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Oncogenic mutations

Sanja Dacic, Liza C Villaruz, Shira Abberbock, Alyssa Mahaffey, Pimpin Incharoen, Marina N Nikiforova
Break-apart ALK FISH probe is the FDA approved approach for detection of ALK rearrangements in lung carcinoma patients who may benefit from ALK kinase inhibitors. The FISH assay can be technically challenging and difficult to interpret. ALK immunohistochemistry and next generation sequencing have been proposed as alternative approaches. In this study, we compared various ALK -FISH patterns to next -generation sequencing (NGS) for gene fusion detection, ALK immunohistochemistry (IHC) and tumor responses to crizotinib...
October 17, 2016: Oncotarget
Zsuzsanna Gaál, Éva Oláh, László Rejtő, Ferenc Erdődi, László Csernoch
Histone deacetylase enzymes, confirmed to have important role in the pathogenesis of leukemia, are promising targets of epigenetic treatment. However, in acute myeloid leukemia, our knowledge on their expression levels is limited, and controversial data have been published about their potential oncogenic or tumorsuppressor properties in solid tumors. In our study, the expression levels of HDAC4 and SIRT6 were evaluated via Western blot analysis in 45 bone marrow samples (2 uninfiltrated and 43 concerned by different kinds of hematological malignancies), including 32 specimens obtained from patients with newly diagnosed AML...
October 20, 2016: Pathology Oncology Research: POR
Kenneth Kaushansky
Thrombopoietin was posited to exist in 1958 and cloned in 1994, and in the ensuing two decades we have learned a great deal about the physiology and pathology of the primary regulator of thrombopoiesis. This paper will review the role of the hormone and its receptor, the product of the c-Mpl proto-oncogene, in health and disease, including many unexpected effects in both normal and neoplastic hematopoiesis. Amongst these unexpected properties are a non-redundant effect on hematopoietic stem cells, a critical role in all three of the acquired, chronic myeloproliferative neoplasms, as well as both gain-of-function and loss-of-function mutations in congenital and acquired states of thrombocytopenia and thrombocythemia...
2016: Thrombosis Journal
Piera Rizzolo, Anna Sara Navazio, Valentina Silvestri, Virginia Valentini, Veronica Zelli, Ines Zanna, Giovanna Masala, Simonetta Bianchi, Marco Scarnò, Stefania Tommasi, Domenico Palli, Laura Ottini
Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from its largely known female counterpart. We aimed at investigating whether MBC cases harbor somatic alterations of genes known as prognostic biomarkers and molecular therapeutic targets in female breast cancer.We examined 103 MBC cases, all characterized for germ-line BRCA1/2 mutations, for somatic alterations in PIK3CA, EGFR, ESR1 and CCND1 genes.Pathogenic mutations of PIK3CA were detected in 2% of MBCs...
September 27, 2016: Oncotarget
Chae Lim Jung, Hyemin Mun, Se-Young Jo, Ju-Hee Oh, ChuHee Lee, Eun-Kyung Choi, Se Jin Jang, Young-Ah Suh
Mutation of p53 occasionally results in a gain of function, which promotes tumor growth. We asked whether destabilizing the gain-of-function protein would kill tumor cells. Downregulation of the gene reduced cell proliferation in p53-mutant cells, but not in p53-null cells, indicating that the former depended on the mutant protein for survival. Moreover, phenformin and 2-deoxyglucose suppressed cell growth and simultaneously destabilized mutant p53. The AMPK pathway, MAPK pathway, chaperone proteins and ubiquitination all contributed to this process...
October 19, 2016: Oncotarget
Hisato Kawakami, Shengbing Huang, Krishnendu Pal, Shamit K Dutta, Debabrata Mukhopadhyay, Frank A Sinicrope
Oncogenic BRAFV600E mutations activate MAP kinase signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer (CRC). In BRAFV600E mutant CRCs, treatment failure may be related to BRAFV600E -mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAFV600E can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using CRC cell lines isogenic for BRAF. BRAFV600E -induced MCL-1 upregulation was confirmed by ectopic BRAFV600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1Thr163) and stabilize MCL-1...
October 7, 2016: Molecular Cancer Therapeutics
Min Wu, Jinyan Huang, Jianming Zhang, Cyril Benes, Bo Jiao, Ruibao Ren
RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block the RAS oncogenic signaling by a distinct mechanism. Since the biological activity of RAS proteins rely upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors...
October 19, 2016: Molecular Cancer Therapeutics
Lisa Brenan, Aleksandr Andreev, Ofir Cohen, Sasha Pantel, Atanas Kamburov, Davide Cacchiarelli, Nicole S Persky, Cong Zhu, Mukta Bagul, Eva M Goetz, Alex B Burgin, Levi A Garraway, Gad Getz, Tarjei S Mikkelsen, Federica Piccioni, David E Root, Cory M Johannessen
Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants...
October 18, 2016: Cell Reports
Songjia Lu, Chunhui Cai, Gonghong Yan, Zhuan Zhou, Yong Wan, Vicky Chen, Lujia Chen, Gregory F Cooper, Lina M Obeid, Yusuf A Hannun, Adrian V Lee, Xinghua Lu
Defining processes that are synthetic lethal with p53 mutations in cancer cells may reveal possible therapeutic strategies. In this study, we report the development of a signal-oriented computational framework for cancer pathway discovery in this context. We applied our bipartite-graph-based functional module discovery algorithm to identify transcriptomic modules abnormally expressed in multiple tumors, such that the genes in a module were likely regulated by a common, perturbed signal. For each transcriptomic module, we applied our weighted k-path merge algorithm to search for a set of somatic genome alterations (SGA) that likely perturbed the signal, i...
October 10, 2016: Cancer Research
Bryan E Essien, Sinju Sundaresan, Ramon Ocadiz-Ruiz, Aaron Chavis, Amy C Tsao, Arthur J Tessier, Michael M Hayes, Amanda Photenhauer, Milena Saqui-Salces, Anthony J Kang, Yatrik M Shah, Balázs Györffy, Juanita L Merchant
In colorectal cancer (CRC), APC-mediated induction of unregulated cell growth involves post-translational mechanisms that prevent proteasomal degradation of proto-oncogene β-catenin (CTNNB1) and its eventual translocation to the nucleus. However, about 10 percent of colorectal tumors also exhibit increased CTNNB1 mRNA. Here we show in CRC that increased expression of ZNF148, the gene coding for transcription factor ZBP-89, correlated with reduced patient survival. Tissue arrays showed that ZBP-89 protein was overexpressed in the early stages of CRC...
October 10, 2016: Cancer Research
Joseph G Crompton, Madhusudhanan Sukumar, Nicholas P Restifo
Pharmacologic inhibitors of the serine/threonine kinase Akt, initially aimed at deranged oncogenic pathways in tumors, have recently been shown to act as immunomodulators that markedly enhance the antitumor properties of T cells. Repurposing Akt inhibitors to improve antitumor immunity may be viewed as a manifestation of a larger paradigmatic shift in which hallmark characteristics of cancer (e.g., immune evasion), rather than merely causal features (e.g., somatic mutations) can be exploited for therapeutic benefit...
2016: Oncoimmunology
Piotr T Filipczak, Cynthia L Thomas, Wenshu Chen, Andrew Salzman, Jacob D McDonald, Yong Lin, Steven A Belinsky
Tuberous sclerosis complex (TSC) is a genetic multi-organ disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach...
October 18, 2016: Cancer Research
Saroor A Patel, Sakari Vanharanta
Genetic analyses of cancer progression in patient samples and model systems have thus far failed to identify specific mutational drivers of metastasis. Yet, at least in experimental systems, metastatic cancer clones display stable traits that can facilitate progression through the many steps of metastasis. How cancer cells establish and maintain the transcriptional programmes required for metastasis remains mostly unknown. Emerging evidence suggests that metastatic traits may arise from epigenetically altered transcriptional output of the oncogenic signals that drive tumour initiation and early progression...
October 8, 2016: Molecular Oncology
Qing Yang, Yingqiu Xie, Lixia Miao
Cancers induced by gene mutation, deletion, and genome instability might be related to aging. With similar pathways of aging but distinct functions, senescence at the cellular level is an irreversible arrest of cell cycle. Senescence has long been believed as a barrier to restrict tumor expansion. However, more and more evidence has been shown that senescence inducers regulate epithelial-mesenchymal transition, stem cell self-renewal, inflammatory response, crosstalk with the oncogenic bypass signaling, and conversion of oncogene to tumor suppressor...
October 18, 2016: Cancer Investigation
Wan-Ru Chao, Chi-Kuan Chen, Lih-Min Han, Chih-Ping Han
No abstract text is available yet for this article.
October 2016: Taiwanese Journal of Obstetrics & Gynecology
Ming-Shyen Yen, Jen-Ruei Chen, Peng-Hui Wang, Kuo-Chang Wen, Yi-Jen Chen, Heung-Tat Ng
Uterine sarcoma is a very aggressive and highly lethal disease. Even after a comprehensive staging surgery or en block cytoreduction surgery followed by multimodality therapy (often chemotherapy and/or radiation therapy), many patients relapse or present with distant metastases, and finally die of diseases. The worst outcome of uterine sarcomas is partly because of their rarity, unknown etiology, and highly divergent genetic aberration. Uterine sarcomas are often classified into four distinct subtypes, including uterine leiomyosarcoma, low-grade uterine endometrial stromal sarcoma, high-grade uterine endometrial stromal sarcoma, and undifferentiated uterine sarcoma...
October 2016: Taiwanese Journal of Obstetrics & Gynecology
Wensheng Zhang, Erik K Flemington, Kun Zhang
Most cancers are driven by somatic mutations in proto-oncogenes and tumor suppressor genes. Genetic changes in a tumor may accumulate in the tissue self-renewal phase prior to neoplasm. The risk of sporadic mutations increases with age. In this regard, a positive association between patient age and the accumulated mutation burden in tumors exists for many cancer types. However, the reported lines of evidence for such a connection are still limited. TP53 is the most frequently mutated cancer gene. The encoded p53 protein plays crucial roles in DNA repair...
September 2016: Cancer Genetics
Jia-Jie Hao, De-Chen Lin, Huy Q Dinh, Anand Mayakonda, Yan-Yi Jiang, Chen Chang, Ye Jiang, Chen-Chen Lu, Zhi-Zhou Shi, Xin Xu, Yu Zhang, Yan Cai, Jin-Wu Wang, Qi-Min Zhan, Wen-Qiang Wei, Benjamin P Berman, Ming-Rong Wang, H Phillip Koeffler
Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others...
October 17, 2016: Nature Genetics
Luca Falzone, Andrea Marconi, Carla Loreto, Sabrina Franco, Demetrios A Spandidos, Massimo Libra
It is well known that the occupational exposure to contaminants and carcinogens leads to the development of cancer in exposed workers. In the 18th century, Percivall Pott was the first to hypothesize that chronic exposure to dust in the London chimney sweeps was associated with an increased risk of developing cancer. Subsequently a growing body of evidence indicated that other physical factors were also responsible for oncogenic mutations. Over the past decades, many carcinogens have been found in the occupational environment and their presence is often associated with an increased incidence of cancer...
October 3, 2016: Molecular Medicine Reports
A Harrod, J Fulton, V T M Nguyen, M Periyasamy, L Ramos-Garcia, C-F Lai, G Metodieva, A de Giorgio, R L Williams, D B Santos, P J Gomez, M-L Lin, M V Metodiev, J Stebbing, L Castellano, L Magnani, R C Coombes, L Buluwela, S Ali
Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations...
October 17, 2016: Oncogene
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