Identification of a Novel Somatic Mutation Leading to Allele Dropout for EGFR L858R Genotyping in Non-Small Cell Lung Ca
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SHORT COMMUNICATION
Identification of a Novel Somatic Mutation Leading to Allele Dropout for EGFR L858R Genotyping in Non-Small Cell Lung Cancer Helio A. Costa1 • Joel W. Neal2 • Carlos D. Bustamante1,3 • James L. Zehnder4
Ó Springer International Publishing Switzerland 2017
Abstract Objective While PCR-based genotyping methods abound in molecular testing for lung cancer therapy, these approaches may not provide the robust sensitivity to detect accurate genotypes in a variable cancer genomic background. Methods Here, we describe a study of a clinical tumor specimen containing a novel somatic single nucleotide variant that caused allele drop-out in EGFR L858R genotyping, resulting in a false-negative interpretation and impacting patient clinical management. Results We demonstrate that a subsequent unbiased nextgeneration sequencing approach correctly identified the driver mutation, and therefore may be more reliable for somatic variant detection. Conclusions These findings magnify the potential pitfalls of PCR amplification-based approaches and stress the importance of unbiased and sensitive molecular testing strategies for therapeutic marker detection as molecular testing becomes the standard for determining clinical management of cancer patients.
& James L. Zehnder [email protected] 1
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
2
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
3
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA
4
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Key Points Correct epidermal growth factor receptor (EGFR) mutation genotyping is critical for the proper therapeutic management of lung cancer patients. This study highlights a major pitfall of a common clinical genotyping methodology that results in a false-negative result for a clinically actionable EGFR mutation. We demonstrate an alternative next-generation sequencing method that is more reliable and robust.
1 Introduction Lung cancer is the leading cause of cancer mortality and accounts for approximately 27% of all cancer deaths in adults in the United States (US) [1]. Further, patients presenting with advanced non-small cell lung cancer (NSCLC) who are left untreated generally have a poor prognosis with a 4- to 5-month median survival time [2]. However, the use of therapeutic agents targeting the epidermal growth factor receptor (EGFR) have dramatically improved the clinical management of the approximately 15% of patients in the US and 50% of patients in Asia with lung adenocarcinomas harboring EGFR mutations. The most common of these mutations are exon 19 deletions and the EGFR L858R mutation. When present, the L858R mutation has been shown to increase patient sensitivity to first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs), leading to longer progression-free
H. A. Costa et al.
survival on TK
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