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

Abstract

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.

Keywords

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)

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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

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