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Clinical and Translational Oncology
Published in: Clinical and Translational Oncology 4/2015

01-04-2015 | Research Article

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

Authors: M. López-Gómez, 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

Published in: Clinical and Translational Oncology | Issue 4/2015

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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.
Literature
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
22.
Iqbal S, Lenz HJ. Determinants of prognosis and response to therapy in colorectal cancer. Curr Oncol Rep. 2001;3(2):102–8.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
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.PubMed
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.PubMed
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.CrossRef
28.
Garraway Levi A. Concordance and discordance in tumor genomic profiling. J Clin Oncol. 2012;30(24):2937–9.CrossRefPubMed
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.
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRef
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
Metadata
Title
Gene expression differences in primary colorectal tumors and matched liver metastases: chemotherapy related or tumoral heterogeneity?
Authors
M. López-Gómez
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
Publication date
01-04-2015
Publisher
Springer Milan
Published in
Clinical and Translational Oncology / Issue 4/2015
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-014-1233-3

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