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intratumor heterogeneity

Wei Jiang, Essel Dulaimi, Karthik Devarajan, Theodore Parsons, Qiong Wang, Lili Liao, Eun-Ah Cho, Raymond O'Neill, Charalambos Solomides, Stephen C Peiper, Joseph R Testa, Robert Uzzo, Haifeng Yang
Recent studies have shown that intratumoral heterogeneity (ITH) is prevalent in clear cell renal cell carcinoma (ccRCC), based on DNA sequencing and chromosome aberration analysis of multiple regions from the same tumor. VHL mutations were found to be universal throughout individual tumors when it occurred (ubiquitous), while the mutations in other tumor suppressor genes tended to be detected only in parts of the tumors (subclonal). ITH has been studied mostly by DNA sequencing in limited numbers of samples, either by whole genome sequencing or by targeted sequencing...
2016: PloS One
Paula D Bos
A prerequisite for tumor evolution toward a malignant state is the establishment of cell intrinsic and extrinsic mechanisms of immune suppression (Hanahan and Weinberg, 2000, 2011; Schreiber, Old, and Smyth, 2011). Widespread recruitment of Foxp3(+) regulatory T cells (TREG) is a prevailing means to dampen antitumor immunity. Advances in the characterization of TREG cell heterogeneity and physiological function of tissue resident TREG cells unfold new possibilities for nontraditional tumor-promoting functions of intratumoral TREG cells...
October 19, 2016: Immunological Investigations
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
Kuan-Yin Ko, Chia-Ju Liu, Chi-Lun Ko, Ruoh-Fang Yen
PURPOSE: The aim of this study was to investigate whether the textural features of pretreatment F-FDG PET images can predict prognosis for nasal type extranodal natural killer/T-cell lymphoma (ENKTL). MATERIALS AND METHODS: A retrospective analysis of the pretreatment F-FDG PET images of the patients with newly diagnosed nasal type ENKTL from 2008 to 2013 was conducted. Progression-free survival (PFS) was the main outcome measure. The primary tumor was identified and then delineated using the 40% maximum standardized uptake value (SUVmax) thresholding method...
October 5, 2016: Clinical Nuclear Medicine
Joo Hwa Lee, Nam Jin Yoo, Min Sung Kim, Sug Hyung Lee
Alterations of genes involved in histone modification are common in cancers. A histone demethylase-encoding gene PHF2 is considered a putative tumor suppressor gene (TSG). PHF2 is essential for p53-mediated TSG functions such as chemotherapy-mediated cancer cell killing. However, inactivating mutations of PHF2 that could inactivate its functions are not reported in cancers. In a genome database, we observed that the PHF2 gene possessed mononucleotide repeats, which could be mutated in cancers with high microsatellite instability (MSI-H)...
October 15, 2016: Pathology Oncology Research: POR
Robert J Gillies, Thomas Beyer
Over the past decades, imaging in oncology has been undergoing a "quiet" revolution to treat images as data, not as pictures. This revolution has been sparked by technological advances that enable capture of images that reflect not only anatomy, but also of tissue metabolism and physiology in situ Important advances along this path have been the increasing power of MRI, which can be used to measure spatially dependent differences in cell density, tissue organization, perfusion, and metabolism. In parallel, PET imaging allows quantitative assessment of the spatial localization of positron-emitting compounds, and it has also been constantly improving in the number of imageable tracers to measure metabolism and expression of macromolecules...
October 11, 2016: Cancer Research
Ju Hwa Lee, Nam Jin Yoo, Min Sung Kim, Chang Hyeok An, Sug Hyung Lee
Loss of ZMPSTE24 is related to progeroid phenotypes in human. Cells in zmpste24-deficient mice show delayed DNA damage response, increased aneuploidy and increased genomic instability, which are considered features of cancer cells. The aim of this study was to address whether ZMPSTE24 gene was mutated in colorectal cancers (CRCs) and gastric (GCs), and its expression was altered. ZMPSTE24 possesses a T9 mononucleotide repeat in an exon, which could be mutated in cancers with defects in mismatch repair that can result in microsatellite instability (MSI)...
October 6, 2016: Pathology, Research and Practice
Shuji Nagata, Hiroshi Nishimura, Kimberly K Amrami, Jun Akiba, Tatsuyuki Tonan, Kiminori Fujimoto, Toshi Abe
OBJECTIVE: The purpose of this study is to evaluate the usefulness of MRI in differentiating between fibrous and cellular solitary fibrous tumors (SFTs). MATERIALS AND METHODS: This retrospective study included 17 patients with histopathologically confirmed SFTs, including 10 patients with fibrous SFTs and seven patients with cellular SFTs. We evaluated the differences between fibrous and cellular SFTs with regard to clinical data and MRI findings, such as tumor margin definition, signal intensity, heterogeneity on T1- and T2-weighted images, presence of capsules, intratumoral cystic changes, flow signal void, perilesional edema, enhancement pattern on dynamic contrast-enhanced MRI (DCE-MRI), and mean apparent diffusion coefficient (ADC) values...
October 11, 2016: AJR. American Journal of Roentgenology
Koji Arihiro, Miyo Oda, Katsunari Ogawa, Yoshie Kaneko, Tomomi Shimizu, Yuna Tanaka, Yukari Marubashi, Katsunari Ishida, Chikako Takai, Chie Taoka, Shuji Kimura, Noriyuki Shiroma
OBJECTIVES: Although updated HER2 testing guidelines have been improved by a collaboration between the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) in 2013, HER2 evaluation is still problematic because of issues involving CEP17 polysomy, heterogeneity, and HER2 score 2+ cases. The aim of this retrospective study was to evaluate the relationship between HER2 gene heterogeneity, or so called CEP17 polysomy, using breast carcinoma cells sampled by scraping and the IHC score graded by automated image analysis using whole slide image...
October 3, 2016: Pathology, Research and Practice
Cristina Morales Torres, Alva Biran, Matthew J Burney, Harshil Patel, Tristan Henser-Brownhill, Ayelet-Hashahar Shapira Cohen, Yilong Li, Rotem Ben-Hamo, Emma Nye, Bradley Spencer-Dene, Probir Chakravarty, Sol Efroni, Nik Matthews, Tom Misteli, Eran Meshorer, Paola Scaffidi
Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which cells within a tumor can sustain the long-term cancer growth. Numerous cancer types exhibit high inter- and intratumor heterogeneity of H1.0, with H1.0 levels correlating with tumor differentiation status, patient survival, and, at the single-cell level, cancer stem cell markers. Silencing of H1.0 promotes maintenance of self-renewing cells by inducing derepression of megabase-sized gene domains harboring downstream effectors of oncogenic pathways...
September 30, 2016: Science
Rudolf A Werner, Constantin Lapa, Harun Ilhan, Takahiro Higuchi, Andreas K Buck, Sebastian Lehner, Peter Bartenstein, Frank Bengel, Imke Schatka, Dirk O Muegge, László Papp, Norbert Zsótér, Tobias Große-Ophoff, Markus Essler, Ralph A Bundschuh
The NETTER-1 trial demonstrated significantly improved progression-free survival (PFS) for peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET) emphasizing the high demand for response prediction in appropriate candidates. In this multicenter study, we aimed to elucidate the prognostic value of tumor heterogeneity as assessed by somatostatin receptor (SSTR)-PET/CT. 141 patients with SSTR-expressing tumors were analyzed obtaining SSTR-PET/CT before PRRT (1-6 cycles, 177Lu somatostatin analog)...
October 2, 2016: Oncotarget
Julie Leca, Sébastien Martinez, Sophie Lac, Jérémy Nigri, Véronique Secq, Marion Rubis, Christian Bressy, Arnauld Sergé, Marie-Noelle Lavaut, Nelson Dusetti, Céline Loncle, Julie Roques, Daniel Pietrasz, Corinne Bousquet, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean Baptiste Bachet, Christine Brun, Juan L Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini
The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk...
October 4, 2016: Journal of Clinical Investigation
Ao Huang, Xin Zhang, Shao-Lai Zhou, Ya Cao, Xiao-Wu Huang, Jia Fan, Xin-Rong Yang, Jian Zhou
PURPOSE: Circulating tumor DNA (ctDNA) is increasingly recognized as liquid biopsy to profile tumor genome. Droplet digital PCR (ddPCR) is a highly sensitive and easily operable platform for mutant detection. Here, we tried to detect ctDNA in hepatocellular carcinoma (HCC) patients using ddPCR. METHODS: Studies sequencing the genome of HCCs and COSMIC (Catalogue of Somatic Mutations in Cancer) database were reviewed to identify hotspot mutations. Circulating cell-free DNAs (cfDNAs) extracted from 1 ml preoperative plasma sample were analyzed to detect circulating mutants using ddPCR...
2016: Journal of Cancer
Myung-Chul Kim, Na-Yon Kim, Yu-Ri Seo, Yongbaek Kim
Intratumoral heterogeneity is a hallmark of all cancers and functions as the major barrier against effective cancer therapy. In contrast to genetic mutations, the role of epigenetic modifications in the generation and maintenance of heterogeneous cancer cells remains largely undetermined. This study was performed to evaluate the epigenetic mechanisms involved in the tumor cell heterogeneity using side population (SP) and non-SP cells isolated from a human malignant mesothelioma (HMM) cell line. The subpopulations of cancer cells were analyzed by methylated DNA immunoprecipitation combined with high-throughput sequencing (MeDIP-seq) and RNA-seq methodology...
2016: Journal of Cancer
Gaia Gozzi, Sonia T Chelbi, Paola Manni, Loredana Alberti, Sergio Fonda, Sara Saponaro, Luca Fabbiani, Francesco Rivasi, Jean Benhattar, Lorena Losi
TBX15 is a gene involved in the development of mesodermal derivatives. As the ovaries and the female reproductive system are of mesodermal origin, the aim of the present study was to determine the methylation status of the TBX15 gene promoter and the expression levels of TBX15 in ovarian carcinoma, which is the most lethal and aggressive type of gynecological tumor, in order to determine the role of TBX15 in the pathogenesis of ovarian carcinoma. This alteration could be used to predict tumor development, progression, recurrence and therapeutic effects...
October 2016: Oncology Letters
David A Braun, Kelly P Burke, Eliezer M Van Allen
Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for patients with advanced cancers. However, such therapy has benefited only a subset of patients, with some patients failing to respond to treatment at all, and others achieving a limited response followed by tumor progression. Understanding factors contributing to an effective response and further elucidating mechanisms of resistance will be crucial as these therapies are applied more broadly...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ahitagni Biswas, Lakhan Kashyap, Aanchal Kakkar, Chitra Sarkar, Pramod Kumar Julka
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal central nervous system tumor commonly affecting children <3 years of age. It roughly constitutes 1%-2% of all pediatric central nervous system tumors. Recent data show that it is the most common malignant central nervous system tumor in children <6 months of age. Management of this aggressive tumor is associated with a myriad of diagnostic and therapeutic challenges. On the basis of radiology and histopathology alone, distinction of AT/RT from medulloblastoma or primitive neuroectodermal tumor is difficult, and hence this tumor has been commonly misdiagnosed as primitive neuroectodermal tumor for decades...
2016: Cancer Management and Research
Saroj Niraula, Alberto Ocana
BACKGROUND: Breast cancer is heterogeneous at different levels: biologic subtypes, intratumoral areas, and sites of metastases. Randomized controlled trials (RCTs) classify metastatic sites as visceral or non-visceral, but this has little influence in treatment decisions, particularly in the absence of clinical urgency. Indeed, it is unclear if response to treatments differs among sites of metastases. PATIENTS AND METHODS: RCTs investigating 3 different anticancer strategies in metastatic breast cancer were identified: (1) new hormonal therapy, (2) new targeted therapies in hormone receptor positive tumours (everolimus or palbociclib), and (3) new anti-HER2 therapies...
September 20, 2016: Cancer Treatment Reviews
Katsuya Mitamura, Yuka Yamamoto, Nobuyuki Kudomi, Yukito Maeda, Takashi Norikane, Keisuke Miyake, Yoshihiro Nishiyama
BACKGROUND: The nucleoside analog 3'-deoxy-3'-(18)F-fluorothymidine (FLT) has been investigated for evaluating tumor proliferating activity in brain tumors. We evaluated FLT uptake heterogeneity using textural features from the histogram analysis in patients with newly diagnosed gliomas and examined correlation of the results with proliferative activity and patient prognosis, in comparison with the conventional PET parameters. METHODS: FLT PET was investigated in 37 patients with newly diagnosed gliomas...
September 29, 2016: Annals of Nuclear Medicine
Mu Zhou, Baishali Chaudhury, Lawrence O Hall, Dmitry B Goldgof, Robert J Gillies, Robert A Gatenby
PURPOSE: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Most GBMs exhibit extensive regional heterogeneity at tissue, cellular, and molecular scales, but the clinical relevance of the observed spatial imaging characteristics remains unknown. We investigated pretreatment magnetic resonance imaging (MRI) scans of GBMs to identify tumor subregions and quantify their image-based spatial characteristics that are associated with survival time. MATERIALS AND METHODS: We quantified tumor subregions (termed habitats) in GBMs, which are hypothesized to capture intratumoral characteristics using multiple MRI sequences...
September 28, 2016: Journal of Magnetic Resonance Imaging: JMRI
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