Development and clinical application of an integrative genomic approach to personalized cancer therapy

Abstract

BackgroundPersonalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics.MethodsWe developed a personalized cancer therapy (PCT) program in a clinical setting, using an integrative genomics approach to fully characterize the complexity of each tumor. We carried out whole exome sequencing (WES) and single-nucleotide polymorphism (SNP) microarray genotyping on DNA from tumor and patient-matched normal specimens, as well as RNA sequencing (RNA-Seq) on available frozen specimens, to identify somatic (tumor-specific) mutations, copy number alterations (CNAs), gene expression changes, gene fusions, and also germline variants. To provide high sensitivity in known cancer mutation hotspots, Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2) was also employed. We integrated the resulting data with cancer knowledge bases and developed a specific workflow for each cancer type to improve interpretation of genomic data.ResultsWe returned genomics findings to 46 patients and their physicians describing somatic alterations and predicting drug response, toxicity, and prognosis. Mean 17.3 cancer-relevant somatic mutations per patient were identified, 13.3-fold, 6.9-fold, and 4.7-fold more than could have been detected using CHPv2, Oncomine Cancer Panel (OCP), and FoundationOne, respectively. Our approach delineated the underlying genetic drivers at the pathway level and provided meaningful predictions of therapeutic efficacy and toxicity. Actionable alterations were found in 91 % of patients (mean 4.9 per patient, including somatic mutations, copy number alterations, gene expression alterations, and germline variants), a 7.5-fold, 2.0-fold, and 1.9-fold increase over what could have been uncovered by CHPv2, OCP, and FoundationOne, respectively. The findings altered the course of treatment in four cases.ConclusionsThese results show that a comprehensive, integrative genomic approach as outlined above significantly enhanced genomics-based PCT strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0313-0) contains supplementary material, which is available to authorized users.

Genomic profiling reveals mutational landscape in parathyroid carcinomas

“…The genes to be included in the panel were chosen based upon recurrence of mutations in our discovery cohort, biological significance, and/or literature review (Supplemental Table 9). In addition to being a complementary technology to Illumina, Ion AmpliSeq was chosen as the selected sequencing platform for the panel as it can yield sequencing libraries from low-input DNA derived from formalin-fixed, paraffin-embedded (FFPE) samples, has a relatively short turnaround time, and provides ultradeep coverage to detect low allelic fraction variants based on our prior experience (47). As shown in Figure 1B, we screened 10 samples from the WES cohort and an additional 12 tumor samples (no matched normal samples; expansion cohort) using the panel.…”

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

“…Il est probable que près de 300 gènes (sur nos 20.000 gènes) justifient d'une analyse en 2017 pour guider le traitement de nos patients. Certains auteurs considèrent que le séquençage de l'ensemble des exomes (Whole-Exome Sequencing, WES), voire le séquençage de l'ensemble du génome (WGS) seraient plus informatif (12,13), C'est un des objectifs du projet France Médecine Génomique 2025 de répondre à cette question (https://www.aviesan.fr/aviesan/accueil/toute-lactualite/plan-france-medecine-genomique-2025).…”

“…Dans les premières publications de ce programme sur 639 patients 2888 (45 %) présentaient une anomalie (voie PTEN/PI3K/AKT pour 84 patients ; FGFR/FGF pour 46 patients ; KRAS/NRAS/HRAS pour 24 patients ; HER2/EGFR pour 22 et 18 patients respectivement). 141 (22%) patients ont reçu une thérapie personnalisée ou un essai de phase I adapté [13]. Dans le programme ProfiLER du LYRIC (SIRIC de Lyon), plus de 2 490 patients (décembre 2016) ont été inclus, et les inclusions sont toujours en cours.…”

The integration of genomics testing and functional proteomics in the era of personalized medicine

“…The mean number of drug targets per patient might be slightly increased when using an integrative omics approach based on whole-exome sequencing, an singlenucleotide polymorphism (SNP) array, and RNA sequencing compared with other genomics-based approaches [25]. However, further drastic improvements in targeted therapy enrollment rates are mandatory for the advancement of personalized cancer therapies.…”