Research

Gene expression deregulation by KRAS G12D and G12V in a BRAF V600E context

Massimiliano Monticone¹, Emanuela Biollo², Massimo Maffei³, Alessandra Donadini³, Francesco Romeo³, Clelia T Storlazzi⁴, Walter Giaretti³ and Patrizio Castagnola^3*

• * Corresponding author: Patrizio Castagnola patrizio.castagnola@istge.it

Author Affiliations

¹ Centro Biotecnologie Avanzate, Genova, Italy

² Dipartimento di Chimica e Tecnologie Farmaceutiche ed Alimentare, Università di Genova, Genova, Italy

³ Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

⁴ Dipartimento di Genetica e Microbiologia, Università di Bari, Bari, Italy

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Molecular Cancer 2008, 7:92 doi:10.1186/1476-4598-7-92

Published: 16 December 2008

Abstract

Background

KRAS and BRAF mutations appear of relevance in the genesis and progression of several solid tumor types but the co-occurrence and interaction of these mutations have not yet been fully elucidated. Using a microsatellite stable (MSS) colorectal cancer (CRC) cell line (Colo741) having mutated BRAF and KRAS^WT, we also aimed to investigate the KRAS-BRAF interaction. Gene expression profiles for control KRAS^WT, KRAS^G12V and KRAS^G12D transfected cells were obtained after cell clone selection and RT-PCR screening. Extensive qPCR was performed to confirm microarray data.

Results

We found that the KRAS^G12V state deregulated several genes associated to cell cycle, apoptosis and nitrogen metabolism. These findings indicated a reduced survival and proliferation with respect to the KRAS^WT state. The KRAS^G12D state was, instead, characterized by several other distinct functional changes as for example those related to chromatin organization and cell-cell adhesion without affecting apoptosis related genes.

Conclusion

These data predict that the G12D mutation may be more likely selected in a BRAF mutated context. At the same time, the presence of the KRAS^G12V mutation in the cells escaping apoptosis and inducing angiogenesis via IL8 may confer a more aggressive phenotype. The present results get along with the observations that CRCs with G12V are associated with a worse prognosis with respect to the WT and G12D states and may help identifying novel CRC pathways and biomarkers of clinical relevance.