Skip to main content

Advertisement

SpringerLink
Log in

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

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

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.

Results

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.

Conclusions

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.

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

Abbreviations

5FU:

5-Fluorouracil

B2M:

Beta 2 microglobulin

BAX:

Bcl-2 associated X protein

BRAF:

v-Raf murine sarcoma viral oncogene homolog B1

CCR 6:

Chemokine receptor 6

CXCR4:

Chemokine receptor 4

DNA:

Deoxyribonucleic acid

DPYD:

Dihydropyrimidine dehydrogenase

E-cadherin:

Cell adhesion promoter

EGFR:

Epidermal growth factor receptor

ERCC1:

Excision repair cross-complementing factor 1

FAS/CD95:

TNF factor superfamily member 6

FFPE:

Formalin fixed paraffin embedded

FOLFIRI:

Chemotherapy scheme including 5-FU leucovorin and irinotecan

FOLFOX:

Chemotherapy scheme including 5-FU leucovorin and oxaliplatin

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase reference gene

GST Pi:

Glutathione S-Transferase Pi

h TERT:

Human telomerase reverse transcriptase

IHC:

Immunohistochemistry

KRAS:

v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

mCRC:

Metastatic colorectal cancer

MMP-9:

Matrix metalloproteinase 9

p :

p value

pAKT:

Phosphorylated v-akt murine thymoma viral oncogene homolog 1

PCR:

Polymerase chain reaction

PIK3CA:

Phosphoinositide-3-Kinase, catalytic, alpha polypeptide

PLAU:

Urokinase-type plasminogen

PTEN:

Phosphatase and tensin homolog

qPCR:

quantitative Polymerase chain reaction

RNA:

Ribonucleic Acid

TLDA:

Taq low density arrays

TOP 1:

Topoisomerase I

TYMP:

Thymidine phosphorylase

TYMS:

Thymidylate synthase

THBS1:

Thrombospondin 1

VEGF A:

Vascular endothelial growth factor

References

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  9. Zeitoun G. Cellular and molecular deregulations driving the metastatic phenotype. Med Sci (Paris) 2009, Spec No 1, p. 29–32.

  10. Gerlinger M, Rowan AJ. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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).

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  22. Iqbal S, Lenz HJ. Determinants of prognosis and response to therapy in colorectal cancer. Curr Oncol Rep. 2001;3(2):102–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  28. Garraway Levi A. Concordance and discordance in tumor genomic profiling. J Clin Oncol. 2012;30(24):2937–9.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

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

Author information

Authors and Affiliations

  1. Medical Oncology Department, Infanta Sofía University Hospital, Paseo de Europa 34, San Sebastián de los Reyes, 28702, Madrid, Spain

    M. López-Gómez, E. Casado, A. M. Jiménez, M. Sereno, C. Gómez-Raposo, F. Zambrana & M. Merino

  2. Translational Oncology Department, La Paz University Hospital, Pº de la Castellana 261, 28046, Madrid, Spain

    P. Cejas

  3. Internal Medicine Department, Infanta Sofía University Hospital, Paseo de Europa 34, San Sebastián de los Reyes, 28702, Madrid, Spain

    I. Suárez-García

  4. Statistics Department, La Paz University Hospital, Pº de la Castellana 261, 28046, Madrid, Spain

    R. Madero

  5. General Surgery Department, Infanta Sofía University Hospital, Paseo de Europa 34, San Sebastián de los Reyes, 28702, Madrid, Spain

    D. Fernández-Luengas

  6. Medical Oncology Department, La Paz University Hospital, Pº de la Castellana 261, 28046, Madrid, Spain

    J. Feliu

  7. Precision Oncology Laboratory (POL), Infanta Sofía University Hospital, Pº de la Castellana 261, 28046, Madrid, Spain

    J. Moreno-Rubio

Authors
  1. M. López-Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Moreno-Rubio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Suárez-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Cejas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Madero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Casado
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. M. Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Sereno
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Gómez-Raposo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F. Zambrana
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. Merino
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D. Fernández-Luengas
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J. Feliu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. López-Gómez.

Additional information

All authors have agreed to the submission and have participated in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

López-Gómez, M., Moreno-Rubio, J., Suárez-García, I. et al. Gene expression differences in primary colorectal tumors and matched liver metastases: chemotherapy related or tumoral heterogeneity?. Clin Transl Oncol 17, 322–329 (2015). https://doi.org/10.1007/s12094-014-1233-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-014-1233-3

Keywords

Search

Navigation