Skip to main content

Advertisement

SpringerLink
Log in

Implication of K-ras and p53 in colorectal cancer carcinogenesis in Tunisian population cohort

  • Research Article
  • Published:
Tumor Biology

Abstract

According to the multistep route of genetic alterations in the colorectal adenoma–carcinoma sequence, the complex K-ras/p53 mutation is one of the first alterations to occur and represent an important genetic event in colorectal cancer (CRC). An evaluation of the mutation spectra in K-ras and p53 gene was effected in 167 Tunisian patients with sporadic CRC to determine whether our populations have similar pattern of genetic alteration as in Maghrebin’s population. Mutation patterns of codon 12–13 of K-ras and exon 5–8 of p53 were analyzed by immunohistochemistry and PCR-SSCP and confirmed by sequencing. Mutations in the K-ras gene were detected in 31.13 % and affect the women more than the men (p = 0.008). Immunostaining showed that expression of p21 ras was correlated with the advanced age (p = 0.004), whereas loss of signal was associated with mucinous histotype (p = 0.003). Kaplan–Meier survival curve found that patients with the K-ras mutation had a shorter survival compared with patients without mutation (p = 0.005). Alteration in p53 was seen in 17.4 % of patients and affects three hot spot codons such as 175, 245, and 248. Overexpression of p53 was seen in 34.1 % and correlated with tumor node metastasis (TNM) advanced stage (p = 0.037) and mucinous histotype (p = 0.001). A high concordance between p53 expression and alteration (p < 0.005) was shown. Concomitant mutations in K-ras and p53 gene were detected in only 4 % of tumors. K-ras and p53 undergo separate pathways in colorectal tumorogenesis. Interestingly, mutations in the K-ras gene might be considered a valuable prognostic factor correlated to poor outcome. p53 gene alterations were rather low in our set, and methylation pattern of p53 is required to elucidate the molecular basis of this protein 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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in colorectal cancer. CA Cancer J Clin. 2009;59:366–78.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Article  CAS  PubMed  Google Scholar 

  3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.

    Article  CAS  PubMed  Google Scholar 

  4. Akkiprik M, Ataizi-Celikel C, Düşünceli F, et al. Clinical significance of p53, K-ras and DCC gene alterations in the stage I-II colorectal cancers. J Gastrointest Liver Dis. 2007;1:11–7.

    Google Scholar 

  5. Edkins S, O’Meara S, Parker A, et al. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther. 2006;5:928–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Gatenby RA, Vincent TL. An evolutionary model of carcinogenesis. Cancer Res. 2003;63:6212–20.

    CAS  PubMed  Google Scholar 

  7. Worthley DL, Whitehall VL, Spring KJ, Leggett BA. Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol. 2007;13:3784–91.

    CAS  PubMed  Google Scholar 

  8. Pietsch EC, Humbey O, Murphy ME. Polymorphisms in the p53 pathway. Oncogene. 2006;25:1602–11.

    Article  CAS  PubMed  Google Scholar 

  9. Schuler M, Green DR. Transcription, apoptosis and p53: catch-22. Trends Genet. 2005;21:182–7.

    Article  CAS  PubMed  Google Scholar 

  10. Meek DW. The p53 response to DNA damage. DNA Repair (Amst). 2004;3:1049–56.

    Article  CAS  Google Scholar 

  11. Samowitz WS, Curtin KM, Edwaeds S, et al. Prognostic significance of p53 mutation in colorectal cancer at the population level. Int J Cancer. 2002;99:597–602.

    Article  CAS  PubMed  Google Scholar 

  12. Paluszkiewicz P, Berbeæ H, Pawlowska-Wakowicz B, et al. p53 protein accumulation in colorectal cancer tissue has prognostic value only in left sided colon tumors. Cancer Detect Prev. 2004;28:252–9.

    Article  CAS  PubMed  Google Scholar 

  13. Soussi T, Beroud C. Significance of p53 mutations in human cancer: a critical analysis of mutations at CpG dinucleotides. Hum Mutat. 2003;21:192–200.

    Article  CAS  PubMed  Google Scholar 

  14. Tominaga T, Iwahashi M, Takifuji K, et al. Combination of p53 codon 72 polymorphism and inactive p53 mutation predicts chemosensitivity to 5-fluorouracil in colorectal cancer. Int J Cancer. 2010;126:1691–701.

    CAS  PubMed  Google Scholar 

  15. Vidaurreta M, Maestro ML, Sanz-Casla MT, Rafael S, Veganzones S, de la Orden V, et al. Colorectal carcinoma prognosis can be predicted by alterations in gene p53 exons 5 and 8. Int. J. Colorectal Dis. 2008;23:581–6.

    Article  CAS  Google Scholar 

  16. Oki E, Zhao Y, Yoshida R, Egashira A, Ohgaki K, Morita M, et al. The difference in p53 mutations between cancers of the upper and lower gastrointestinal tract. Digestion. 2009;79:33–9.

    Article  CAS  PubMed  Google Scholar 

  17. Lea IA, Jackson MA, Dunnick JK. Genetic pathways to colorectal cancer. Mutat Res. 2009;670:96–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Bond, C. E.,Umapathy,A., Ramsnes, I. et al. (2011) P53mutation is common in microsatellite stable, BRAF mutant colorectal cancers. Int. J. Cancer. 2012;130(7):1567–76.

  19. Russo A, Bazan V, Agnese V, et al. Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies. Ann Oncol. 2005;16:iv44–9.

    Article  PubMed  Google Scholar 

  20. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the “RASCAL II” study. Br J Cancer. 2001;85:692–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Urosevic N, Krtolica K, Skaro-Milic A, et al. Prevalence of G-to-C tranversions among K-ras oncogene mutations in human colorectal tumors in Yugoslavia. Int J Cancer. 1993;54:249–54.

    Article  CAS  PubMed  Google Scholar 

  22. Capella G, Cronauer-Mitra S, Pienado MA, et al. Frequency and spectrum of mutations at codons 12 and 13 of the c-K-ras gene in human tumors. Environ Health Perspect. 1991;93:125–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Soong R, Powell B, Elsaleh H, et al. Prognostic significance of TP53 gene mutation in 995 cases of colorectal carcinoma. Influence of tumour site, stage, adjuvant chemotherapy and type of mutation. Eur J Cancer. 2000;36:2053–60.

    Article  CAS  PubMed  Google Scholar 

  24. Conlin A, Smith G, Carey FA, Wolf CR, Steele RJ. The prognostic significance of K-ras, p53and APC mutations in colorectal carcinoma. Gut. 2005;54(9):1283–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Calistri D, Rengucci C, Seymour I, Lattuneddu A, Polifemo AM, Monti F, et al. Mutation analysis of p53, K-ras, and BRAF genes in colorectal cancer progression. J Cell Physiol. 2005;204(2):484–8.

    Article  CAS  PubMed  Google Scholar 

  26. Jeon CH, Lee HI, Shin IH, Park JW. Genetic alterations of APC, K-ras, p53, MSI, and MAGE in Korean colorectal cancer patients. Int J Colorectal Dis. 2008;23(1):29–35.

    Article  PubMed  Google Scholar 

  27. Pan Z-Z, Wan D-S, Chen G, Li L-R, Zhen-Hai L, Huang B-J. Co-mutation of p53, K-ras genes and accumulation of p53 protein and its correlation to clinicopathological features in rectal cancer. World J Gastroenterol. 2004;10(24):3688–90.

    CAS  PubMed  Google Scholar 

  28. Worthley DL, Leggett BA. Colorectal cancer: molecular features and clinical opportunities. Clin Biochem. 2010;31:31–8.

    Google Scholar 

  29. Iacopetta B. TP53 Mutation in Colorectal Cancer. Hum Mutat. 2003;21:271–6.

    Article  CAS  PubMed  Google Scholar 

  30. Rodrigues NR, Rowan A, Smith ME, Kerr IB, Bodmer WF, Gannon JV, et al. p53 mutations in colorectal cancer. Proc Natl Acad Sci U S A. 1990;87(19):7555–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Tullo A, D’Erchia AM, Honda K, Mitry RR, Kelly MD, Habib NA, et al. Characterization of p53 mutations in colorectal liver metastases and correlation with clinical parameters. Clin Cancer Res. 1999;5(11):3523–8.

    CAS  PubMed  Google Scholar 

  32. Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 2002;21(48):7435–51.

    Article  CAS  PubMed  Google Scholar 

  33. Liu Y, Bodmer WF. Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines. Proc Natl Acad Sci U S A. 2006;103(4):976–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Dix BR, Robbin P, Soong R, Jenner D, House AK, Iacopetta BJ. The common molecular genetics alteration in Dukes’B and C colorectel carcinomas are not short-term prognostic indicators of survival. Int J Cancer. 1994;59:747–51.

    Article  CAS  PubMed  Google Scholar 

  35. Iacopetta B, Russo A, Bazan V, et al. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study. Ann Oncol. 2006;17:842–7.

    Article  CAS  PubMed  Google Scholar 

  36. Munro AJ, Lain S, Lane DP. P53 abnormalities and outcomes in colorectal cancer: a systematic review. Br J Cancer. 2005;92(3):434–44.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Soong R, Robbins PD, Dix BR, Grieu F, Lim B, Knowles S, et al. Concordance between p53 protein overexpression and gene mutation in a large series of common human carcinomas. Hum Pathol. 1996;27(10):1050–5.

    Article  CAS  PubMed  Google Scholar 

  38. Dix B, Robbins P, Carrello S, House A, Iacopetta B. Comparison of p53 gene mutation and protein overexpression in colorectal carcinomas. Br J Cancer. 1994;70(4):585–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Cripps KJ, Purdie CA, Carder PJ, White S, Komine K, Bird CC, et al. A study of stabilisation of p53 protein versus point mutation in colorectal carcinoma. Oncogene. 1994;9(9):2739–43.

    CAS  PubMed  Google Scholar 

  40. Thomas E. Rohan1, Shu-Qiu Li2, Robert Hartwick2 and Rita A. Kandel2. (2006) p53 Alterations and protein accumulation in benign breast tissue and breast cancer risk: a cohort study. Cancer Epidemiol Biomarkers Prev. 2006;15(7):1316–23.

  41. Leopoldo S, Lorena B, Cinzia A, Gabriella DC, Angela Luciana B, Renato C, et al. Two subtypes of mucinous adenocarcinoma of the colorectum: clinicopathological and genetic features. Ann Surg Oncol. 2008;15:1429–39.

    Article  PubMed  Google Scholar 

  42. Westra JL, Schaapveld M, Hollema H, de Boer JP, Kraak MM, de Jong D, et al. Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol. 2005;23(24):5635–43.

    Article  CAS  PubMed  Google Scholar 

  43. Georgee T, Eleni K, Joanna GP, et al. p53 and EGFR expression in colorectal cancer: a reappraisal of ‘old’ tissue markers in patients with long follow-up. Anticancer Res. 2009;29:785–92.

    Google Scholar 

  44. Yuan-Tzu L, Shih-Ching C, Anna Fen-Yau L, et al. p53 protein accumulation as a prognostic marker in sporadic colorectal cancer. Int J Colorectal Dis. 2007;22:499–506.

    Article  Google Scholar 

  45. Nasif WA, Lotfy M, El-Sayed IH, et al. Implications of CEA and p53 overexpression in the poor prognosis of colorectal cancer. Med Oncol. 2007;23:237–44.

    Article  Google Scholar 

  46. Fabien S, Marie-Aude Le Frere B, Rodrigo Q, et al. Pretreatment p53 nuclear overexpression as a prognostic marker in superficial bladder cancer treated with Bacillus Calmette-Guérin (BCG). Eur Urol. 2004;45:475–82.

    Article  Google Scholar 

  47. Lun-Xiu Q, Zhao-You T, Zeng-Chen M, et al. p53 immunohistochemical scoring: an independent prognostic marker for patients after hepatocellular carcinoma resection. World J Gastroenterol. 2002;8:459–63.

    Google Scholar 

  48. Garg K, Leitao Jr MM, Christine AW, et al. p53 overexpression in morphologically ambiguous endometrial carcinomas correlates with adverse clinical outcomes. Mod Pathol. 2010;23:80–92.

    Article  CAS  PubMed  Google Scholar 

  49. Kim H, Yom C, Lee J, et al. Overexpression of p53 is correlated with poor outcome in premenopausal women with breast cancer treated with tamoxifen after chemotherapy. Breast Cancer Res Treat. 2010;121:777–88.

    Article  CAS  PubMed  Google Scholar 

  50. Sundström M, Edlund K, Lindell M, et al. KRAS analysis in colorectal carcinoma: analytical aspects of pyrosequencing and allele-specific PCR in clinical practice. BMC Cancer. 2010;10:660.

    Article  PubMed Central  PubMed  Google Scholar 

  51. Wójcik P, Kulig J, Okor K, et al. KRAS mutation profile in colorectal carcinoma and novel mutation-internal tandem duplication in KRAS. Pol J Pathol. 2008;59:93–6.

    PubMed  Google Scholar 

  52. Servomaa K, Kiuru A, Kosma VM, et al. p53 and K-ras gene mutations in carcinoma of the rectum among Finnish women. Mol Pathol. 2000;53:24–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Morin M, Kelly M, Barrett N, et al. Mutations of Ki-ras and p53 genes in colorectal cancer and their prognostic significance. Gut. 1994;35:1627–31.

    Article  Google Scholar 

  54. Sameer AS, Chwdhri NA, Abdullah S, et al. Mutation pattern of K-ras gene of colorectal cancer patients in Kashmir: a report. Indian J Cancer. 2009;46:219–25.

    Article  CAS  PubMed  Google Scholar 

  55. Akkiprik M, Celikel CA, Düsünceli F, et al. Relationship between overexpression of ras p21 oncoprotein and K-ras codon 12 and 13 mutations in Turkish colorectal cancer patients. Turk J Gastroenterol. 2008;19:22–7.

    PubMed  Google Scholar 

  56. Scheffzek K, Ahmadian M, Wittinghofer A. GTPase-activating proteins: helping hands to complement an active site. Trends Biochem Sci. 1998;23:257–62.

    Article  CAS  PubMed  Google Scholar 

  57. Samowitz WS, Curtin K, Schaffer D, et al. 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 

  58. Delattre O, Olschwang S, Law DJ, et al. Multiple genetic alterations in distal and proximal colorectal cancer. Lancet. 1989;2:353–6.

    Article  CAS  PubMed  Google Scholar 

  59. Oudejans JJ, Slebos RJ, Zoetmulder FA, et al. Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int J Cancer. 1991;49:875–9.

    Article  CAS  PubMed  Google Scholar 

  60. Bazan V, Migliavacca M, Zanna I, et al. Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. Ann Oncol. 2002;13:1438–46.

    Article  CAS  PubMed  Google Scholar 

  61. Francoise P, Laurent M, Caroline C, et al. Les voies de la carcinogenése colorectale: intérê t et application pour la pathologiste. Ann Pathol. 2002;22:277–88.

    Google Scholar 

  62. Hanski C. Is mucinous carcinoma of the colorectum a distinct genetic entity? Br J Cancer. 1995;72:1350–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Ikeda S, Shimizu Y, Fujimori M, et al. Immunohistochemical and mutational analyses of beta-catenin, Ki-ras, and p53 in two subtypes of colorectal mucinous carcinoma. Clin Cancer Res. 2003;9:5660–5.

    CAS  PubMed  Google Scholar 

  64. Chiang JM, Wu Chou YH, Ma SC, et al. Influence of age on adenomatous polyposis coli and p53 mutation frequency in sporadic colorectal cancer Frarity of co-occurrence of mutations in APC, K-ras, and p53 genes. Virchows Arch. 2004;445:465–71.

    Article  CAS  PubMed  Google Scholar 

  65. Andreyev HJN, 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 

  66. Smith G, Carey FA, Beattie J, Wilkie MJ, Lightfoot TJ, Coxhead J, et al. Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer. Proc Natl Acad Sci U S A. 2002;99:9433–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the Ministry of Health and Scientific Research for the support of this study.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Laboratory of Colorectal Cancer Research UR03ES04, Science University Tunis, 2047 Sidi Daoud, Tunis, Tunisia

    Chaar Ines, Ounissi Donia, Boughriba Rahma, Azza Ben Ammar, Amara Sameh, Taher Khalfallah, Mzabi Sabeh & Bouraoui Saadia

  2. Department of Pathology and Cytology, Mongi Slim Hospital La Marsa, Tunis, Tunisia

    Mzabi Sabeh & Bouraoui Saadia

  3. Department of Epidemiology and Preventive Medicine, Medicine University of Tunis, Tunis, Tunisia

    Taher Khalfallah & Ben hmida Abdelmajid

  4. Department of General Surgery, Mongi Slim Hospital La Marsa, Tunis, Tunisia

    Chaar Ines, Ounissi Donia, Boughriba Rahma, Azza Ben Ammar, Amara Sameh, Ben hmida Abdelmajid, Mzabi Sabeh & Bouraoui Saadia

  5. Science University of Tunis UTM, Tunis, Tunisia

    Chaar Ines, Ounissi Donia, Boughriba Rahma, Azza Ben Ammar, Amara Sameh, Taher Khalfallah, Ben hmida Abdelmajid, Mzabi Sabeh & Bouraoui Saadia

Authors
  1. Chaar Ines
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ounissi Donia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Boughriba Rahma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Azza Ben Ammar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amara Sameh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taher Khalfallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ben hmida Abdelmajid
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mzabi Sabeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bouraoui Saadia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chaar Ines.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ines, C., Donia, O., Rahma, B. et al. Implication of K-ras and p53 in colorectal cancer carcinogenesis in Tunisian population cohort. Tumor Biol. 35, 7163–7175 (2014). https://doi.org/10.1007/s13277-014-1874-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-1874-4

Keywords

Search

Navigation