High-throughput oncogene mutation profiling in human cancer.

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.

Noninvasive risk stratification for sudden death in asymptomatic patients with Wolff-Parkinson-White syndrome.

Sudden cardiac death (SCD) as the first clinical manifestation of Wolff-Parkinson-White (WPW) syndrome is a well-documented, although rare occurrence. The incidence of SCD in patients with WPW ranges from 0% to 0.39% annually. Controversy exists regarding risk stratification for patients with preexcitation on surface electrocardiogram (ECG), particularly in those who are asymptomatic. This article focuses on the role of risk stratification using exercise and pharmacologic testing in patients with WPW pattern on ECG.

Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.

Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.

Enhanced electrocardiographic monitoring of patients with Coronavirus Disease 2019.

Background: Many of the drugs being used in the treatment of the ongoing pandemic coronavirus disease 2019 (COVID-19) are associated with QT prolongation. Expert guidance supports electrocardiographic (ECG) monitoring to optimize patient safety. Objective: The purpose of this study was to establish an enhanced process for ECG monitoring of patients being treated for COVID-19. Methods: We created a Situation Background Assessment Recommendation tool identifying the indication for ECGs in patients with COVID-19 and tagged these ECGs to ensure prompt over reading and identification of those with QT prolongation (corrected QT interval > 470 ms for QRS duration ≤ 120 ms; corrected QT interval > 500 ms for QRS duration > 120 ms). This triggered a phone call from the electrophysiology service to the primary team to provide management guidance and a formal consultation if requested. Results: During a 2-week period, we reviewed 2006 ECGs, corresponding to 524 unique patients, of whom 103 (19.7%) met the Situation Background Assessment Recommendation tool-defined criteria for QT prolongation. Compared with those without QT prolongation, these patients were more often in the intensive care unit (60 [58.3%] vs 149 [35.4%]) and more likely to be intubated (32 [31.1%] vs 76 [18.1%]). Fifty patients with QT prolongation (48.5%) had electrolyte abnormalities, 98 (95.1%) were on COVID-19-related QT-prolonging medications, and 62 (60.2%) were on 1-4 additional non-COVID-19-related QT-prolonging drugs. Electrophysiology recommendations were given to limit modifiable risk factors. No patient developed torsades de pointes. Conclusion: This process functioned efficiently, identified a high percentage of patients with QT prolongation, and led to relevant interventions. Arrhythmias were rare. No patient developed torsades de pointes.

Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.