Skip to main content

Advertisement

SpringerLink
Log in

Immunohistochemical analysis of K-RAS expression in curatively treated colorectal cancer patients: Correlations of clinicopathological features with clinical outcome

  • Clinical - Lab Study
  • Published:
Hellenic Journal of Surgery

Abstract

Aim-Background

The study was conducted to assess the relationship between the presence of K-RAS oncogene expression in samples of colorectal carcinomas (CRC) and the clinicopathological data of investigated patients.

Methods

One hundred patients (55 females/mean age 64.55 years) with curable CRC treated during period 1/1/2000–31/12/2006 were studied. Eligibility criteria for cases included diagnosis with first primary incident CRC, age up to 75 years, and mental competence. Patients with distant metastasis, severe concomitant disease, coexistent malignancy, ulcerative colitis or Crohn’s disease, familial adenomatous polyposis, or immediate severe complication or death were excluded. The tumours concerned adenocarcinomas at TNM stages 0-I (26 patients), II (46 patients), and III (28 patients). Eighty-seven patients received chemotherapy, chemoradiotherapy or radiotherapy. All tumour specimens were reviewed for immunohistochemistry. Expressions of K-RAS and secondarily P53 were identified, and intensity/distribution was evaluated. All clinicopathological parameters were recorded. The cross-tabulation technique was used for variance analysis. P-values ≤0.05 were considered statistically significant.

Results

At 5-year-follow-up, 11 deaths had occurred (stages II:4, III:7) among 20 recurrences (N1:8, N2:2). Deaths were associated with moderate (3 patients), moderate-intense (2 patients) and intense (6 patients) K-RAS staining (p=0.008), and with invasiveness of the tumour (p=0.0089), lymphnode metastasis (p<0.0001) and worse tumour differentiation (p<0.0001). A statistical significance was revealed among the general population between K-RAS intense staining and both worse tumour differentiation (p=0.0066) and N1 lymph-node metastasis (p=0.0469). A statistical significance between K-RAS and P53 expressions in women with T3 tumours was also noted (p=0.0387).

Conclusions

K-RAS overexpression correlated well with worse differentiation, lymph-node metastasis and invasive histologic mode in CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–767

    Article  PubMed  CAS  Google Scholar 

  2. Morrin M, Kelly M, Barrett N, Delaney P. Mutations of Ki-ras and p53 genes in colorectal cancer and their prognostic significance. Gut 1997;35:1127–1131

    Google Scholar 

  3. Baba S. Recent advances in molecular genetics in colorectal cancer. World J Surg 1997;21:678–687

    Article  PubMed  CAS  Google Scholar 

  4. Miranda E, Destro A, Malesci A, Balladore E, Bianchi P, Baryshnikova E, Franchi G, Morenghi E, Laghi L, Gennari L, Roncalli M. Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer. Br J Cancer 2006;95:1101–1107

    Article  PubMed  CAS  Google Scholar 

  5. Akkiprik M, Ataizi-Celikel C, Düsünceli F, Sönmez O, Gulluoglu BM, Sav A, Ozer A. Clinical significance of p53, K-ras and DCC gene alterations in the stage I-II colorectal cancers. J Gastrointestin Liver Dis 2007;16:11–17

    PubMed  Google Scholar 

  6. Harada K, Hiraoka S, Kato J, Horii J, Fujita H, Sakaguchi K, Shiratori Y. Genetic and epigenetic alterations of Ras signalling pathway in colorectal neoplasia: analysis based on tumour clinicopathological features. Br J Cancer 2007;97:1425–1431

    Article  PubMed  CAS  Google Scholar 

  7. Pohl A, Lenz HJ. Individualization of therapy for colorectal cancer based on clinical and molecular parameters. Gastrointest Cancer Res 2008;2:S38–S41

    PubMed  Google Scholar 

  8. Orbell J, West NJ. Improving detection of colorectal cancer. Practitioner 2010;254(1733):17–21

    PubMed  Google Scholar 

  9. 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;9:1193–1197

    PubMed  CAS  Google Scholar 

  10. Winder T, Mündlein A, Rhomberg S, Dirschmid K, Hartmann BL, Knauer M, Drexel H, Wenzl E, De Vries A, Lang A. Different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer. Oncol Rep 2009;21:1283–1287

    Article  PubMed  CAS  Google Scholar 

  11. Chang YS, Yeh KT, Chang TJ, Chai C, Lu HC, Hsu NC, Chang JG. Fast simultaneous detection of K-RAS mutations in colorectal cancer. BMC Cancer 2009;9:179

    Article  PubMed  Google Scholar 

  12. Zlobec I, Molinari F, Kovac M, Bihl MP, Altermatt HJ, Diebold J, Frick H, Germer M, Horcic M, Montani M, Singer G, Yurtsever H, Zettl A, Terracciano L, Mazzucchelli L, Saletti P, Frattini M, Heinimann K, Lugli A. Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients. Br J Cancer 2010;102:151–161

    Article  PubMed  CAS  Google Scholar 

  13. Lee WS, Heum Baek J, Nam Lee J, Kee Lee W. Mutations in K-ras and Epidermal Growth Factor Receptor expression in Korean patients with stages III and IV colorectal cancer. Int J Surg Pathol 2011;19:145–151

    Article  PubMed  Google Scholar 

  14. Onozato W, Yamashita K, Yamashita K, Kuba T, Katoh H, Nakamura T, Sato T, Ihara A, Okayasu I, Watanabe M. Genetic alterations of K-ras may reflect prognosis in stage III colon cancer patients below 60 years of age. J Surg Oncol 2011;103:25–33

    Article  PubMed  CAS  Google Scholar 

  15. Nash GM, Gimbel M, Cohen AM, Zeng ZS, Ndubuisi MI, Nathanson DR, Ott J, Barany F, Paty PB. KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer. Ann Surg Oncol 2010;17:416–424

    Article  PubMed  Google Scholar 

  16. Ahnen DJ, Feigl P, Quan G, Zeng ZS, Ndubuisi MI, Nathanson DR, Ott J, Barany F, Paty PB. Ki-ras mutation and p53 overexpression predict the clinical behaviour of colorectal cancer: a Southwest Oncology Group study. Cancer Res 1998;58:1149–1158

    PubMed  CAS  Google Scholar 

  17. Bouzourene H, Gervaz P, Cerottini JP, Benhattar J, Chaubert P, Saraga E, Pampallona S, Bosman FT, Givel JC. P53 and Ki-ras as prognostic factors for Dukes’ stage B colorectal cancer. Eur J Cancer 2010;36:1008–1015

    Article  Google Scholar 

  18. Morris M, Platell C, Iacopetta B. A population-based study of age-related variation in clinicopathological features, molecular markers and outcome from colorectal cancer. Anticancer Res 2007;27:2833–2838

    PubMed  CAS  Google Scholar 

  19. Duffy MJ, van Dalen A, Haglund C, Hansson L, Holinski-Feder E, Klapdor R, Lamerz R, Peltomaki P, Sturgeon C, Topolcan O. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer 2007;43:1348–1360

    Article  PubMed  CAS  Google Scholar 

  20. Mahdavinia M, Bishehsari F, Verginelli F, Cumashi A, Lattanzio R, Sotoudeh M, Ansari R, Semeraro D, Hormazdi M, Fakheri H, Rakhshani N, De Lellis L, Curia MC, Cama A, Piantelli M, Malekzadeh R, Iacobelli S, Mariani-Costantini R. P53 mutations in colorectal cancer from northern Iran: Relationships with site of tumor origin, microsatellite instability and K-ras mutations. J Cell Physiol 2008.216:543–550

    Article  PubMed  CAS  Google Scholar 

  21. Winder T, Lenz HJ. Molecular predictive and prognostic markers in colon cancer. Cancer Treat Rev 2010;36:550–556 Epub

    Article  PubMed  CAS  Google Scholar 

  22. Jiang Y, Kimchi ET, Staveley-O’Carroll KF, Cheng H, Ajani JA. Assessment of K-ras mutation: a step toward personalized medicine for patients with colorectal cancer. Cancer 2009;115:3609–3617

    Article  PubMed  CAS  Google Scholar 

  23. Jung Y, Lee S, Choi HS, Kim SN, Lee E, Shin Y, Seo J, Kim B, Jung Y, Kim WK, Chun HK, Lee WY, Kim J. Clinical validation of colorectal cancer biomarkers identified from bioinformatics analysis of public expression data. Clin Cancer Res 2011;17:700–709 Epub

    Article  PubMed  CAS  Google Scholar 

  24. Gervaz P, Bouzourene H, Cerottini JP, Chaubert P, Benhattar J, Secic M, Wexner S, Givel JC, Belin B. Dukes B colorectal cancer: distinct genetic categories and clinical outcome based on proximal or distal tumor location. Dis Colon Rectum 2001;44:364–372, discussion 372–373

    Article  PubMed  CAS  Google Scholar 

  25. Rao B, Gao Y, Huang J, Gao X, Fu X, Huang M, Yao J, Wang J, Li W, Zhang J, Liu H, Wang L, Wang J. Mutations of p53 and K-ras correlate TF expression in human colorectal carcinomas: TF downregulation as a marker of poor prognosis. Int J Colorectal Dis 2011;26:593–601 Epub

    Article  PubMed  Google Scholar 

  26. Krens LL, Baas JM, Gelderblom H, Guchelaar HJ. Therapeutic modulation of k-ras signaling in colorectal cancer. Drug Discov Today 2010;15:502–516 Epub

    Article  PubMed  CAS  Google Scholar 

  27. Kapiteijn E, Liefers GJ, Los LC, Kranenbarg EK, Hermans J, Tollenaar RA, Moriya Y, van de Velde CJ, van Krieken JH. Mechanisms of carcinogenesis in colon versus rectal cancer. J Pathol 2001;195:171–178

    Article  PubMed  CAS  Google Scholar 

  28. Galizia G, Lieto E, Ferraraccio F, Orditura M, De Vita F, Castellano P, Imperatore V, Romano C, Ciardiello F, Agostini B, Pignatelli C. Determination of molecular marker expression can predict clinical outcome in colon carcinomas. Clin Cancer Res 2004;10:3490–3499

    Article  PubMed  CAS  Google Scholar 

  29. El-Serafi MM, Bahnassy AA, Ali NM, Eid SM, Kamel MM, Abdel-Hamid NA, Zekri AR. The prognostic value of c-Kit, K-ras codon 12, and p53 codon 72 mutations in Egyptian patients with stage II colorectal cancer. Cancer 2010;116(21):4954–64.

    Article  PubMed  CAS  Google Scholar 

  30. Scartozzi M, Mandolesi A, Giampieri R, Pierantoni C, Loupakis F, Zaniboni A, Galizia E, Giustini L, Silva RR, Bisonni R, Berardi R, Biagetti S, Menzo S, Falcone A, Bearzi I, Cascinu S. Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan. Int J Cancer 2010;127(8):1941–7.

    Article  PubMed  CAS  Google Scholar 

  31. Tai CJ, Lee CH, Chen HC, Wang HK, Jiang MC, Su TC, Shen KH, Lin SH, Yeh CM, Chen CJ, Yeh KT, Chang CC. High nuclear expression of phosphorylated extracellular signal-regulated kinase in tumor cells in colorectal glands is associated with poor outcome in colorectal cancer. Ann Diagn Pathol 2012. doi:pii: S1092-9134(12)00129-3. 10.1016/j.anndiagpath.2012.09.004. [Epub ahead of print]

    Google Scholar 

  32. Duffy MJ, O’Donovan N, Crown J. Use of molecular markers for predicting therapy response in cancer patients. Cancer Treat Rev 2011;37:151–159 Epub

    Article  PubMed  CAS  Google Scholar 

  33. Turaga K, Shibata D. K-Ras and MSI: Potential markers of both patient prognosis and treatment. Ann Surg Oncol 2010;17:354–355

    Article  PubMed  Google Scholar 

  34. Scartozzi M, Giampieri R, Maccaroni E, Mandolesi A, Giustini L, Silva R, Zaniboni A, Biscotti T, Biagetti S, Galizia E, Loupakis F, Falcone A, Bearzi I, Cascinu S. Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecancetuximab. Ann Oncol 2012;23(7):1706–1712. Epub 2011.

    Article  PubMed  CAS  Google Scholar 

  35. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765

    Article  PubMed  CAS  Google Scholar 

  36. Eng C. The evolving role of monoclonal antibodies in colorectal cancer: early presumptions and impact on clinical trial development. Oncologist 2010;15:73–84 Epub

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. 2nd Surgical Dept. of Gen. Hospital of N. Ionia “Constantopoulion, Aghia Olga”, Athens, Greece

    C. Avgoustou, D. Giannousis & P. Penlidis

  2. Histopathologoanatomical Dept. of Gen. Hospital of N. Ionia “Constantopoulion, Aghia Olga”, Athens, Greece

    J. Gigondi

  3. Oncologist, Aghioi Anargiroi Hospital, Athens, Greece

    C. Boukis

  4. Metabolic Engineering and Bioinformatics Programme, Institute of Biological Research & Biotechnology, National Hellenic Research Foundation, Athens, Greece

    A. Chatziioannou

Authors
  1. C. Avgoustou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Giannousis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Penlidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Gigondi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Boukis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Chatziioannou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Avgoustou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Avgoustou, C., Giannousis, D., Penlidis, P. et al. Immunohistochemical analysis of K-RAS expression in curatively treated colorectal cancer patients: Correlations of clinicopathological features with clinical outcome. Hellenic J Surg 85, 165–174 (2013). https://doi.org/10.1007/s13126-013-0031-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13126-013-0031-7

Key words

Search

Navigation