Tumor Biology

, Volume 37, Issue 5, pp 5727–5734 | Cite as

Segmental distribution of some common molecular markers for colorectal cancer (CRC): influencing factors and potential implications



Proximal and distal colorectal cancers (CRCs) are regarded as distinct disease entities, evolving through different genetic pathways and showing multiple clinicopathological and molecular differences. Segmental distribution of some common markers (e.g., KRAS, EGFR, Ki-67, Bcl-2, COX-2) is clinically important, potentially affecting their prognostic or predictive value. However, this distribution is influenced by a variety of factors such as the anatomical overlap of tumorigenic molecular events, associations of some markers with other clinicopathological features (stage and/or grade), and wide methodological variability in markers’ assessment. All these factors represent principal influences followed by intratumoral heterogeneity and geographic variation in the frequency of detection of particular markers, whereas the role of other potential influences (e.g., pre-adjuvant treatment, interaction between markers) remains rather unclear. Better understanding and elucidation of the various influences may provide a more accurate picture of the segmental distribution of molecular markers in CRC, potentially allowing the application of a novel patient stratification for treatment, based on particular molecular profiles in combination with tumor location.


Colorectal cancer Biomarkers Tumor location Treatment Prognosis Prediction 



The author thanks Ms. Aggeliki Oikonomaki for grammatical and spelling correction of the text.

Compliance with ethical standards

Conflicts of interest


Human and animal rights and informed consent

This article does not contain any studies with human participants or animals performed by any of the authors. For this type of studies, formal consent is not required.


  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates in worldwide burden of cancer in 2008: CLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMedGoogle Scholar
  2. 2.
    Shen H, Yang J, Huang Q, Jiang MJ, Tan YN, Fu JF, et al. Different treatment strategies and molecular features between right-sided and left-sided colon cancers. WJG. 2015;21:6470–5. doi: 10.3748/wjg.v21.i21.6470.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Iacopetta B. Are there two sites to colorectal cancer? Int J Cancer. 2002;101:403–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Carethers J. One colon lumen but two organs. Gastroenterol. 2011;141:411–2. doi: 10.1053/j.gastro.2011.06.029.CrossRefGoogle Scholar
  5. 5.
    Hemminki K, Santi I, Weires M, Thomsen H, Sundquist J, Bermejo JL. Tumor location and patient characteristics of colon and rectal adenocarcinomas in relation to survival and TNM classes. BMC Cancer. 2010;10:688.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ghazi S, Lindforss U, Lindberg G, Berg E, Lindblom A, Papadogiannakis N. Analysis of colorectal cancer morphology in relation to sex, age, location and family history. J Gastroenterol. 2012;47:619–34.CrossRefPubMedGoogle Scholar
  7. 7.
    Nawa T, Kato J, Kawamoto H, Okada H, Yamamoto H, Kohno H, et al. Differences between right and left-sided colon cancer in patient characteristics, cancer morphology and histology. J Gastroenterol Hepatol. 2008;23:418–23.CrossRefPubMedGoogle Scholar
  8. 8.
    Hansen I, Jess P. Possible better long-term survival in left versus right-sided colon cancer—a systematic review. Dan Med. 2012;59:6.Google Scholar
  9. 9.
    Greystoke A, Mullamitha SA. How many diseases are colorectal cancer? Gastroenterol Res Pract. 2012. doi: 10.1155/2012/564741.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Russo A, Bazan V, Iacopetta D, Kerr D, Soussi T, Gebbia N. The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol. 2005;23:7518–28.CrossRefPubMedGoogle Scholar
  11. 11.
    Hutchins G, Southward K, Handley K, Magil L, Beaumont C, Stahischmidt J, et al. Value of mismatch repair, KRAS, and BRAF mutations is predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011;29:1261–70.CrossRefPubMedGoogle Scholar
  12. 12.
    Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 2012;61:847–54.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Li F, Lai M. Colorectal cancer, one entity or three. J Zhejiang Univ Sci B. 2009;10:219–29. doi: 10.1631/jzus.B0820273.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Minoo P, Zlobec I, Peterson M, Terracciano L, Lugli A. Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol. 2010;37:707–18.CrossRefPubMedGoogle Scholar
  15. 15.
    Krajewska M, Kim H, Kim C, Kang H, Welsh K, Matsuzawa S, et al. Analysis of apoptosis protein expression in early-stage colorectal cancer suggests opportunities for new prognostic biomarkers. Clin Cancer Res. 2005;11:5451–61.CrossRefPubMedGoogle Scholar
  16. 16.
    Han SH, Park YM, Hwang TS. Differential expression of Bcl-2, Bcl-XL and p53 in colorectal cancer. J Gastroenterol Hepatol. 2006;21:1108–14.CrossRefPubMedGoogle Scholar
  17. 17.
    McKay JA, Murray LJ, Curran S, Ross VG, Clark C, Murray GI, et al. Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases. Eur J Cancer. 2002;38:2258–64.CrossRefPubMedGoogle Scholar
  18. 18.
    Buglioni S, D'Agnano I, Cosimelli M, Vasselli S, D'Angelo C, Tedesco M, et al. Evaluation of multiple bio-pathological factors in colorectal adenocarcinomas: independent prognostic role of p53 and Bcl-2. Int J Cancer. 1999;84:545–52.CrossRefPubMedGoogle Scholar
  19. 19.
    Benedix F, Meyer F, Kube R, Kropf S, Kuester D, Lippert H, et al. Influence of anatomical subsite on the incidence of microsatellite instability, and KRAS and BRAF mutations rates in patients with colon carcinoma. Pathol Res Pract. 2012;208:592–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Harrison S, Benziger H. The molecular biology of colorectal carcinoma and its implications: a review. Surgeon. 2011;9:200–10.CrossRefPubMedGoogle Scholar
  21. 21.
    Elnatan J, Coh HS, Smith DR. C-KRAS activation and the biological behaviour of proximal and distal colonic adenocarcinomas. Eur J Cancer. 1996;32A:491–7. doi: 10.1038/sj.bjc.6690683.CrossRefPubMedGoogle Scholar
  22. 22.
    Papagiorgis P, Zizi A, Tseleni S, Oikonomakis I, Sofras L, Patsouris E, et al. Disparate clinicopathological correlations of p53 and Bcl-2 in colorectal cancer. Molecular Medicine Reports. 2012;5:377–82.PubMedGoogle Scholar
  23. 23.
    Papagiorgis P, Zizi A, Tseleni S, Oikonomakis N, Nikiteas N. The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location. Oncology Letters. 2012;3:1129–35.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Hilska M, Collan YU, Laine VJ O, Kössi J, Hirsimäki P, Laato M, et al. The significance of tumor markers for proliferation and apoptosis in predicting survival in colorectal cancer. Dis Colon Rectum. 2005;48:2197–208.CrossRefPubMedGoogle Scholar
  25. 25.
    Nehls O, Okech T, Hsieh CJ, Enzinger T, Sarbia M, Borchard F, et al. Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX. Br J Cancer. 2007;96:1409–18.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50:113–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Gawlick U, Lu KC, Douthit MA, Diggs BS, Schuff KG, Herzig DO, et al. Stage III & IV colon and rectal cancers share a similar genetic profile: a review of the Oregon colorectal cancer registry. Am J Surg. 2013;205:608–12.CrossRefPubMedGoogle Scholar
  28. 28.
    Papagiorgis PC, Zizi AE, Tseleni S, Oikonomakis IN, Sofras L, Elemenoglou IS, et al. Site impact on colorectal cancer biological behavior in terms of clinicopathological and molecular features. J BUON. 2011;16:84–92.PubMedGoogle Scholar
  29. 29.
    Russo AL, Borger DR, Szymonifka J, Ryan DP, Wo JY, Blaszkowsky LS, et al. Mutational analysis and clinical correlation of metastatic colorectal cancer. Cancer. 2014;120:1482–90.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Reimers M, Zeestraten E, Kuppen P, Gerrit L, van der Velde C. Biomarkers in precision therapy in colorectal cancer. Gastroenterol Rep. 2013;1:166–83. doi: 10.1093/gastro/got022.CrossRefGoogle Scholar
  31. 31.
    Zeestraten E, Benard A, Reimers M, Schouten P, Liefers G, van de Velde C, et al. The prognostic value of the apoptosis pathway in colorectal cancer: a review of the literature on biomarkers identified by immunohistochemistry. Biomark Cancer. 2013;5:13–29. doi: 10.4137/BIC.S11475.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Garrity M, Burgart L, Mahoney M, et al. Prognostic value of proliferation, apoptosis, defective DNA mismatch repair and p53 overexpression in patients with Dukes B2 or C colon cancer. J Clin Oncol. 2004;22:1572–82.CrossRefPubMedGoogle Scholar
  33. 33.
    Zlobec I, Steele R, Michel R, Compton C, Lugli A, Jass J. Scoring of p53, VEGF, Bcl-2 and APAF-1 immunohistochemistry and interobserver reliability in colorectal cancer. Mod Pathol. 2006;19:1236–42.CrossRefPubMedGoogle Scholar
  34. 34.
    Sugai T, Habano W, Yu-Fei Jiao Y-F, Tsukahara M, Takeda Y, Otsuka K, et al. Analysis of molecular alterations in left- and right- sided colorectal carcinomas reveals distinct pathways of carcinogenesis. J Mol Diagn. 2006;8:193–201. doi: 10.2353/jmoldx.2006.050052.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Neuman J, Wehweck L, Maatz S, Engel J, Kirchner T, Jung A. Alterations in the EGFR pathway coincide in colorectal cancer and impact of prognosis. Virchows Arch. 2013;463:509–23.CrossRefGoogle Scholar
  36. 36.
    Issa JP. Colon cancer: it’s CIN or CIMP. Clin Cancer Res. 2008;14:5939–40.CrossRefPubMedGoogle Scholar
  37. 37.
    Corso G, Pascale V, Flauti G, Ferrara F, Marrelli D, Roviello F. Oncogenic mutations and microsatellite instability phenotype predict specific anatomical subsite in colorectal cancer patients. Eur J Human Genetics. 2013;21:1383–8.CrossRefGoogle Scholar
  38. 38.
    Coppedè F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World Gastroenterol. 2014;20:943–56. doi: 10.3748/wjg.v20.i4.943.CrossRefGoogle Scholar
  39. 39.
    Ogino S, Kirkner GJ, Nosho K, Irahara N, Kure S, Shima K, et al. Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res. 2008;14:8221–7.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Blons H, Emile JF, Le Malicot K, et al. Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset. Ann Oncol. 2014;25:2378–85.CrossRefPubMedGoogle Scholar
  41. 41.
    Ruder EH, Laiyemo AO, Graubard BI, Hollenbeck AR, Schatzkin A, Cross AJ. Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol. 2011;106:1340–50.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sinicrope FA, Mahoney MR, Yoo HH et al. Analysis of molecular markers by anatomic tumor site in stage III colon carcinomas from adjuvant chemotherapy trial NCCTG N0147 (Alliance). Clin Cancer Res. 2015.Google Scholar
  43. 43.
    Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatment for individual patients. J Clin Oncol. 2015.Google Scholar
  44. 44.
    Domingo E, Ramamoorthy R, Oukrif D, et al. Use of multivariate analysis to suggest a new molecular classification of colorectal cancer. J Pathol. 2013;229(3):441–8. doi: 10.1002/path.4139.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Phipps AI, Limburg PJ, Baron JA, et al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology. 2015;148(1):77–87.e2. doi: 10.1053/j.gastro.2014.09.038.CrossRefPubMedGoogle Scholar
  46. 46.
    Sinicrope FA, Shi Q, Smyrk TC. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015;148(1):88–99. doi: 10.1053/j.gastro.2014.09.041.CrossRefPubMedGoogle Scholar
  47. 47.
    Lugli A. Towards a molecular classification of colorectal cancer. Front Oncol. 2015. doi: 10.3389/fonc.2015.00046.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Fearon E, Carethers A. Molecular subtyping of CRC: time to explore both intertumoral and intratumoral heterogeneity to evaluate patient outcome. Gastroenterol. 2015;148:10–3.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Technological Educational Institute of AthensAthensGreece

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