Identification of<i>BRAF</i>Kinase Domain Duplications Across Multiple Tumor Types and Response to RAF Inhibitor Therapy

Klempner, Samuel J.; Bordoni, Rodolfo; Gowen, Kyle; Kaplan, Henry G.; Stephens, Philip J.; Ou, Sai‐Hong Ignatius; Ali, Siraj M.

doi:10.1001/jamaoncol.2015.4437

Cited by 16 publications

(14 citation statements)

References 6 publications

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“…In fact, BRAF‐KDDs have also been reported in gliomas . More recently, the analysis of 50,000 samples spanning multiple tumor types found that BRAF‐KDDs comprised 0.5% of all BRAF alterations identified . Additionally, KDD events were identified in other genes, including MET, FGFR1, FGFR3, RET, ERBB2, ALK , and NTRK in different types of tumors as potential driver mutations .…”

Section: Discussionmentioning

confidence: 99%

“…14 More recently, the analysis of 50,000 samples spanning multiple tumor types found that BRAF-KDDs comprised 0.5% of all BRAF alterations identified. 15 Additionally, KDD events were identified in other genes, including MET, FGFR1, FGFR3, RET, ERBB2, ALK, and NTRK in different types of tumors as potential driver mutations. 16 It is therefore important to increase the panel coverage of intronic regions of such kinases for comprehensive NGS analyses in the future.…”

Section: Discussionmentioning

confidence: 99%

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Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

Wang

Xue³

et al. 2018

Intl Journal of Cancer

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Kinase domain duplications of the epidermal growth factor receptor (EGFR‐KDD) have been identified and implicated to be oncogenic in nonsmall cell lung cancers (NSCLCs). However, its prevalence and clinical contributions in lung cancer are largely unknown. Here, we conducted a multicenter record review of 10,759 NSCLC patients who underwent genetic testing using next‐generation sequencing (NGS) targeting EGFR exons and the introns involved in EGFR‐KDD rearrangements. EGFR‐KDDs were identified in a total of 13 patients, which is approximately 0.12% of the total population reviewed, and also consisted of 0.24% (13/5394) of EGFR mutation‐positive patients. A total of 85% of patients (11/13) were identified with the canonical EGFR‐KDD duplication of exons 18–25, while the remaining two cases harbored duplications of EGFR exons 14–26 and exons 17–25, which have not been previously described. Importantly, none of the 13 patients had other coexisting driver mutations, highlighting the potential oncogenic role of this type of alteration. Three out of five patients who had exon 18–25 duplications showed partial antitumor responses to targeted therapies, while the other two patients demonstrated no clinical improvement. Furthermore, our data suggested that the EGFR T790 M mutation and EGFR amplification may represent the major resistance mechanisms against targeted therapies in tumors bearing EGFR‐KDD. In summary, our findings provide valuable insight into the prevalence of EGFR‐KDDs in NSCLCs and their clinical outcomes to targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

Wang

Xue³

et al. 2018

Intl Journal of Cancer

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“…This study identified other noteworthy genomic targets in a wide range of SGCs. For instance, though BRAF mutations were not common in this study, they did tend to be activating and one AciCC patient with a BRAF gene fusion responded to a multikinase inhibitor targeting BRAF [ 21 ]. The BRAF GA rate in this study (2.7%) was similar to the 2% observed in COSMIC, though the rate reported here is a little lower than that reported in another SDC study [ 12 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies

Ross

Wang

Vergilio³

et al. 2017

Annals of Oncology

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BackgroundRelapsed/metastatic salivary gland carcinomas (SGCs) have a wide diversity of histologic subtypes associated with variable clinical aggressiveness and response to local and systemic therapies. We queried whether comprehensive genomic profiling could define the tumor subtypes and uncover clinically relevant genomic alterations, revealing new routes to targeted therapies for patients with relapsed and metastatic disease.Patients and methodsFrom a series of 85 686 clinical cases, DNA was extracted from 40 µm of formalin-fixed paraffin embedded (FFPE) sections for 623 consecutive SGC. CGP was carried out on hybridization-captured, adaptor ligation-based libraries (mean coverage depth, >500×) for up to 315 cancer-related genes. Tumor mutational burden was determined on 1.1 Mb of sequenced DNA. All classes of alterations, base substitutions, short insertions/deletions, copy number changes, and rearrangements/fusions were determined simultaneously.ResultsThe clinically more indolent SGC including adenoid cystic carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma, mammary analog secretory carcinoma, and epithelial–myoepithelial carcinomas have significantly fewer genomic alterations, TP53 mutations, and lower tumor mutational burden than the typically more aggressive SGCs including mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified, carcinoma NOS, and carcinoma ex pleomorphic adenoma. The more aggressive SGCs are commonly driven by ERBB2 PI3K pathway genomic alterations. Additional targetable GAs are frequently seen.ConclusionsGenomic profiling of SGCs demonstrates important differences between traditionally indolent and aggressive cancers. These differences may provide therapeutic options in the future.

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“…We also found that EGFR -KDD occurred in other types of human tumors, including gliomas, sarcoma and Wilms’ tumor [ 143 ]. BRAF -KDD has been reported in gliomas and advanced acinic cell tumor [ 144 , 145 ]. BRAF is an intracellular serine/threonine kinase; however, we discuss here as demonstration of principle.…”

Section: Oncogenic Activation Of Receptor Tyrosine Kinasesmentioning

confidence: 99%

Mechanisms of receptor tyrosine kinase activation in cancer

2018

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Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.

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Identification ofBRAFKinase Domain Duplications Across Multiple Tumor Types and Response to RAF Inhibitor Therapy

Cited by 16 publications

References 6 publications

Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies

Mechanisms of receptor tyrosine kinase activation in cancer

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