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

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.

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Acknowledgments

The authors thank Ms. Yu Hui Wong, Mr. Huashi Ding and Dr. Soo Chin Liew for technical assistance, the Department of Clinical Research, SGH for the use of the Affymetrix Fluidics station, and the Singapore Polyposis Registry for clinical data retrieval. This work is supported in part by a grant from the National Medical Research Council, Singapore (NMRC/0988/2005) to P.Y. Cheah.

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Correspondence to Peh Yean Cheah.

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Hong, Y., Downey, T., Eu, K.W. et al. A ‘metastasis-prone’ signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis 27, 83–90 (2010). https://doi.org/10.1007/s10585-010-9305-4

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Keywords

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