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  • br Keywords Bioinformatics Colorectal cancer Genetic alterat

    2019-10-07


    Keywords: Bioinformatics, Colorectal cancer, Genetic alterations, IDEA, Next generation sequencing
    G.C. and A.B. contributed equally to this article as first authors.
    F.D.N., E.M., and A.B. contributed equally to this article as senior and corresponding authors.
    1Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy 2University of Turin, Department of Oncology, Candiolo (TO), Italy 3Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
    4Department of Oncology and HaematologyeOncology, University of Milano, Milano, Italy 5FIRC Institute of Molecular Oncology (IFOM), Milan, Italy
    Address for correspondence: Federica Di Nicolantonio, PhD, Enzo Medico, MD, PhD,
    or Alberto Bardelli, PhD, Candiolo Cancer Institute, SP 142 km 3.95, 10060 Candiolo (TO), Italy E-mail contact: [email protected]; [email protected]; alberto. [email protected]
    IDEA NGS Workflow
    Introduction
    Colorectal cancer (CRC) is the third most frequently diagnosed and the second most common cause of cancer death worldwide.1 It arises from the sequential transformation of the normal intestinal epithelium into benign adenoma and then into an invasive adeno-carcinoma. The gradual morphologic transformation parallels with stepwise accumulation of genetic and epigenetic alterations.2 Neutral evolution and short periods of genomic instability may lead to the concomitant occurrence of several molecular alterations and contribute to CRC polyclonal landscapes.3-5
    The molecular landscape of CRC has prognostic relevance and affects the choice of therapeutic strategies, directing the rational deployment of targeted drugs directed against deregulated cellular processes to which CRC Galactose 1-phosphate  are dependent for their survival and proliferation.
    A key factor in determining CRC cell proliferation is aberrant activation of the epidermal growth factor receptor (EGFR) signaling pathway.6,7 Activation of EGFR, elicited by epidermal growth factor, leads to sequential activation of intracellular signaling pro-teins, such as the Kirsten rat sarcoma viral oncogene homolog (KRAS), the B-Raf serine/threonine-protein kinase (BRAF), and the extracellular signal-regulated kinase 1 (ERK1), conveying prolifer-ative signals through regulation of gene expression.8 Standard treatment of patients with metastatic CRC (mCRC) is mainly based on cytotoxic chemotherapy with ad hoc addition of molecular-targeted regimens.9 For example, anti-EGFR monoclonal anti-bodies, such as cetuximab and panitumumab, are administered as first- or second-line therapy in combination with chemotherapy. Even with the combination of these drugs, the median overall survival of patients with mCRC does not go beyond 30 months.10,11 Furthermore, EGFR targeted inhibition is effective only in a molecularly-defined subgroup of patients. CRC tumors carrying activating mutations in KRAS or BRAF genes are usually refractory to EGFR blockade,12,13 and anti-EGFR monoclonal antibodies are approved only for treatment of RAS/BRAF wild-type tumors.14-16 Notably, a sizable fraction of wild-type cases are intrinsically resistant to anti-EGFR treatments, and their resistance is often associated with alterations in genes (such as NRAS, ERBB2, EGFR, FGFR1, PDGFRA, MAP2K1, or MET ) that lead to downstream or parallel signaling activation.17-19 Unfortunately, even in responding patients, acquired resistance eventually emerges within 3 to 12 months of initiating therapies.20-23 From a molecular standpoint, the unsuccessful outcome of anti-EGFR therapy is
    mainly related to the emergence of mutations in the EGFR-RAS pathway.20,24
    In addition to EGFR blockade, we previously demonstrated in preclinical models that amplification of ERBB2 (encoding the hu-man epidermal growth factor receptor 2 [HER2] tyrosine kinase receptor) is an effective therapeutic target in cetuximab-resistant tumors.25 Based on these observations, HER2 Amplification for Colo-rectaL cancer Enhanced Stratification (HERACLES), a phase