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.

/pdf/activating-mutations-in-the-epidermal-growth-factor-receptor-4a7r2t8eq0.pdf

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

Short segment acid reflux: Markedly increased acid load on distal oesophagus revealed by novel pH metry

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC

Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with this asbestos-associated disease. The receptor tyrosine kinases EGFR and MET are activated in subsets of mesothelioma, suggesting these kinases might represent novel therapeutic targets. However, clinical trials have not shown activity for EGFR inhibitors in mesothelioma. We had previously demonstrated activation of multiple receptor tyrosine kinases, including EGFR, MET, and AXL, in individual mesothelioma cell lines, targeting HSP90 suppressed the multiple activated RTKs in mesothelioma cell lines, resulting in apo-apoptotic and anti-proliferative effects. Thus, we hypothesized that a coordinated network of multi-RTK activation contributes collectively to activate PI3-K/AKT/mTOR and/or RAF/MAPK signalings for the tumorigenesis of mesothelioma. Herein, we demonstrate abnormal activation of the PI3-K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, as compared with normal mesothelial cells. Multiple receptor tyrosine kinases, including EGFR, MET, and AXL, in individual mesothelioma cell lines, collectively activated survival signaling intermediate AKT, but not MAPK. The anti-proliferative responses of the coordinate inhibition of these multi-kinase signaling were comparable with suppression of PI3-K/AKT/mTOR pathway. Dual targeting AKT/mTOR signaling has substantially greater effect on mesothelioma proliferation and survival, compared to inhibition of individual activated kinases and downstream signaling alone, suggesting that no one activated RTK is the predominant oncogenic control mechanism in mesothelioma and PI3-K/AKT/mTOR is a crucial survival pathway. The AKT/mTOR signaling inhibition by BEZ235 resulting in pro-apoptotic and anti-proliferative effects in mesothelioma, was associated with the blockage of MDM2-p53 interaction.

Citation Format: Shengmei Zhou, Li Liu, Weijiang Hu, Hailong Li, Fanguo Meng, Haimeng Zhou, Jonathan A. Fletcher, Wenbin Ou. Dual targeting of the AKT/mTOR signaling pathwayinhibits mesothelioma: Targeted therapies against multiple activated receptor tyrosine kinases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2168. doi:10.1158/1538-7445.AM2013-2168

Abstract 2168: Dual targeting of the AKT/mTOR signaling pathwayinhibits mesothelioma: Targeted therapies against multiple activated receptor tyrosine kinases.

Jonathan A. Fletcher

Papers

Short segment acid reflux: Markedly increased acid load on distal oesophagus revealed by novel pH metry

Abstract 2168: Dual targeting of the AKT/mTOR signaling pathwayinhibits mesothelioma: Targeted therapies against multiple activated receptor tyrosine kinases.

High nitric oxide levels at gastro-oesophageal (GO) junction induced by dietary nitrate. ?cause of mutagenesis at go junction

328 Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumors)

Supplementary Material 10