Dataset Information

Detection of Targetable Genetic Alterations in Korean Lung Cancer Patients: A Comparison Study of Single-Gene Assays and Targeted Next-Generation Sequencing.

ABSTRACT: PURPOSE:Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) are 'must-test' biomarkers in the molecular diagnostics of advanced-stage lung cancer patients. Although single-gene assays are currently considered the gold standard for these genes, next-generation sequencing (NGS) tests are being introduced to clinical practices. We compared the results of current diagnostics and aimed to suggest timely effective guidance for their clinical use. MATERIALS AND METHODS:Patients with lung cancer who received both conventional single-gene assays and subsequent targeted NGS testing were enrolled, and the results of their tests were compared. RESULTS:A total of 241 patients were enrolled, and the EGFR real-time polymerase chain reaction, ALK fluorescence in situ hybridization (FISH), and ROS1 FISH assays exhibited 92.9%, 99.6%, and 99.5% concordance with the NGS tests, respectively. The discordant cases were mostly false-negatives of the single-gene assays, probably due to technical limitation. Of 158 cases previously designated as wild-type, EGFR, ALK, and ROS1 alterations were identified in 10.1%, 1.9%, and 1.3%, respectively, and other targetable alterations were identified in 36.1% of the cases. Of patients with additionally identified actionable alterations, 32.6% (31/95) received matched therapy with a clinical benefit of 48.4% (15/31). CONCLUSION:Even though the conventional and NGS methods were concordant in the majority of cases, NGS testing still revealed a considerable number of additional EGFR, ALK, and ROS1 alterations, as well as other targetable alterations, in Korean advanced-stage lung cancer patients. Given the high frequency of EGFR and other targetable mutations identified in the present study, NGS testing is highly recommended in the diagnosis of Korean lung cancer patients.

SUBMITTER: Park E

PROVIDER: S-EPMC7176968 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Detection of Targetable Genetic Alterations in Korean Lung Cancer Patients: A Comparison Study of Single-Gene Assays and Targeted Next-Generation Sequencing.

Park Eunhyang E Shim Hyo Sup HS

Cancer research and treatment 20191108 2

<h4>Purpose</h4>Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) are 'must-test' biomarkers in the molecular diagnostics of advanced-stage lung cancer patients. Although single-gene assays are currently considered the gold standard for these genes, next-generation sequencing (NGS) tests are being introduced to clinical practices. We compared the results of current diagnostics and aimed to suggest timely effective guidance for their clinic ...[more]

PMID: 31726498

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Project description:The aim of this study was to assess the frequency of potentially actionable genomic alterations in breast cancer that could be targeted with approved agents or investigational drugs in clinical trials using a next-generation sequencing-based genomic profiling assay performed in a Clinical Laboratory Improvement Amendments-certified and College of American Pathologists-accredited commercial laboratory. Methods. Fifty-one breast cancers were analyzed, including primary tumor biopsies of 33 stage I-II and 18 stage IV cancers (13 soft tissue, 3 liver, and 2 bone metastases). We assessed 3,230 exons in 182 cancer-related genes and 37 introns in 14 genes often rearranged in cancer for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 1,154×. Results. We observed 158 genomic alterations in 55 genes in 48 of 51 (94%) tumors (mean 3.1, range 0-9). The average number of potentially therapeutically relevant alterations was similar in primary (1.6, range 0-4) and in heavily pretreated metastatic cancers (2.0, range 0-4) (p = .24). The most common actionable alterations were in PIK3CA (n = 9, phosphatidylinositol 3-kinase [PI3K]/mammalian target of rapamycin [mTOR] inhibitors), NF1 (n = 7, PI3K/mTOR/mitogen-activated protein kinase inhibitors), v-akt murine thymoma viral oncogene homolog 1-3 (n = 7, PI3K/mTOR/AKT inhibitors), BRCA1/2 (n = 6, poly[ADP-ribose] polymerase inhibitors), and CCND1,2 and CCNE (n = 8)/cycline dependent kinase (CDK)6 (n = 1) (CDK4/6 inhibitors), KIT (n = 1, imatinib/sunitinib), ALK (n = 1, crizotinib), FGFR1,2 (n = 5, fibroblast growth factor receptor inhibitors), and EGFR (n = 2, epidermal growth factor receptor inhibitors). Our sequencing assay also correctly identified all six cases with HER2 (ERBB2) amplification by fluorescence in situ hybridization when tumor content was adequate. In addition, two known activating HER2 mutations were identified, both in unamplified cases. Conclusion. Overall, 84% of cancers harbored at least one genomic alteration linked to potential treatment options. Systematic evaluation of the predictive value of these genomic alterations is critically important for further progress in this field.

Project description:Background: Differential diagnosis of developmental delay (DD) and/or intellectual disability (ID) is challenging because of the diversity of phenotypic manifestations as DD/ID patients usually have combined congenital malformations, autism-spectrum disorders, and/or seizure disorder. Thus, unbiased genomic approaches are needed to discover genetic alterations leading to DD and/or ID. Objective: The aim of this study was to investigate the clinical usefulness of targeted next-generation sequencing (NGS) to investigate genetic causes in 35 Korean patients with unexplained DD/ID. Methods: Targeted next-generation sequencing (NGS) using the TruSight One Panel was analyzed in 35 patients with unexplained DD/ID. Sanger sequencing was used to confirm candidate variants, and to define genetic inheritance mode of candidate variant as familial segregation testing. Results: Of 35 patients with DD and/or ID, 10 were found to have underlying genetic etiology and carried X-linked recessive inheritance of ZDHHC9 or autosomal dominant inheritance of SMARCB1, CHD8, LAMA5, NSD1, PAX6, CACNA1H, MBD5, FOXP1, or KCNK18 mutations. No autosomal recessive inherited mutation was identified in this study. As a result, the diagnostic yield of DD/ID by targeted NGS was 29% (10/35), mostly involving may be de novo mutation present in the proband only. A total of seven may be de novo mutations, one paternally inherited, and one maternally inherited mutations that had been reported previously to concede the genetic pathogenesis as known DD and/or ID genes were found in nine patients with available inheritance pattern except LAMA5. Mutations in nine causative genes were detected in patients with similar DD/ID phenotypes in the OMIM database, providing support for genetic evidence as the cause of DD and/or ID. Conclusion: Targeted NGS through singleton analysis with phenotype-first approaches was able to explain 10 out of 35 DD/ID cases. However, the excavation of plausible genetic causes may be de novo, and X-linked disease-causative variants in DD/ID-associated genes requires further genetic analysis.

Dataset Information

Detection of Targetable Genetic Alterations in Korean Lung Cancer Patients: A Comparison Study of Single-Gene Assays and Targeted Next-Generation Sequencing.

Publications

Detection of Targetable Genetic Alterations in Korean Lung Cancer Patients: A Comparison Study of Single-Gene Assays and Targeted Next-Generation Sequencing.

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