WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

BACKGROUND Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

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Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

Recent advances in sequencing technology make it possible to comprehensively catalogue genetic variation in population samples, creating a foundation for understanding human disease, ancestry and evolution. The amounts of raw data produced are prodigious and many computational steps are required to translate this output into high-quality variant calls. We present a unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs. Our process includes (1) initial read mapping; (2) local realignment around indels; (3) base quality score recalibration; (4) SNP discovery and genotyping to find all potential variants; and (5) machine learning to separate true segregating variation from machine artifacts common to next-generation sequencing technologies. We discuss the application of these tools, instantiated in the Genome Analysis Toolkit (GATK), to deep whole-genome, whole-exome capture, and multi-sample low-pass (~4×) 1000 Genomes Project datasets.

/pdf/a-framework-for-variation-discovery-and-genotyping-using-1mhes6klgp.pdf

A framework for variation discovery and genotyping using next-generation DNA sequencing data

Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or

https://science.sciencemag.org/content/sci/early/2004/04/29/science.1099314.full.pdf

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

World Health Organization Classification of Tumours

Laboratory investigation and genetics in sarcomas.

1417pdphase 2 study of ponatinib in patients (pts) with advanced gastrointestinal stromal tumors (gist) after failure of tyrosine kinase inhibitor (tki) therapy: early results

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. Activating mutations in KIT or PDGFRA receptor tyrosine kinases (RTKs) are central to GIST biology and drive GIST growth and progression [1]. This oncogenic addiction to KIT/PDGFRA signaling explains the profound impact of their inhibition with first-line imatinib on metastatic GIST patients’ outcomes [2]. However, disease progression eventually occurs in approximately two years after treatment initiation largely due to the polyclonal emergence of resistant subpopulations harboring different KIT secondary mutations [3]. Resistance mutations are not random and cluster in two regions of the KIT kinase domain: the ATP binding pocket (encoded by exons 13 and 14) and the activation loop (encoded by exons 17 and 18). Thus, KIT reactivation due to secondary resistance mutations in KIT underscores the prominent role of KIT as the disease driver and firmly supports therapeutic strategies aiming to suppress KIT signaling after imatinib failure. Consequently, drug development in imatinibresistant GIST during the past decade focused on tyrosine kinase inhibitors (TKIs) targeting a broader spectrum of KIT-mutant oncoproteins, and sunitinib (second-line) and more recently regorafenib (third-line) were granted with worldwide approval [4, 5]. Of note, sunitinib and regorafenib, although effective, display a modest activity, with a median progression free survival between four to six months. Several other TKIs with KIT inhibitory activity have been or are currently being studied in phase I to phase III clinical trials showing similar efficacy irrespective of the single-agent TKI used [6]. In a recent publication [7], we demonstrated that the molecular basis for the limited clinical benefit observed with successive lines of treatment in imatinib-resistant GIST roots in their drug-specific activity profile against a subset of the KIT secondary mutational spectrum. Importantly, KIT primary genotype predicts the efficacy of imatinib in TKI-naïve GIST, and KIT secondary genotype to sunitinib. Our studies in human GIST cell lines and transfected models showed that KIT secondary genotype predicted the activity of third-line regorafenib, displaying KIT oncogenic signaling suppression among most activation-loop mutants. Specifically, regorafenib effectively inhibited, to a greater or lesser extent, resistant secondary mutations emerging in KIT codons D820, N822, Y823, several in D816 (i.e.: D816E, D816H) except for D816V, and likely A829P. KIT exon 14 T670I gatekeeper mutation was also suppressed by regorafenib, but not KIT exon 13 V654A resistance mutation, the most common secondary mutation present at the onset of imatinib failure. These results were further corroborated in biopsies from GIST patients treated with regorafenib in the phase II trial, underscoring V654A mutation as the main vulnerability for regorafenib treatment. Remarkably, we found that all TKIs, either approved or investigated in clinical trials, had activity profiles targeting only a subset of KIT secondary mutations (Figure 1). Therefore, disease progression occurs earlier after imatinib failure Editorial

/pdf/overcoming-heterogenity-in-imatinib-resistant-4napho957h.pdf

Overcoming heterogenity in imatinib-resistant gastrointestinal stromal tumor.

This disclosure provides tyrosine kinase protein and nucleic acid variants, particularly PDGFRA variants, which are activating forms of these molecules and are linked to neoplasms and/or the development or progression of cancer. The disclosure further provides methods of diagnosis and prognosis, and development of new therapeutic agents using these molecules and fragments thereof, and kits for employing these methods and compositions.

Activating mutations of platelet derived growth factor receptor alpha (pdgfra) as diagnostic markers and therapeutic targets

10008 Background: 85% of GISTs in children are wildtype, lacking activating mutations in KIT or PDGFRA. The Carney-Stratakis Syndrome is an inherited predisposition to GIST and paraganglioma, cause...

Jonathan A. Fletcher

Papers

Laboratory investigation and genetics in sarcomas.

1417pdphase 2 study of ponatinib in patients (pts) with advanced gastrointestinal stromal tumors (gist) after failure of tyrosine kinase inhibitor (tki) therapy: early results

Overcoming heterogenity in imatinib-resistant gastrointestinal stromal tumor.

Activating mutations of platelet derived growth factor receptor alpha (pdgfra) as diagnostic markers and therapeutic targets

Succinate dehydrogenase in KIT/PDGFRA wild-type gastrointestinal stromal tumors.