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

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

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.

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References

  1. Skibber J, Minsky B, Hoff P. Cancer of the colon. In: DeVita VT, Rosenberg SA, editors. Principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2001.

    Google Scholar 

  2. Chapuis PH, Fisher R, Dent OF, Newland RC, Pheils MT. The relationship between different staging methods and survival in colorectal carcinoma. Dis Colon Rectum. 1985;28:158–61.

    Article  CAS  PubMed  Google Scholar 

  3. Barillari P, de Angelis R, Valabrega S, Indinnimeo M, Gozzo P, Ramacciato G, et al. Relationship of symptom duration and survival in patients with colorectal carcinoma. Eur J Surg Oncol. 1989;15:441–5.

    CAS  PubMed  Google Scholar 

  4. Robinson M, Hardcastle J. Should we be screening for colorectal cancer? Br Med Bull. 1998;54:807–821.

    CAS  PubMed  Google Scholar 

  5. Culliford A, Paty P. Surgery of colon cancer. In: Saltz L, editor. Colorectal cancer: multimodality management. Oxford, UK: Blackwell; 2002.

    Google Scholar 

  6. Diep CB, Thorstensen L, Meling GI, Skovlund E, Rognum TO, Lothe RA. Genetic tumor markers with prognostic impact in Dukes’ stages B and C colorectal cancer patients. J Clin Oncol. 2003;21:820–9.

    Article  PubMed  Google Scholar 

  7. Elsaleh H, Powell B, McCaul K, Grieu F, Grant R, Joseph D, et al. P53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma. Clin Cancer Res. 2001;7:1343–9.

    CAS  PubMed  Google Scholar 

  8. Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.

    Article  CAS  PubMed  Google Scholar 

  9. Halling KC, French AJ, McDonnell SK, Burgart LJ, Schaid DJ, Peterson BJ, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst. 1999;91:1295–303.

    Article  CAS  PubMed  Google Scholar 

  10. Peltomäki P, Lothe RA, Aaltonen LA, Pylkkänen L, Nyström-Lahti M, Seruca R, et al. Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res. 1993;53:5853–5.

    PubMed  Google Scholar 

  11. Slattery ML, Curtin K, Schaffer D, Anderson K, Samowitz W. Associations between family history of colorectal cancer and genetic alterations in tumors. Int J Cancer. 2002;97:823–7.

    Article  CAS  PubMed  Google Scholar 

  12. Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R, Haller DG, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344:1196–206.

    Article  CAS  PubMed  Google Scholar 

  13. Lièvre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374–9.

    Article  PubMed  CAS  Google Scholar 

  14. Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85:692–6.

    Article  CAS  PubMed  Google Scholar 

  15. Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst. 1998;90:675–84.

    Article  CAS  PubMed  Google Scholar 

  16. Klump B, Hehls O, Okech T, Hsieh CJ, Gaco V, Gittinger FS, et al. Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature. Int J Colorectal Dis. 2004;19:23–42.

    Article  CAS  PubMed  Google Scholar 

  17. Duffy MJ, van Dalen A, Haglund C, Hansson L, Holinski-Feder E, Klapdor R, et al. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer. 2007;43:1348–60.

    Article  CAS  PubMed  Google Scholar 

  18. Duffy MJ, van Dalen A, Haglund C, Hansson L, Klapdor R, Lamerz R, et al. Clinical utility of biochemical markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines. Eur J Cancer. 2003;39:718–27.

    Article  CAS  PubMed  Google Scholar 

  19. Graziano F, Cascinu S. Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes’ B colorectal cancer patients: how much evidence is enough? Ann Oncol. 2003;14:1026–38.

    Article  CAS  PubMed  Google Scholar 

  20. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363:558–61.

    Article  CAS  PubMed  Google Scholar 

  21. Kolodner RD, Marsischky GT. Eukaryotic DNA mismatch repair. Curr Opin Genet Dev. 1999;9:89–96.

    Article  CAS  PubMed  Google Scholar 

  22. Pedroni M, Sala E, Scarselli A, Borghi F, Menigatti M, Benatti P, et al. Microsatellite instability and mismatch-repair protein expression in hereditary and sporadic colorectal carcinogenesis. Cancer Res. 2001;61:896–9.

    CAS  PubMed  Google Scholar 

  23. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer. 2003;3:695–701.

    Article  CAS  PubMed  Google Scholar 

  24. Yamashita K, Dai T, Dai Y, Yamamoto F, Perucho M. Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell. 2003;4:121–31.

    Article  CAS  PubMed  Google Scholar 

  25. Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 2001;10:917–23.

    CAS  PubMed  Google Scholar 

  26. Nash GM, Gimbel M, Shia J, Culliford AT, Nathanson DR, Ndubuisi M, et al. Automated, multiplex assay for high-frequency microsatellite instability in colorectal cancer. J Clin Oncol. 2003;21:3105–12.

    Article  CAS  PubMed  Google Scholar 

  27. Suraweera N, Duval A, Reperant M, Vaury C, Furlan D, Leroy K, et al. Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology. 2002;123:1804–11.

    Article  CAS  PubMed  Google Scholar 

  28. Xicola RM, Llor X, Pons E, Castells A, Alenda C, Piñol V, et al. Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. J Natl Cancer Inst. 2007;99:244–52.

    Article  CAS  PubMed  Google Scholar 

  29. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–8.

    Article  CAS  PubMed  Google Scholar 

  30. Cox AD, Der CJ: Ras family signaling: therapeutic targeting. Cancer Biol Ther. 2002;1:599–606.

    CAS  PubMed  Google Scholar 

  31. Sahai E, Olson MF, Marshall CJ. Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. EMBO J. 2001;20:755–66.

    Article  CAS  PubMed  Google Scholar 

  32. Porta M, Ayude D, Alguacil J, Jariod M. Exploring environmental causes of altered ras effects: fragmentation plus integration? Mol Carcinog. 2003;36:45–52.

    Article  CAS  PubMed  Google Scholar 

  33. Cheng L, Lai MD. Aberrant crypt foci as microscopic precursors of colorectal cancer. World J Gastroenterol. 2003;9:2642–9.

    CAS  PubMed  Google Scholar 

  34. Shibata D, Schaeffer J, Li ZH, Capella G, Perucho M. Genetic heterogeneity of the c-K-ras locus in colorectal adenomas but not in adenocarcinomas. J Natl Cancer Inst. 1993;85:1058–63.

    Article  CAS  PubMed  Google Scholar 

  35. Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 2004;23:29–39.

    Article  CAS  PubMed  Google Scholar 

  36. Ahnen DJ, Feigl P, Quan G, Fenoglio-Preiser C, Lovato LC, Bunn PA Jr., et al. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res. 1998;58:1149–58.

    CAS  PubMed  Google Scholar 

  37. Samowitz WS, Curtin K, Schaffer D, Robertson M, Leppert M, Slattery ML. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer Epidemiol Biomarkers Prev. 2000;9:1193–7.

    CAS  PubMed  Google Scholar 

  38. Umetani N, Sasaki S, Watanabe T, Ishigami H, Ueda E, Nagawa H. Diagnostic primer sets for microsatellite instability optimized for a minimal amount of damaged DNA from colorectal tissue samples. Ann Surg Oncol. 2000;7:276–80.

    Article  CAS  PubMed  Google Scholar 

  39. Khanna M, Park P, Zirvi M, Cao W, Picon A, Day J, et al. Multiplex PCR/LDR for detection of K-ras mutations in primary colon tumors. Oncogene. 1999;18:27–38.

    Article  CAS  PubMed  Google Scholar 

  40. Alrawi SJ, Schiff M, Carroll RE, Dayton M, Gibbs JF, Kulavlat M, et al. Aberrant crypt foci. Anticancer Res. 2006;26:107–19.

    CAS  PubMed  Google Scholar 

  41. Pretlow TP, Brasitus TA, Fulton NC, Cheyer C, Kaplan EL. K-ras mutations in putative preneoplastic lesions in human colon. J Natl Cancer Inst. 1993;85:2004–7.

    Article  CAS  PubMed  Google Scholar 

  42. Shibata D, Peinado MA, Ionov Y, Malkhosyan S, Perucho M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nat Genet. 1994;6:273–81.

    Article  CAS  PubMed  Google Scholar 

  43. Losi L, Benhattar J, Costa J. Stability of K-ras mutations throughout the natural history of human colorectal cancer. Eur J Cancer. 1992;28A:1115–20.

    Article  CAS  PubMed  Google Scholar 

  44. Finkelstein SD, Sayegh R, Christensen S, Swalsky PA. Genotypic classification of colorectal adenocarcinoma. Biologic behavior correlates with K-ras-2 mutation type. Cancer. 1993;71:3827–38.

    Article  CAS  PubMed  Google Scholar 

  45. Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y, et al. Allelotype of colorectal carcinomas. Science. 1989;244:207–11.

    Article  CAS  PubMed  Google Scholar 

  46. Curran B, Lenehan K, Mulcahy H, Tighe O, Bennett MA, Kay EW, et al. Replication error phenotype, clinicopathological variables, and patient outcome in Dukes’ B stage II (T3,N0,M0) colorectal cancer. Gut. 2000;46:200–4.

    Article  CAS  PubMed  Google Scholar 

  47. Gnanasampanthan G, Elsaleh H, McCaul K, Iacopetta B. Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes’ C colorectal cancer. J Pathol. 2001;195:543–8.

    Article  CAS  PubMed  Google Scholar 

  48. Wang C, van Rijnsoever M, Grieu F, Bydder S, Elsaleh H, Joseph D, et al. Prognostic significance of microsatellite instability and Ki-ras mutation type in stage II colorectal cancer. Oncology. 2003;64:259–65.

    Article  CAS  PubMed  Google Scholar 

  49. Rodriguez R, Hansen LT, Phear G, Scorah J, Spang-Thomsen M, Cox A, et al. Thymidine selectively enhances growth suppressive effects of camptothecin/irinotecan in MSI+ cells and tumors containing a mutation of MRE11. Clin Cancer Res. 2008;14:5476–83.

    Article  CAS  PubMed  Google Scholar 

  50. Fink D, Aebi S, Howell SB. The role of DNA mismatch repair in drug resistance. Clin Cancer Res. 1998;4:1–6.

    CAS  PubMed  Google Scholar 

  51. Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–5.

    Article  PubMed  Google Scholar 

  52. Fallik D, Borrini F, Boige V, Viguier J, Jacob S, Miquel C, et al. Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res. 2003;63:5738–44.

    CAS  PubMed  Google Scholar 

  53. Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR 21. J Clin Oncol. 2008;26:4268–75.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This study was supported by a grant from the National Cancer Institute (2 P01 CA65930-05A2) awarded to P.B.P., and by the philanthropy of Marie and William Bianco honoring Cathy Kiley.

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Authors and Affiliations

  1. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA

    Garrett M. Nash MD, Mark Gimbel MD, Zhao-Shi Zeng MD, Mackevin I. Ndubuisi PhD, Daniel R. Nathanson MD & Philip B. Paty MD

  2. University of Arizona Cancer Center, Tucson, AZ, USA

    Alfred M. Cohen MD

  3. Laboratory of Statistical Genetics, Rockefeller University, New York, USA

    Jurg Ott PhD

  4. Department of Microbiology, Weill Medical College of Cornell University, New York, USA

    Francis Barany PhD

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  1. Garrett M. Nash MD
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  2. Mark Gimbel MD
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Correspondence to Philip B. Paty MD.

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Nash, G.M., Gimbel, M., Cohen, A.M. et al. KRAS Mutation and Microsatellite Instability: Two Genetic Markers of Early Tumor Development That Influence the Prognosis of Colorectal Cancer. Ann Surg Oncol 17, 416–424 (2010). https://doi.org/10.1245/s10434-009-0713-0

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