Clinical and Translational Oncology

, Volume 17, Issue 4, pp 322–329 | Cite as

Gene expression differences in primary colorectal tumors and matched liver metastases: chemotherapy related or tumoral heterogeneity?

  • M. López-GómezEmail author
  • J. Moreno-Rubio
  • I. Suárez-García
  • P. Cejas
  • R. Madero
  • E. Casado
  • A. M. Jiménez
  • M. Sereno
  • C. Gómez-Raposo
  • F. Zambrana
  • M. Merino
  • D. Fernández-Luengas
  • J. Feliu
Research Article



Treatment of metastatic colorectal cancer (mCRC) is generally based on genetic testing performed in primary tumor biopsies, but whether the genomic status of primary tumors is identical to that of metastases is not well known. We compared the gene expression profiles of formalin-fixed paraffin-embedded (FFPE) biopsies of colorectal primary tumors and matched liver metastases.

Patients and methods

We compared the expression of 18 genes in FFPE CRC tumors and their matched liver metastases from 32 patients. The expression of each gene in CRC primary tumors and their matched liver metastases was tested using Student’s t test for paired samples. Pairwise correlations of each gene in the primary tumors and matched liver metastases were evaluated by Pearson’s correlation coefficient.


The expression of six genes was significantly different in primary tumors compared with their matched liver metastases [CXCR4 (p < 0.001), THBS1 (p = 0.007), MMP 9 (p = 0.048), GST Pi (p = 0.050), TYMP (p = 0.042) and DPYD (p < 0.001)]. For the remaining genes, where no significant differences were observed, only SMAD4 (r s = 0.447, p = 0.010), ERCC1 (r s = 0.423, p = 0.016) and VEGF A (r s = 0.453, p = 0.009) showed significant correlation in expression between the two tissues. Therefore, we only detected similar gene expression levels between the tumor and the metastases in these three markers.


We only found similar gene expression levels between the tumor and the metastases in three genes (SMAD4, ERCC1, and VEGF A). However, our study could not assess whether the differences in gene expression were secondary to tumoral heterogeneity or to molecular changes induced by previous chemotherapy.


Colon cancer Liver metastasis Predictive biomarkers Prognostic factors 





Beta 2 microglobulin


Bcl-2 associated X protein


v-Raf murine sarcoma viral oncogene homolog B1


Chemokine receptor 6


Chemokine receptor 4


Deoxyribonucleic acid


Dihydropyrimidine dehydrogenase


Cell adhesion promoter


Epidermal growth factor receptor


Excision repair cross-complementing factor 1


TNF factor superfamily member 6


Formalin fixed paraffin embedded


Chemotherapy scheme including 5-FU leucovorin and irinotecan


Chemotherapy scheme including 5-FU leucovorin and oxaliplatin


Glyceraldehyde 3-phosphate dehydrogenase reference gene


Glutathione S-Transferase Pi


Human telomerase reverse transcriptase




v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog


Metastatic colorectal cancer


Matrix metalloproteinase 9


p value


Phosphorylated v-akt murine thymoma viral oncogene homolog 1


Polymerase chain reaction


Phosphoinositide-3-Kinase, catalytic, alpha polypeptide


Urokinase-type plasminogen


Phosphatase and tensin homolog


quantitative Polymerase chain reaction


Ribonucleic Acid


Taq low density arrays


Topoisomerase I


Thymidine phosphorylase


Thymidylate synthase


Thrombospondin 1


Vascular endothelial growth factor


Conflict of interest

All listed authors have no conflicts of interest regarding the material presented in this article.


  1. 1.
    Amado RG, Wolf M, Peeters M, Cutsem E, Siena S, Freeman DJ, et al. Wildtype KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.CrossRefPubMedGoogle Scholar
  2. 2.
    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.CrossRefPubMedGoogle Scholar
  3. 3.
    Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-Folfox 4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34.CrossRefPubMedGoogle Scholar
  4. 4.
    De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62.CrossRefPubMedGoogle Scholar
  5. 5.
    Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69:1851–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Oden-Gangloff A, Di Fiore F, Bibeau F, Lamy A, Bougeard G, Charbonnier F, et al. TYMP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy. Br J Cancer. 2009;100(8):1330–5.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Cejas P, López-Gómez M, Aguayo C, Madero R, Moreno-Rubio J, de Castro Carpeño J, et al. Analysis of the concordance in the EGFR pathway status between primary tumors and related metastases of colorectal cancer patients: implications for cancer therapy. Curr Cancer Drug Targets. 2012;12(2):124–31.CrossRefPubMedGoogle Scholar
  8. 8.
    Miranda E, Bianchi P, Destro A, Morenghi E, Malesci A, Santoro A, et al. Genetic and epigenetic alterations in primary colorectal cancers and related lymph node and liver metastases. Cancer. 2013;119(2):266–76.CrossRefPubMedGoogle Scholar
  9. 9.
    Zeitoun G. Cellular and molecular deregulations driving the metastatic phenotype. Med Sci (Paris) 2009, Spec No 1, p. 29–32.Google Scholar
  10. 10.
    Gerlinger M, Rowan AJ. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92.CrossRefPubMedGoogle Scholar
  11. 11.
    Albanese I, Scibetta AG, Migliavacca M, Russo A, Bazan V, Tomasino RM, et al. Heterogeneity within and between primary colorectal carcinomas and matched metastases as revealed by analysis of Ki-ras and p53 mutations. Biochem Biophys Res Commun. 2004;325:784–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Arapantoni-Dadioti P, Valavanis C, Gavressea T, Tzaida O, Trihia H, Lekka I. Discordant expression of hormone receptors and HER2 in breast cancer. A retrospective comparison of primary tumors with paired metachronous recurrences or metastases. J BUON. 2012;17(2):277–83.PubMedGoogle Scholar
  13. 13.
    Jensen NF, Smith DH, Nygard SB. Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer. Scand J Gastroenterol. 2012;47(3):340–55.CrossRefPubMedGoogle Scholar
  14. 14.
    Soong RC, Sha N, Salto-Tellez M, Han HC, Ng SS, Zeps N, et al. Prognostic and predictive significance of 5-fluorouracil metabolic enzymes in colorectal cancer. J Clin Oncol, ASCO Annual Meeting Proceedings Part I, 2006, vol 24, No. 18S (June 20 Supplement).Google Scholar
  15. 15.
    Arnould S, Hennebelle I, Canal P, Bugat R, Guichard S. Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines. Eur J Cancer. 2003;39(1):112–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Mathijssen RH, Loos WJ, Verweij J, Sparreboom A. Pharmacology of TOPBP1isomerase I inhibitors irinotecan (CPT-11) and TOPBP1tecan. Curr Cancer Drug Targets. 2002;2(2):103–23.CrossRefPubMedGoogle Scholar
  17. 17.
    Schimanski C, Schwald S, Simiantonaki N, Jayasinghe C, Gönner U, Wilsberg V, et al. Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer. Clin Cancer Res. 2005;11(5):1743–50.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang YY, Chen B, Ding YQ. Metastasis-associated factors facilitating the progression of colorectal cancer. Asian Pac J Cancer Prev. 2012;13(6):2437–44.CrossRefPubMedGoogle Scholar
  19. 19.
    Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3(7):RESEARCH0034.Google Scholar
  20. 20.
    Vermaat JS, Nijman IJ, Koudijs MJ, Gerritse FL, Scherer SF, Mokry M, et al. Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment. Clin Cancer Res. 2012;18(3):688–99.CrossRefPubMedGoogle Scholar
  21. 21.
    Ganepola GA, Mazziotta RM, Weeresinghe D, Corner GA, Parish CJ, Chang DH, et al. Gene expression profiling of primary and metastatic colon cancer identifies a reduced proliferative rate in metastatic tumors. Clin Exp Metastasis. 2010;27(1):1–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Iqbal S, Lenz HJ. Determinants of prognosis and response to therapy in colorectal cancer. Curr Oncol Rep. 2001;3(2):102–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Gmeiner WH, Hellmann GM, Shen Pj. Tissue-dependent and independent gene expression changes in metastatic colon cancer. Oncol Rep. 2008;19(1):245–51.PubMedGoogle Scholar
  24. 24.
    Stoehlmacher J, Park DJ, Zhang W. Association between glutathione S-transferase P1, T1 and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst. 2002;94(12):936–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Ban N, Takahashi Y, Takayama T, Kura T, Katahira T, Sakamaki S, et al. Transfection of glutathione S-transferase (GST-Pi) antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan and eTOPBP1side. Cancer Res. 1996;56(15):3577–82.PubMedGoogle Scholar
  26. 26.
    Nishimura T, Newkirk K, Sessions RB, Andrews PA, Trock BJ, Rasmussen AA, et al. Immunohistochemical staining for gluthatione S-transferase predicts response to platinum-based chemotherapy in head and neck cancer. Clin Cancer Res. 1996;2(11):1859–65.PubMedGoogle Scholar
  27. 27.
    Goto S, Iida T, Cho S, Oka M, Kohno S, Kondo T. Overexpression of gluthatione S-transferase pi enhances the adduct formation of cisplatin with gluthatione in human cancer cells. Free Radic Res. 1996;31(6):549–58.CrossRefGoogle Scholar
  28. 28.
    Garraway Levi A. Concordance and discordance in tumor genomic profiling. J Clin Oncol. 2012;30(24):2937–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Guichard S, Terret C, Hennebelle I, Lochon I, Chevreau P, Frétigny E, et al. CPT-11 converting carboxylesterase and TOPBP1isomerase activities in tumor and normal colon and liver tissues. Br J Cancer. 1996;80(3–4):364–70.Google Scholar
  30. 30.
    Backus HH, Van Groeningen CJ, Vos W, Dukers DF, Bloemena E, Wouters D, et al. Differential expression of cell cycle and apoptosis related proteins in colorectal mucosa, primary colon tumors, and liver metastases. J Clin Pathol. 2002;55(3):206–11.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Inokuchi M, Uetake H, Shirota Y, Yamada H, Tajima M, Sugihara K. Gene expression of 5 fluorouracil metabolic enzymes in primary colorectal cancer and corresponding liver metastases. Cancer Chemother Pharmacol. 2004;53(5):391–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Kim J, Mori T, Chen SL, Amersi FF, Martinez SR, Kuo C, et al. Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome. Ann Surg. 2006;244(1):113–20.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Ghadjar P, Coupland SE, Na IK. Chemokine receptor CCR6 expression level and liver metastases in colorectal cancer. J Clin Oncol. 2006;24(12):1910–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Kuramochi H, Hayashi K, Uchida K, Miyakura S, Shimizu D, Vallböhmer D, et al. Vascular endothelial growth factor messenger RNA expression level is preserved in liver metastases compared with corresponding primary colorectal cancer. Clin Cancer Res. 2006;12(1):29–33.CrossRefPubMedGoogle Scholar
  35. 35.
    Illemann M, Bird N, Majeed A, Sehested M, Laerum OD, Lund LR, et al. MMP-9 is differentially expressed in primary human colorectal adenocarcinomas and their metastases. Mol Cancer Res. 2009;4(5):293–302.CrossRefGoogle Scholar
  36. 36.
    Kobayashi H, Sugihara K, Uetake H, Higuchi T, Yasuno M, Enomoto M, et al. Messenger RNA expression of TS and ERCC1 in colorectal cancer and matched liver metastasis. Int J Oncol. 2008;33(6):1257–62.PubMedGoogle Scholar
  37. 37.
    Koh KH, Rhee H, Kang HJ, Yang E, You KT, Lee H, et al. Differential gene expression profiles of metastases in paired primary and metastatic colorectal carcinomas. Oncology. 2008;75(1–2):92–101.CrossRefPubMedGoogle Scholar
  38. 38.
    Illemann M, Bird N, Majeed A, Laerum OD, Lund LR, Danø K, et al. Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases. Int J Cancer. 2009;124(8):1860–70.CrossRefPubMedGoogle Scholar
  39. 39.
    Kuramochi H, Hayashi K, Nakajima G, Kamikozuru H, Yamamoto M, Danenberg KD, et al. Epidermal growth factor receptor (EGFR) mRNA levels and protein expression levels in primary colorectal cancer and corresponding liver metastases. Cancer Chemother Pharmacol. 2010;65(5):825–31.CrossRefPubMedGoogle Scholar
  40. 40.
    Chen J, Li Q, Wang C, Wu J, Zhao G. Prognostic significance of c-erbB-2 and vascular endothelial growth factor in colorectal liver metastases. Ann Surg Oncol. 2010;17(6):1555–63.CrossRefPubMedGoogle Scholar
  41. 41.
    Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J, et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol. 2012;30(24):2956–62.CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Miranda E, Destro A, Malesci A, Balladore E, Bianchi P, Baryshnikova E, et al. Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer. Br J Cancer. 2006;95(8):1101–7.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2014

Authors and Affiliations

  • M. López-Gómez
    • 1
    Email author
  • J. Moreno-Rubio
    • 7
  • I. Suárez-García
    • 3
  • P. Cejas
    • 2
  • R. Madero
    • 4
  • E. Casado
    • 1
  • A. M. Jiménez
    • 1
  • M. Sereno
    • 1
  • C. Gómez-Raposo
    • 1
  • F. Zambrana
    • 1
  • M. Merino
    • 1
  • D. Fernández-Luengas
    • 5
  • J. Feliu
    • 6
  1. 1.Medical Oncology DepartmentInfanta Sofía University HospitalMadridSpain
  2. 2.Translational Oncology DepartmentLa Paz University HospitalMadridSpain
  3. 3.Internal Medicine DepartmentInfanta Sofía University HospitalMadridSpain
  4. 4.Statistics DepartmentLa Paz University HospitalMadridSpain
  5. 5.General Surgery DepartmentInfanta Sofía University HospitalMadridSpain
  6. 6.Medical Oncology DepartmentLa Paz University HospitalMadridSpain
  7. 7.Precision Oncology Laboratory (POL)Infanta Sofía University HospitalMadridSpain

Personalised recommendations