Clinical & Experimental Metastasis

, Volume 27, Issue 2, pp 83–90 | Cite as

A ‘metastasis-prone’ signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics

  • Yi Hong
  • Thomas Downey
  • Kong Weng Eu
  • Poh Koon Koh
  • Peh Yean Cheah
Original Paper


Metastasis is the major cause of cancer mortality. We aimed to find a metastasis-prone signature for early stage mismatch-repair proficient sporadic colorectal cancer (CRC) patients for better prognosis and informed use of adjuvant chemotherapy. The genome-wide expression profiles of 82 age-, ethnicity- and tissue-matched patients and healthy controls were analyzed using the Affymetrix U133 Plus 2 array. Metastasis-negative patients have 5 years or more of follow-up. A 10 × 10 two-level nested cross-validation design was used with several families of classification models to identify the optimal predictor for metastasis. The best classification model yielded a 54 gene-set (74 probe sets) with an estimated prediction accuracy of 71%. The specificity, sensitivity, negative and positive predictive values of the signature are 0.88, 0.58, 0.84 and 0.65, respectively, indicating that the gene-set can improve prognosis for early stage sporadic CRC patients. These 54 genes, including node molecules YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFATC2, and TGM2, integrate multiple bio-functions in various compartments into an intricate molecular network, suggesting that cell-wide perturbations are involved in metastasis transformation. Further, querying the `Connectivity Map’ with a subset (70%) of these genes shows that Gly-His-Lys and securinine could reverse the differential expressions of these genes significantly, suggesting that they have combinatorial therapeutic effect on the metastasis-prone patients. These two perturbagens promote wound-healing, extracellular matrix remodeling and macrophage activation thus highlighting the importance of these pathways in metastasis suppression for early-stage CRC.


Early stage colorectal cancer Genome-wide expression profiling Metastasis predictor Mismatch-repair proficient Connectivity map query 

Supplementary material

10585_2010_9305_MOESM1_ESM.doc (1.4 mb)
Supplementary material 1 (DOC 1409 kb)


  1. 1.
    Chia KS, Seow A, Lee HP et al (2000) Cancer incidence in Singapore 1993–1997. Singapore Cancer Registry Report: No. 5Google Scholar
  2. 2.
    Wang Y, Jatkoe T, Zhang Y et al (2004) Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol 22:1564–1571CrossRefPubMedGoogle Scholar
  3. 3.
    De Gramont A, Boni C, Navarro M et al (2007) Oxaliplatin/5FU/LV in adjuvant colon cancer: updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years. Proc AM Soc Clin Oncol 25:165s (suppl; abstr 4007)Google Scholar
  4. 4.
    O’Dwyer PJ, Eckhardt SG, Haller DG et al (2007) Priorities in colorectal cancer research: recommendations from the Gastrointestinal Scientific Leadership Council of the Coalition of Cancer Cooperative Groups. J Clin Oncol 25:2313–2321CrossRefPubMedGoogle Scholar
  5. 5.
    Bild AH, Potti A, Nevins JR (2006) Linking oncogenic pathways with therapeutic opportunities. Nat Rev Cancer 6:735–741CrossRefPubMedGoogle Scholar
  6. 6.
    van’t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536CrossRefGoogle Scholar
  7. 7.
    Barrier A, Boelle P, Roser F et al (2006) Stage II colon cancer prognosis prediction by tumor gene expression profiling. J Clin Oncol 24:4685–4691CrossRefPubMedGoogle Scholar
  8. 8.
    Garman KS, Acharya CR, Edelman E et al (2008) A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities. Proc Natl Acad Sci USA 105:19432–19437CrossRefPubMedGoogle Scholar
  9. 9.
    Kruhoffer M, Jensen JL, Laiho P et al (2005) Gene expression signatures for colorectal cancer microsatellite status and HNPCC. Br J Cancer 92:2240–2248CrossRefPubMedGoogle Scholar
  10. 10.
    Giacomini CP, Leung SY, Chen X et al (2005) A gene expression signature of genetic instability in colon cancer. Cancer Res 65:9200–9205CrossRefPubMedGoogle Scholar
  11. 11.
    Watanabe T, Kobunai T, Toda E et al (2006) Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers. Cancer Res 66:9804–9808CrossRefPubMedGoogle Scholar
  12. 12.
    Hong Y, Ho KS, Eu KW et al (2007) A susceptibility gene set for early onset colorectal cancer that integrates diverse signalling pathways: implication for tumorigenesis. Clin Cancer Res 13:1107–1113CrossRefPubMedGoogle Scholar
  13. 13.
    Varma S, Simon R (2006) Bias in error estimation when using cross-validation for model selection. BMC Bioinform 7:91CrossRefGoogle Scholar
  14. 14.
    Ambroise C, McLachlan GJ (2002) Selection bias in gene extraction on the basis of microarray gene-expression data. Proc Nat Acad Sci USA 99:6562–6566CrossRefPubMedGoogle Scholar
  15. 15.
    Lamb J, Crawford ED, Peck D et al (2006) The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313:1929–1935CrossRefPubMedGoogle Scholar
  16. 16.
    Lamb J (2007) The connectivity map: a new tool for biomedical research. Nat Rev Cancer 7:54–60CrossRefPubMedGoogle Scholar
  17. 17.
    Ramaswamy S, Ross KN, Lander ES et al (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33:49–54CrossRefPubMedGoogle Scholar
  18. 18.
    Jones S, Chen W, Parmigiani G et al (2008) Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci USA 105:4283–4288CrossRefPubMedGoogle Scholar
  19. 19.
    Minn AJ, Gupta GP, Siegel PM et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524CrossRefPubMedGoogle Scholar
  20. 20.
    Wittner BS, Sgroi DC, Ryan PD et al (2008) Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal cohort. Clin Cancer Res 14:2988–2993CrossRefPubMedGoogle Scholar
  21. 21.
    Vilar E, Mukherjee B, Kuick R et al (2009) Gene expression patterns in mismatch repair-deficient colorectal cancers highlight the potential therapeutic role of inhibitors of the phosphatidylinositol 3-kinase-AKT-Mammalian target of Rapamycin pathway. Clin Cancer Res 15:2829–2839PubMedGoogle Scholar
  22. 22.
    Simeon A, Emonard H, Hornebeck W et al (2000) The tripeptide-copper complex glycyl-l-histidyl-l-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci 67:2257–2265CrossRefPubMedGoogle Scholar
  23. 23.
    Pickart L (2008) The human tri-peptide GHK and tissue remodelling. J Biomater Sci Polym Ed 19:969–988CrossRefPubMedGoogle Scholar
  24. 24.
    Dong NA, Gu ZL, Chou WH et al (1999) Securinine induced apoptosis in human leukemia HL-60 cells. Zhongguo Yao Li Xue Bao 20:267–270PubMedGoogle Scholar
  25. 25.
    Lubick K, Radke M, Jutlia M (2007) Securinine, a GABAA receptor antagonist, enhances macrophage clearance of phase II C.burnetii: comparison with TLR agonists. J Leukoc Biol 82:1062–1069CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Yi Hong
    • 1
  • Thomas Downey
    • 2
  • Kong Weng Eu
    • 1
  • Poh Koon Koh
    • 1
  • Peh Yean Cheah
    • 1
  1. 1.Department of Colorectal SurgerySingapore General HospitalSingaporeSingapore
  2. 2.Partek IncorporatedSt. LouisUSA

Personalised recommendations