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
Source: PubMed


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). "
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    • "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 [8] [9]. 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. "
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