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  • Kashimura S Saze Z Terashima M Soeta N Ohtani S

    2019-10-07

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    A Genomic Analysis Workflow for Colorectal Cancer Precision Oncology
    Giorgio Corti,1 Alice Bartolini,1 Giovanni Crisafulli,1,2 Luca Novara,1 Giuseppe Rospo,1 Monica Montone,1 Carola Negrino,1 Benedetta Mussolin,1 Michela Buscarino,1 Claudio Isella,1,2 Ludovic Barault,1,2 Giulia Siravegna,1,2 Salvatore Siena,3,4 Silvia Marsoni,4,5 Federica Di Nicolantonio,1,2 Enzo Medico,1,2 Alberto Bardelli1,2
    Abstract
    Accurate diagnosis and precision medicine of colorectal cancer (CRC) rely on patient-specific genomic maps. We present IDEA, an integrated DNA next generation sequencing and bioinformatic approach to determine the molecular landscape of CRC. First, genomic targets are predefined to obtain optimal sensitivity for tissue or blood samples. IDEA then pinpoints genetic variations with predictive and prognostic value, defines actionable targets, and unveils drug resistance mechanisms in patients with metastatic CRC. Results are presented in a final report, which includes clinically relevant information.
    Background: The diagnosis of colorectal cancer (CRC) is routinely accomplished through histopathologic exami-nation. Prognostic information and treatment decisions are mainly determined by TNM classification, first defined in 1968. In the last decade, patient-specific CRC genomic landscapes were shown to provide important prognostic and predictive information. Therefore, there is a need for developing next generation sequencing (NGS) and bioinformatic workflows nerve cord can be routinely used for the assessment of prognostic and predictive biomarkers. Materials and Methods: To foster the application of genomics in the clinical management of CRCs, the IDEA workflow has been built LY3009120 to easily adapt to the availability of patient specimens and the clinical question that is being asked. Initially, IDEA deploys ad-hoc NGS assays to interrogate predefined genomic target sequences (from 600 kb to 30 Mb) with optimal detection sensitivity. Next, sequencing data are processed through an integrated bioinformatic pipeline to assess single nucleotide variants, insertions and deletions, gene copy-number alterations, and chromosomal rearrangements. The overall results are gathered into a user-friendly report. Results: We provide evidence that IDEA is capable of identifying clinically relevant molecular alterations. When optimized to analyze circulating tumor DNA, IDEA can be used to monitor response and relapse in the blood of patients with metastatic CRC receiving targeted agents. IDEA detected primary and secondary resistance mechanisms to ERBB2 blockade including sub-clonal RAS and BRAF mutations. Conclusions: The IDEA workflow provides a flexible platform to integrate NGS and bioinformatic tools for refined diagnosis and management of patients with advanced CRC.