Clinical Utility of Molecular Profiling in Recurrent Glioblastoma Multiforme

Introduction: Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor found in adults. GBM has limited therapeutic options. Initial tumor sampling establishes the histopathologic diagnosis, identifies prognostic and therapeutic biomarkers, and provides an opportunity for molecular profiling. By contrast, the utility of repeat tumor sampling and molecular profiling in recurrent GBM is not well established. Clinical Findings: We present a 69-year-old woman with GBM whose tumor recurred after standard treatment with temozolomide (TMZ) and concurrent radiation, followed by adjuvant TMZ. This patient had a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter, which ordinarily predicts a favorable response to TMZ. Main Diagnosis, Therapeutic Interventions, and Outcomes: Our patient’s recurrent tumor was rechallenged with TMZ based on persistent methylation of the MGMT promoter. However, her tumor was refractory to TMZ, and she floridly progressed through multiple treatments. We performed retrospective molecular profiling using next-generation sequencing (NGS) on her recurrent tumor. The NGS results showed a TMZ hypermutation signature that confers resistance to TMZ. This signature impacted our patient’s treatment plan in real time and prompted an immediate discontinuation of TMZ. Conclusions: Advances in NGS provide further insight into the molecular landscape of GBM. As NGS becomes more timely and cost-effective, molecular profiling of recurrent tumors could impact treatment decisions through either avoiding a particular treatment paradigm or identifying a potential targetable mutation. For this reason, we suggest that clinical practice routinely consider repeat biopsy and molecular profiling for recurrent GBM

Technical and Regulatory Considerations for Taking Liquid Biopsy to the Clinic: Validation of the JAX PlasmaMonitor

The standard of care in oncology has been genomic profiling of tumor tissue biopsies for the treatment and management of disease, which can prove to be quite challenging in terms of cost, invasiveness of procedure, and potential risk for the patient. As the number of available drugs in oncology continues to increase, so too does the demand for technologies and testing applications that can identify genomic alterations targetable by these new therapies. Liquid biopsies that use a blood draw from the diseased patient may offset the many disadvantages of the invasive procedure. However, as with any new technology or finding in the clinical field, the clinical utility of an analytical test such as that of the liquid biopsy has to be established. Here, we review the clinical testing space for liquid biopsy offerings and elucidate the technical and regulatory considerations to develop such an assay, using our recently validated PlasmaMonito

Genomic Profiling of Two Histologically Distinct Rare Urothelial Cancers in a Clinical Setting to Identify Potential Therapeutic Options for Treatment and Management of Disease.

Molecular profiling of urothelial cancers for therapeutic and prognostic potential has been very limited due to the absence of cancer-specific targeted therapies. We describe here 2 clinical cases with a histological diagnosis of an invasive sarcomatoid and a poorly differentiated carcinoma favoring urothelial with some neuroendocrine differentiation, two of the rarer types of urothelial cancers, which were evaluated for mutations in 212 genes for single-nucleotide variants and copy-number variants and 53 genes for fusions associated with solid tumors. In both cases, we identified variants in 2 genes, Case Rep Oncol 2018 Mar 27; 11(1):196-205

Poirier-Bienvenu neurodevelopmental syndrome: A report of a patient with a pathogenic variant in CSNK2B with abnormal linear growth

Casein kinase 2-related disorders have been linked to pathogenic variants in CSNK2A1 and CSNK2B. CSNK2B-related disease is predominantly associated with neurodevelopmental abnormalities affecting cognition; however, the extent of the phenotype associated with CSNK2B pathogenic variants is yet to be fully explored. Here, we describe a patient with features suggestive of Poirier-Bienvenu neurodevelopmental syndrome, harboring a novel CSNK2B pathogenic variant. We also report that the linear growth abnormalities could be a recurrent presentation in patients with this syndrome and suggest the effect of growth hormone therapy in our patient's stature

Evaluating gene fusions in solid tumors - clinical experience using an RNA based 53 gene next-generation sequencing panel.

Given the known association of gene fusions with solid tumor morbidity and the need to clarify the role of fusions in therapeutic, prognostic and diagnostic outcomes, we reviewed the positive yield rate for fusions in solid tumors using cases that were referred to our laboratory for clinical testing. We retrospectively evaluated results from 183 solid tumor samples that were received during a 24 month period for testing using the FusionSeq™ assay, an RNA-based Next Generation Sequencing (NGS) panel of 53 genes known to form fusions in solid tumors. Positive yield rate (actionable fusions) was evaluated for all samples tested, as a correlate for clinical utility. Twenty five fusions (actionable, variants of uncertain significance – VUS, and benign) were identified, of which 7 were classified as actionable gene fusions, resulting in an overall positive yield rate of ∼3.8% (7/183). Sixteen mostly novel fusions were classified and reported as VUSs. Five fusion events were classified as false positives, occurring due to mispriming or wild-type read through while 2 were classified as likely benign. Additionally 68% of fusions (17 of 25) detected in our study were present in prostate, colorectal, and gynecological cancers, suggesting that the frequency of fusions identified is dependent on specific tumor type. The high number of novel fusions identified highlights the potential for fusions in precision medicine

Molecular Modeling and Phenotypic Description of a Patient with a Novel Exonic Deletion of GALNS with Resultant Morquio Syndrome with Two Successful Pregnancies

In this report, we describe phenotypic features of a patient with mucopolysaccharidosis type IVA (Morquio syndrome) harboring a novel exon 1 deletion in GALNS with enzymatic confirmation consistent with Morquio syndrome. To our knowledge, this is the first reported case of this variant. Additionally, we protein modelled wild-type GALNS and the pathogenic variant with an exon 1 deletion for comparative analysis using statistical mechanics methods described herein. We demonstrate that, even when the protein is translated, the mutation would affect protein stability and function via homodimer interaction modifications. Lastly, given the patient's 2 successful pregnancies, data about the management of pregnancies in mucopolysaccharidoses are reviewed, and we discuss the management of pregnancy in patients with Morquio syndrome

Technical and Regulatory Considerations for Taking Liquid Biopsy to the Clinic: Validation of the JAX PlasmaMonitor Assay

The standard of care in oncology has been genomic profiling of tumor tissue biopsies for the treatment and management of disease, which can prove to be quite challenging in terms of cost, invasiveness of procedure, and potential risk for the patient. As the number of available drugs in oncology continues to increase, so too does the demand for technologies and testing applications that can identify genomic alterations targetable by these new therapies. Liquid biopsies that use a blood draw from the diseased patient may offset the many disadvantages of the invasive procedure. However, as with any new technology or finding in the clinical field, the clinical utility of an analytical test such as that of the liquid biopsy has to be established. Here, we review the clinical testing space for liquid biopsy offerings and elucidate the technical and regulatory considerations to develop such an assay, using our recently validated PlasmaMonitor TM test