Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-10

AUTHORS

F Graziano, E Canestrari, F Loupakis, A Ruzzo, N Galluccio, D Santini, M Rocchi, B Vincenzi, L Salvatore, C Cremolini, C Spoto, V Catalano, S D'Emidio, P Giordani, G Tonini, A Falcone, M Magnani

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. More... »

PAGES

458

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/tpj.2010.9

DOI

http://dx.doi.org/10.1038/tpj.2010.9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1028086336

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20177422


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