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Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab–irinotecan

The Pharmacogenomics Journal volume 10, pages 458–464 (2010)Cite this article

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Abstract

There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3′-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab–irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.

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Acknowledgements

This study was performed with a grant from Consorzio Interuniversitario per le Biotecnologie and Fanoateneo.

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Author notes

  1. F Graziano and E Canestrari: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Onco-Hematology, Medical Oncology Unit, Azienda Ospedaliera Ospedale San Salvatore, Pesaro, Italy

    F Graziano, V Catalano, S D'Emidio & P Giordani

  2. Department of Biomolecular Sciences, University of Urbino, Urbino, Italy

    E Canestrari, A Ruzzo, N Galluccio & M Magnani

  3. Department of Oncology, Medical Oncology Unit, Transplants and New Technologies in Medicine University of Pisa, Pisa, Italy

    F Loupakis, L Salvatore, C Cremolini & A Falcone

  4. Medical Oncology Unit, University Campus Biomedico, Rome, Italy

    D Santini, B Vincenzi, C Spoto & G Tonini

  5. Institute of Biostatistics, University of Urbino, Urbino, Italy

    M Rocchi

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  1. F Graziano
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Correspondence to F Graziano.

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Graziano, F., Canestrari, E., Loupakis, F. et al. Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab–irinotecan. Pharmacogenomics J 10, 458–464 (2010). https://doi.org/10.1038/tpj.2010.9

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  • DOI: https://doi.org/10.1038/tpj.2010.9

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