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

Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and platelet‑derived growth factor receptor A (PDGFRA). Imatinib, sunitinib and regorafenib are all effective tyrosine kinase inhibitors; however, acquired resistance is inevitable. The E26 variant 1 (ETV1) pathway has been found to be a key downstream effector of KIT and is therefore a reasonable therapeutic target for this disease. In this study, we explored the potential agents targeting ETV1 in GISTs by uploading an ETV1 knockout gene signature of GIST cell lines to the pattern‑matching software 'Connectivity Map'. The activity and mechanisms of identified agents were examined using an in vitro model. Four drugs were identified: Suberanilohydroxamic acid and trichostatin [two histone deacetylase inhibitors (HDACIs)] and trifluoperazine and thioridazine (two phenothiazine‑class drugs). Western blot analysis demonstrated that all four drugs had ETV1‑downregulating effects. As HDACIs have been previously studied in GISTs, we focused on phenothiazine. Phenothiazine was found to exert cytotoxicity and to induce apoptosis and autophagy in GISTs. Treatment with phenothiazine had little effect on the KIT/AKT/mammalian target of rapamycin (mTOR) pathway, but instead upregulated extracellular‑signal‑regulated kinase (ERK) activity. A combination of phenothiazine and a MEK inhibitor had a synergistic cytotoxic effect on GISTs. Western blot analysis indicated that ELK1 and early growth response 1 (EGR1) were activated/upregulated following phenothiazine treatment, and the MEK inhibitor/phenothiazine combination downregulated the ERK/ELK1/EGR1 pathway, resulting in diminished autophagy, as well as enhanced apoptosis. On the whole, the findings of this study established phenothiazine as a novel class of therapeutic agents in GIST treatment and demonstrate that a combination of phenothiazine and MEK inhibitor has great potential for use in the treatment of GISTs.

/pdf/identification-of-phenothiazine-as-an-etv1-targeting-agent-3dv29c2b6l.pdf

Identification of phenothiazine as an ETV1‑targeting agent in gastrointestinal stromal tumors using the Connectivity Map.

The sarcomas, particularly those of soft-tissue origin, pose substantial diagnostic challenges for the clinician and pathologist. Several small round cell sarcomas, including Ewing's sarcoma, peripheral primitive neuroectodermal tumor, and alveolar rhabdomyosarcoma, can be difficult to distinguish from one another. These same sarcomas can be difficult to distinguish from other small round cell tumors, including non-Hodgkin's lymphoma and neuroblastoma. Spindle cell sarcomas, including malignant peripheral nerve sheath tumor, synovial sarcoma, and leiomyosarcoma, present similar diagnostic challenges. This review discusses 1) recent advances in immunohistochemistry, electron microscopy, and cytogenetics that enable a specific diagnosis in virtually all sarcoma cases; 2) cell biology and oncogenetic implications of novel morphologic and genetic findings in sarcomas; and 3) clinical implications of the recent characterization of several family cancer syndrome genes.

Laboratory investigation, genetics, and experimental models in sarcomas.

The Histologic Features of Endometrial Stromal Sarcomas Characterized by YWHAE Rearrangement - Distinction from Usual Low-Grade Endometrial Stromal Sarcoma with JAZF1 Rearrangement

Most pathologists now are aware that the overwhelming majority of gastrointestinal stromal tumors (GISTs), as currently defined, express KIT (CD117), that this expression most often is accompanied by a KIT-activating mutation, and that these formerly untreatable neoplasms now can be very effectively palliated in around 70% of cases by treatment with Gleevec (STI-571, Novartis Pharmaceuticals, East Hanover, NJ), which binds directly to the transmembrane KIT tyrosine kinase receptor. This remarkable “bench-to-bedside” story, which has evolved rapidly over the past 4 years, is a truly impressive model of how molecular medicine can substantially affect the classification and the treatment of human disease. However, there is a potential blot on this “blue sky” horizon. Because, in most cases, one of the key criteria for a GIST to be treated with Gleevec is immunohistochemical positivity for KIT, the Food and Drug Administration (FDA) is considering (and perhaps favoring) the requirement that a standardized immunohistochemical test for KIT be introduced. Positivity using this standardized test would be required to be eligible for drug treatment. The justification for this requirement is based on the belief that FDA approval of 1 immunohistochemical assay (or perhaps more) would be helpful for identifying patients whose GIST will respond to Gleevec. The FDA-approved KIT assay, one assumes, would be regarded as a “black and white” test, more comparable to a clinical laboratory test, which theoretically would not be susceptible to variation or pathologist subjectivity. This, despite the facts that any immunostain can be meaningfully assessed only in the context of skilled but, to some extent, subjective interpretation of the HE • That some GISTs express substantial amounts of plateletderived growth factor receptor alpha and other receptor tyrosine kinases that might serve as concurrent or alternative Gleevec targets, yet not be detected by KIT immunostaining; • That small numbers of other tumor types (eg, angiosarcoma and Ewing sarcoma) may be positive for KIT, yet show

Testing for KIT (CD117) in gastrointestinal stromal tumors: another HercepTest?

The histologic features of endometrial stromal sarcomas characterized by YWHAE rearrangement – distinction from usual low-grade endometrial stromal sarcoma with JAZF1 rearrangement

Jonathan A. Fletcher

Papers

Identification of phenothiazine as an ETV1‑targeting agent in gastrointestinal stromal tumors using the Connectivity Map.

Laboratory investigation, genetics, and experimental models in sarcomas.

The Histologic Features of Endometrial Stromal Sarcomas Characterized by YWHAE Rearrangement - Distinction from Usual Low-Grade Endometrial Stromal Sarcoma with JAZF1 Rearrangement

Testing for KIT (CD117) in gastrointestinal stromal tumors: another HercepTest?

The histologic features of endometrial stromal sarcomas characterized by YWHAE rearrangement – distinction from usual low-grade endometrial stromal sarcoma with JAZF1 rearrangement