Development of Personalized Tumor Biomarkers Using Massively Parallel Sequencing
Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.Science translational medicine (Impact Factor: 15.84). 02/2010; 2(20):20ra14. DOI: 10.1126/scitranslmed.3000702
Clinical management of human cancer is dependent on the accurate monitoring of residual and recurrent tumors. The evaluation of patient-specific translocations in leukemias and lymphomas has revolutionized diagnostics for these diseases. We have developed a method, called personalized analysis of rearranged ends (PARE), which can identify translocations in solid tumors. Analysis of four colorectal and two breast cancers with massively parallel sequencing revealed an average of nine rearranged sequences (range, 4 to 15) per tumor. Polymerase chain reaction with primers spanning the breakpoints was able to detect mutant DNA molecules present at levels lower than 0.001% and readily identified mutated circulating DNA in patient plasma samples. This approach provides an exquisitely sensitive and broadly applicable approach for the development of personalized biomarkers to enhance the clinical management of cancer patients.
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- "A specific biomarker of disease burden are mutations which have previously been identified in the primary tumor,.molonc.2015.12.004and several studies have focused on the detection of such specific and predetermined mutations in corresponding peripheral blood from the same patient (Diehl et al., 2005Diehl et al., , 2008aDiehl et al., , 2008bLeary et al., 2010;McBride et al., 2010;Nawroz et al., 1996;Yung et al., 2009). Tumor-specific structural chromosomal rearrangements, i.e. breakpoints, identified by wholegenome sequencing of primary tumors, which are then subsequently used to monitor in plasma of the respective patients minimal residual disease (MRD) by high-sensitive PCR approaches have a particularly high specificity (Leary et al., 2010;McBride et al., 2010;Olsson et al., 2015). Various approaches for the non-invasive identification of somatic mutations in blood at high resolution have been developed (Bettegowda et al., 2014;Dawson et al., 2013;Forshew et al., 2012;Misale et al., 2012;Murtaza et al., 2013;Newman et al., 2014;Thierry et al., 2014). "
ABSTRACT: Liquid biopsies, i.e. the analysis of circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA), are evolving into promising clinical tools. Indeed, a plethora of liquid biopsy technologies to deduce non-invasively characteristics of the tumor genome from the peripheral blood have been developed over the last few years. For example, liquid biopsies have been used to assess the tumor burden, to monitor the evolution of tumor genomes, to unravel mechanisms of resistance, to establish the tumor heterogeneity, and for the identification of prognostic and predictive markers. In this review we focus on methods to establish genome-wide profiles of somatic copy number alterations (SCNAs) from plasma DNA and show how they provide novel insights into the biology of cancer and their impact on the management of patients.
- "In some instances, structural variants present only in a patient's tumor and detected by massively parallel sequencing have provided an opportunity to generate highly specific, personalized tumor markers enabling monitoring of patients throughout their disease course  . We report the case of a 59-year-old female who was originally diagnosed and treated for stage III ovarian cancer and highlight the use of genomic technologies to deliver a tool for more accurate disease surveillance and, concurrently , identification of a candidate therapy. "
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- "Boston-based FM offers the Foundation One panel that reports on the mutational status of 285 genes that are found to be commonly mutated in cancers; it has also recently announced a similar panel for hematological malignancies (46). PGD, based out of Baltimore, offers a clinical targeted cancer gene panel cancer select for the detection of genetic alterations in 120 well-characterized cancer and pharmacogenomics genes (47). These companies thus offer an alternative to local laboratory testing for clinical trials. "
ABSTRACT: Over the past decade, next-generation sequencing (NGS) technology has experienced meteoric growth in the aspects of platform, technology, and supporting bioinformatics development allowing its widespread and rapid uptake in research settings. More recently, NGS-based genomic data have been exploited to better understand disease development and patient characteristics that influence response to a given therapeutic intervention. Cancer, as a disease characterized by and driven by the tumor genetic landscape, is particularly amenable to NGS-based diagnostic (Dx) approaches. NGS-based technologies are particularly well suited to studying cancer disease development, progression and emergence of resistance, all key factors in the development of next-generation cancer Dxs. Yet, to achieve the promise of NGS-based patient treatment, drug developers will need to overcome a number of operational, technical, regulatory, and strategic challenges. Here, we provide a succinct overview of the state of the clinical NGS field in terms of the available clinically targeted platforms and sequencing technologies. We discuss the various operational and practical aspects of clinical NGS testing that will facilitate or limit the uptake of such assays in routine clinical care. We examine the current strategies for analytical validation and Food and Drug Administration (FDA)-approval of NGS-based assays and ongoing efforts to standardize clinical NGS and build quality control standards for the same. The rapidly evolving companion diagnostic (CDx) landscape for NGS-based assays will be reviewed, highlighting the key areas of concern and suggesting strategies to mitigate risk. The review will conclude with a series of strategic questions that face drug developers and a discussion of the likely future course of NGS-based CDx development efforts.