KRAS Mutation and Microsatellite Instability: Two Genetic Markers of Early Tumor Development That Influence the Prognosis of Colorectal Cancer

• Published in: Annals of surgical oncology Vol. 17; no. 2; pp. 416 - 424
• Main Authors: Nash, Garrett M., Gimbel, Mark, Cohen, Alfred M., Zeng, Zhao-Shi, Ndubuisi, Mackevin I., Nathanson, Daniel R., Ott, Jurg, Barany, Francis, Paty, Philip B.
• Format: Journal Article
• Language: English
• Published: New York Springer-Verlag 01.02.2010; Springer Nature B.V
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma - surgery; Adult; Aged; Aged, 80 and over; Colon - metabolism; Colon - pathology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Colorectal Neoplasms - surgery; Disease Progression; Female; Follow-Up Studies; Gastrointestinal Oncology; Genetic Markers; Humans; Male; Medicine; Medicine & Public Health; Microsatellite Instability; Middle Aged; Mutation - genetics; Oncology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Rectum - metabolism; Rectum - pathology; Surgery; Surgical Oncology; Survival Rate; Treatment Outcome; Young Adult; Microsatellite Instability; Metastatic Progression; KRAS Mutation; KRAS Status; Cetuximab
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/s10434-009-0713-0

Introduction We examined two genetic markers established early in colorectal tumor development, microsatellite instability (MSI) and mutation of the KRAS proto-oncogene, to see if these genetic changes influence metastatic disease progression and survival. Patients and methods MSI and KRAS mutation status were assessed in 532 primary adenocarcinomas (stage I–IV) from patients treated by colon resection. Median follow-up was 4.1 years (range 0–13.3 years) overall, 5.4 years for survivors. Results MSI and KRAS mutation were detected in 12 and 36% of cases, respectively. MSI was more common in early-stage disease (I, 15%; II, 21%; III, 10%; IV, 2%; P  = 0.0001). Prevalence of KRAS mutation did not vary with stage (I, 36%; II, 34%; III, 35%; IV, 40%; P  = ns). Disease-specific survival was far superior for MSI tumors than for microsatellite stability (MSS) tumors (5-year survival 92 vs. 59%, P  < 0.0001). KRAS mutation was a marker of poor survival (5-year survival 55 vs. 68%, P  = 0.0002). Using Cox regression analysis MSI, KRAS mutation, and stage were strong independent predictors of survival in the entire patient population. A high-mortality group with MSS/ KRAS -mutant tumors was identified within the stage I and II cohort. Conclusions MSI and KRAS mutation provide fundamental genetic signatures influencing tumor behavior across patient subsets and stages of tumor development.