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Molecular profiles and clinical outcome of stage UICC II colon cancer patients

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

Published multigene classifiers suggesting outcome prediction for patients with stage UICC II colon cancer have not been translated into a clinical application so far. Therefore, we aimed at validating own and published gene expression signatures employing methods which enable their reconstruction in routine diagnostic specimens.

Methods

Immunohistochemistry was applied to 68 stage UICC II colon cancers to determine the protein expression of previously published prognostic classifier genes (CDH17, LAT, CA2, EMR3, and TNFRSF11A). RNA from macrodissected tumor samples from 53 of these 68 patients was profiled on Affymetrix GeneChips (HG-U133 Plus 2.0). Prognostic signatures were generated by “nearest shrunken centroids” with cross-validation. Previously published gene signatures were applied to our data set using “global tests” and leave-one-out cross-validation

Results

Correlation of protein expression with clinical outcome failed to separate patients with disease-free follow-up (group DF) and relapse (group R). Although gene expression profiling allowed the identification of differentially expressed genes (“DF” vs. “R”), a stable classification/prognosis signature was not discernable. Furthermore, the application of previously published gene signatures to our data was unable to predict clinical outcome (prediction rate 75.5% and 64.2%; n.s.). T-stage was the only independent prognostic factor for relapse with established clinical and pathological parameters including microsatellite status (multivariate analysis).

Conclusions

Our protein and gene expression analyses do not support application of molecular classifiers for prediction of clinical outcome in current routine diagnostic as a basis for patient-orientated therapy in stage UICC II colon cancer. Further studies are needed to develop prognosis signatures applicable in patient care.

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References

  1. Anwar S, Frayling IM, Scott NA, Carlson GL (2004) Systematic review of genetic influences on the prognosis of colorectal cancer. Br J Surg 91:1275–1291

    Article  PubMed  CAS  Google Scholar 

  2. Fowble B, Gray R, Gilchrist K, Goodman RL, Taylor S, Tormey DC (1988) Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 6:1107–1117

    PubMed  CAS  Google Scholar 

  3. Kappers I, Belderbos JS, Burgers JA, van Zandwijk N, Groen HJ, Klomp HM (2008) Non-small cell lung carcinoma of the superior sulcus: favourable outcomes of combined modality treatment in carefully selected patients. Lung Cancer 59:385–390

    Article  PubMed  CAS  Google Scholar 

  4. Wehrli LA, Braun J, Buetti LN, Hagleitner N, Hengartner H, Kuhne T, Luer S, Ozsahin H, Popovic MB, Niggli FK, Betts DR, Bourquin JP (2009) Non-classical karyotypic features in relapsed childhood B-cell precursor acute lymphoblastic leukemia. Cancer Genet Cytogenet 189:29–36

    Article  PubMed  CAS  Google Scholar 

  5. Gill S, Loprinzi CL, Sargent DJ, Thome SD, Alberts SR, Haller DG, Benedetti J, Francini G, Shepherd LE, Francois Seitz J, Labianca R, Chen W, Cha SS, Heldebrant MP, Goldberg RM (2004) Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 22:1797–1806

    Article  PubMed  CAS  Google Scholar 

  6. Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, Chen G, Gharib TG, Thomas DG, Lizyness ML, Kuick R, Hayasaka S, Taylor JM, Iannettoni MD, Orringer MB, Hanash S (2002) Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med 8:816–824

    PubMed  CAS  Google Scholar 

  7. Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 98:13790–13795

    Article  PubMed  CAS  Google Scholar 

  8. Bueno-de-Mesquita JM, Linn SC, Keijzer R, Wesseling J, Nuyten DS, van Krimpen C, Meijers C, de Graaf PW, Bos MM, Hart AA, Rutgers EJ, Peterse JL, Halfwerk H, de Groot R, Pronk A, Floore AN, Glas AM, Van't Veer LJ, van de Vijver MJ (2009) Validation of 70-gene prognosis signature in node-negative breast cancer. Breast Cancer Res Treat 117:483–495

    Article  PubMed  CAS  Google Scholar 

  9. Guo L, Ma Y, Ward R, Castranova V, Shi X, Qian Y (2006) Constructing molecular classifiers for the accurate prognosis of lung adenocarcinoma. Clin Cancer Res 12:3344–3354

    Article  PubMed  CAS  Google Scholar 

  10. Huber W, von Heydebreck A, Sultmann H, Poustka A, Vingron M (2002) Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18(Suppl 1):S96–S104

    Article  PubMed  Google Scholar 

  11. Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TF, Bernd HW, Cogliatti SB, Dierlamm J, Feller AC, Hansmann ML, Haralambieva E, Harder L, Hasenclever D, Kuhn M, Lenze D, Lichter P, Martin-Subero JI, Moller P, Muller-Hermelink HK, Ott G, Parwaresch RM, Pott C, Rosenwald A, Rosolowski M, Schwaenen C, Sturzenhofecker B, Szczepanowski M, Trautmann H, Wacker HH, Spang R, Loeffler M, Trumper L, Stein H, Siebert R (2006) A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med 354:2419–2430

    Article  PubMed  CAS  Google Scholar 

  12. Jais JP, Haioun C, Molina TJ, Rickman DS, de Reynies A, Berger F, Gisselbrecht C, Briere J, Reyes F, Gaulard P, Feugier P, Labouyrie E, Tilly H, Bastard C, Coiffier B, Salles G, Leroy K (2008) The expression of 16 genes related to the cell of origin and immune response predicts survival in elderly patients with diffuse large B-cell lymphoma treated with CHOP and rituximab. Leukemia 22:1917–1924

    Article  PubMed  CAS  Google Scholar 

  13. Karlsson E, Delle U, Danielsson A, Olsson B, Abel F, Karlsson P, Helou K (2008) Gene expression variation to predict 10-year survival in lymph-node-negative breast cancer. BMC Cancer 8:254

    Article  PubMed  Google Scholar 

  14. Larsen JE, Pavey SJ, Passmore LH, Bowman RV, Hayward NK, Fong KM (2007) Gene expression signature predicts recurrence in lung adenocarcinoma. Clin Cancer Res 13:2946–2954

    Article  PubMed  CAS  Google Scholar 

  15. Mook S, Van't Veer LJ, Rutgers EJ, Piccart-Gebhart MJ, Cardoso F (2007) Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics 4:147–155

    PubMed  CAS  Google Scholar 

  16. Rimsza LM, Leblanc ML, Unger JM, Miller TP, Grogan TM, Persky DO, Martel RR, Sabalos CM, Seligmann B, Braziel RM, Campo E, Rosenwald A, Connors JM, Sehn LH, Johnson N, Gascoyne RD (2008) Gene expression predicts overall survival in paraffin-embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP. Blood 112:3425–3433

    Article  PubMed  CAS  Google Scholar 

  17. van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536

    Article  Google Scholar 

  18. Ntzani EE, Ioannidis JP (2003) Predictive ability of DNA microarrays for cancer outcomes and correlates: an empirical assessment. Lancet 362:1439–1444

    Article  PubMed  CAS  Google Scholar 

  19. Pawitan Y, Michiels S, Koscielny S, Gusnanto A, Ploner A (2005) False discovery rate, sensitivity and sample size for microarray studies. Bioinformatics 21:3017–3024

    Article  PubMed  CAS  Google Scholar 

  20. Walther A, Johnstone E, Swanton C, Midgley R, Tomlinson I, Kerr D (2009) Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer 9:489–499

    Article  PubMed  CAS  Google Scholar 

  21. Barrier A, Boelle PY, Roser F, Gregg J, Tse C, Brault D, Lacaine F, Houry S, Huguier M, Franc B, Flahault A, Lemoine A, Dudoit S (2006) Stage II colon cancer prognosis prediction by tumor gene expression profiling. J Clin Oncol 24:4685–4691

    Article  PubMed  CAS  Google Scholar 

  22. Lin YH, Friederichs J, Black MA, Mages J, Rosenberg R, Guilford PJ, Phillips V, Thompson-Fawcett M, Kasabov N, Toro T, Merrie AE, van Rij A, Yoon HS, McCall JL, Siewert JR, Holzmann B, Reeve AE (2007) Multiple gene expression classifiers from different array platforms predict poor prognosis of colorectal cancer. Clin Cancer Res 13:498–507

    Article  PubMed  CAS  Google Scholar 

  23. Wang Y, Jatkoe T, Zhang Y, Mutch MG, Talantov D, Jiang J, McLeod HL, Atkins D (2004) Gene expression profiles and molecular markers to predict recurrence of Dukes' B colon cancer. J Clin Oncol 22:1564–1571

    Article  PubMed  CAS  Google Scholar 

  24. Noske A, Denkert C, Schober H, Sers C, Zhumabayeva B, Weichert W, Dietel M, Wiechen K (2005) Loss of Gelsolin expression in human ovarian carcinomas. Eur J Cancer 41:461–469

    Article  PubMed  CAS  Google Scholar 

  25. Kauffmann A, Gentleman R, Huber W (2009) arrayQualityMetrics—a bioconductor package for quality assessment of microarray data. Bioinformatics 25:415–416

    Article  PubMed  CAS  Google Scholar 

  26. Tibshirani R, Hastie T, Narasimhan B, Chu G (2002) Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc Natl Acad Sci USA 99:6567–6572

    Article  PubMed  CAS  Google Scholar 

  27. Ruschhaupt M, Mansmann U, Warnat P, Huber W, Benner A. (2006) MCRestimate: misclassification error estimation with cross-validation. [R package version 1.8.0.]

  28. Goeman JJ, van de Geer SA, de Kort F, van Houwelingen HC (2004) A global test for groups of genes: testing association with a clinical outcome. Bioinformatics 20:93–99

    Article  PubMed  CAS  Google Scholar 

  29. Doll D, Keller L, Maak M, Boulesteix AL, Siewert JR, Holzmann B, Janssen KP (2010) Differential expression of the chemokines GRO-2, GRO-3, and interleukin-8 in colon cancer and their impact on metastatic disease and survival. Int J Colorectal Dis 25:573–581

    Article  PubMed  Google Scholar 

  30. Huang ML, Chen CC, Chang LC (2009) Gene expressions of HMGI-C and HMGI(Y) are associated with stage and metastasis in colorectal cancer. Int J Colorectal Dis 24:1281–1286

    Article  PubMed  Google Scholar 

  31. Peng J, Wang Z, Chen W, Ding Y, Wang H, Huang H, Huang W, Cai S (2010) Integration of genetic signature and TNM staging system for predicting the relapse of locally advanced colorectal cancer. Int J Colorectal Dis 25:1277–1285

    Article  PubMed  Google Scholar 

  32. Zimmermann T, Moehler M, Gockel I, Sgourakis GG, Biesterfeld S, Muller M, Berger MR, Lang H, Galle PR, Schimanski CC (2010) Low expression of chemokine receptor CCR5 in human colorectal cancer correlates with lymphatic dissemination and reduced CD8+ T-cell infiltration. Int J Colorectal Dis 25:417–424

    Article  PubMed  Google Scholar 

  33. Bertucci F, Salas S, Eysteries S, Nasser V, Finetti P, Ginestier C, Charafe-Jauffret E, Loriod B, Bachelart L, Montfort J, Victorero G, Viret F, Ollendorff V, Fert V, Giovaninni M, Delpero JR, Nguyen C, Viens P, Monges G, Birnbaum D, Houlgatte R (2004) Gene expression profiling of colon cancer by DNA microarrays and correlation with histoclinical parameters. Oncogene 23:1377–1391

    Article  PubMed  CAS  Google Scholar 

  34. Alon U, Barkai N, Notterman DA, Gish K, Ybarra S, Mack D, Levine AJ (1999) Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays. Proc Natl Acad Sci USA 96:6745–6750

    Article  PubMed  CAS  Google Scholar 

  35. Notterman DA, Alon U, Sierk AJ, Levine AJ (2001) Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays. Cancer Res 61:3124–3130

    PubMed  CAS  Google Scholar 

  36. Ioannidis JP, Allison DB, Ball CA, Coulibaly I, Cui X, Culhane AC, Falchi M, Furlanello C, Game L, Jurman G, Mangion J, Mehta T, Nitzberg M, Page GP, Petretto E, van Noort V (2009) Repeatability of published microarray gene expression analyses. Nat Genet 41:149–155

    Article  PubMed  CAS  Google Scholar 

  37. Michiels S, Koscielny S, Hill C (2005) Prediction of cancer outcome with microarrays: a multiple random validation strategy. Lancet 365:488–492

    Article  PubMed  CAS  Google Scholar 

  38. Dupuy A, Simon RM (2007) Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. J Natl Cancer Inst 99:147–157

    Article  PubMed  Google Scholar 

  39. Shi L, Reid LH, Jones WD, Shippy R, Warrington JA, Baker SC, Collins PJ, de Longueville F, Kawasaki ES, Lee KY, Luo Y, Sun YA, Willey JC, Setterquist RA, Fischer GM, Tong W, Dragan YP, Dix DJ, Frueh FW, Goodsaid FM, Herman D, Jensen RV, Johnson CD, Lobenhofer EK, Puri RK, Schrf U, Thierry-Mieg J, Wang C, Wilson M, Wolber PK, Zhang L, Amur S, Bao W, Barbacioru CC, Lucas AB, Bertholet V, Boysen C, Bromley B, Brown D, Brunner A, Canales R, Cao XM, Cebula TA, Chen JJ, Cheng J, Chu TM, Chudin E, Corson J, Corton JC, Croner LJ, Davies C, Davison TS, Delenstarr G, Deng X, Dorris D, Eklund AC, Fan XH, Fang H, Fulmer-Smentek S, Fuscoe JC, Gallagher K, Ge W, Guo L, Guo X, Hager J, Haje PK, Han J, Han T, Harbottle HC, Harris SC, Hatchwell E, Hauser CA, Hester S, Hong H, Hurban P, Jackson SA, Ji H, Knight CR, Kuo WP, LeClerc JE, Levy S, Li QZ, Liu C, Liu Y, Lombardi MJ, Ma Y, Magnuson SR, Maqsodi B, McDaniel T, Mei N, Myklebost O, Ning B, Novoradovskaya N, Orr MS, Osborn TW, Papallo A, Patterson TA, Perkins RG, Peters EH, Peterson R, Philips KL, Pine PS, Pusztai L, Qian F, Ren H, Rosen M, Rosenzweig BA, Samaha RR, Schena M, Schroth GP, Shchegrova S, Smith DD, Staedtler F, Su Z, Sun H, Szallasi Z, Tezak Z, Thierry-Mieg D, Thompson KL, Tikhonova I, Turpaz Y, Vallanat B, Van C, Walker SJ, Wang SJ, Wang Y, Wolfinger R, Wong A, Wu J, Xiao C, Xie Q, Xu J, Yang W, Zhong S, Zong Y, Slikker W Jr (2006) The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements. Nat Biotechnol 24:1151–1161

    Article  PubMed  CAS  Google Scholar 

  40. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268

    Article  PubMed  CAS  Google Scholar 

  41. Takamura M, Ichida T, Matsuda Y, Kobayashi M, Yamagiwa S, Genda T, Shioji K, Hashimoto S, Nomoto M, Hatakeyama K, Ajioka Y, Sakamoto M, Hirohashi S, Aoyagi Y (2004) Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma. Cancer Lett 212:253–259

    Article  PubMed  CAS  Google Scholar 

  42. Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB (1998) Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase. J Biol Chem 273:20551–20555

    Article  PubMed  CAS  Google Scholar 

  43. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE (1998) LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92:83–92

    Article  PubMed  CAS  Google Scholar 

  44. Stacey M, Lin HH, Hilyard KL, Gordon S, McKnight AJ (2001) Human epidermal growth factor (EGF) module-containing mucin-like hormone receptor 3 is a new member of the EGF-TM7 family that recognizes a ligand on human macrophages and activated neutrophils. J Biol Chem 276:18863–18870

    Article  PubMed  CAS  Google Scholar 

  45. Kummola L, Hamalainen JM, Kivela J, Kivela AJ, Saarnio J, Karttunen T, Parkkila S (2005) Expression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colorectal mucosa. BMC Cancer 5:41

    Article  PubMed  Google Scholar 

  46. Abe Y, Matsumoto S, Kito K, Ueda N (2000) Cloning and expression of a novel MAPKK-like protein kinase, lymphokine-activated killer T-cell-originated protein kinase, specifically expressed in the testis and activated lymphoid cells. J Biol Chem 275:21525–21531

    Article  PubMed  CAS  Google Scholar 

  47. Simons-Evelyn M, Bailey-Dell K, Toretsky JA, Ross DD, Fenton R, Kalvakolanu D, Rapoport AP (2001) PBK/TOPK is a novel mitotic kinase which is upregulated in Burkitt's lymphoma and other highly proliferative malignant cells. Blood Cells Mol Dis 27:825–829

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Anke Sommerfeld, Erika Berg, and Marco Arndt for their excellent technical assistance and Dr. Bernhard Heine for support in sample survey before processing.

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Authors and Affiliations

  1. Department of General, Vascular and Thoracic Surgery, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Jörn Gröne & Heinz-Johannes Buhr

  2. Institute of Pathology, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Dido Lenze, Harald Stein & Michael Hummel

  3. Institut für Medizinische Informatik Biometrie Epidemiologie (IBE), Munich, Germany

    Vindi Jurinovic & Ulrich Mansmann

  4. Core Facilities-Microarray Unit, Centre for Genomic Regulation, C/Dr. Aiguader 88, 08003, Barcelona, Spain

    Manuela Hummel

  5. Target Discovery, Bayer Schering Pharma AG, Müllerstr. 178, 13353, Berlin, Germany

    Henrik Seidel, Gabriele Leder, Georg Beckmann & Anette Sommer

  6. Department of Visceral, Thoracic and Vascular Surgery, University Hospital Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    Robert Grützmann & Christian Pilarsky

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  1. Jörn Gröne
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  2. Dido Lenze
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  3. Vindi Jurinovic
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  4. Manuela Hummel
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  8. Anette Sommer
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  9. Robert Grützmann
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  11. Ulrich Mansmann
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  12. Heinz-Johannes Buhr
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  13. Harald Stein
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  14. Michael Hummel
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Correspondence to Jörn Gröne.

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Gröne, J., Lenze, D., Jurinovic, V. et al. Molecular profiles and clinical outcome of stage UICC II colon cancer patients. Int J Colorectal Dis 26, 847–858 (2011). https://doi.org/10.1007/s00384-011-1176-x

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