 5-FU for 2 days. In microsatellite stable SW480 cells, MSH2 levels markedly increased in the nucleus following 150 µM oxaliplatin treatment for 3 days. However, no significant change was observed regarding KRAS distribution in these cells. The results of the present study suggest that it is important to identify patients with CRC who may benefit from adjuvant chemotherapy with 5-FU or oxaliplatin, particularly CRC patients with MSS and mutatedKRASorBRAF, who have poorer overall survival rates than patients with microsatellite instability. Knowledge of the microsatellite status of patients and whether they harborKRASorBRAFmutations may enable more effective therapeutic strategies to be developed. Further prospective studies are required to validate the findings of the current study.
authors.affiliation: Department of Medical Research, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C.; Department of Biochemistry, National Defense Medical Center, Taipei 11490, Taiwan, R.O.C.
authors.forename: Chi-Jung
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Department of Pathology, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C.
authors.forename: Shih-Hung
authors.initials: SH
authors.lastname: Huang
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei 24257, Taiwan, R.O.C.; Department of Anesthesiology, Sijhih Cathay General Hospital, New Taipei 22174, Taiwan, R.O.C.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chien
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei 24257, Taiwan, R.O.C.; Department of Surgery, Hsinchu Cathay General Hospital, Hsinchu 30060, Taiwan, R.O.C.; Graduate Institute of Translational and Interdisciplinary Medicine, College of Health Sciences and Technology, National Central University, Taoyuan 32001, Taiwan, R.O.C.
authors.forename: Henry Hsin-Chung
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.; School of Medicine, National Yang Ming University, Taipei 11221, Taiwan, R.O.C.
authors.forename: Shung-Haur
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan, R.O.C.; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
authors.forename: Chun-Chao
authors.initials: CC
authors.lastname: Chang
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei 24257, Taiwan, R.O.C.; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.; Department of Internal Medicine, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C.
authors.forename: Chia-Long
authors.initials: CL
authors.lastname: Lee
keywords: 5-fluorouracil; BRAF; DNA mismatch repair; KRAS; colorectal cancer; microsatellite status; oxaliplatin