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intratumor heterogeneity

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https://www.readbyqxmd.com/read/28323123/circumventing-intratumoral-heterogeneity-to-identify-potential-therapeutic-targets-in-hepatocellular-carcinoma
#1
Ao Huang, Xin Zhao, Xin-Rong Yang, Fu-Qiang Li, Xin-Lan Zhou, Kui Wu, Xin Zhang, Qi-Man Sun, Ya Cao, Hong-Mei Zhu, Xiang-Dong Wang, Huan-Ming Yang, Jian Wang, Zhao-You Tang, Yong Hou, Jia Fan, Jian Zhou
BACKGROUND AND AIMS: Intratumoral heterogeneity (ITH) challenges identifying mutations with target therapy potential whereas circulating cell-free DNAs (cfDNAs) in blood could possibly reflect the entire mutation spectrum in certain tumors. We investigated how to minimize the limit of ITH for profiling hepatocellular carcinoma (HCC). METHODS: Thirty-two multi-regional tumor samples from five patients were subjected to whole exome sequencing (WES) and targeted deep sequencing (TDS); matched preoperative cfDNAs were sequenced accordingly...
March 17, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28321395/detection-of-intratumor-heterogeneity-in-modern-pathology-a-multisite-tumor-sampling-perspective
#2
Jesús M Cortés, Giovanni de Petris, José I López
Current sampling protocols of neoplasms along the digestive tract and in the urinary bladder have to be updated, as they do not respond to the necessities of modern personalized medicine. We show here that an adapted version of multisite tumor sampling (MSTS) is a sustainable model to overcome current deficiencies in digestive and bladder tumors when they are large enough so as to make unaffordable a total sampling. The new method is based on the divide-and-conquer algorithm and includes a slight modification of the MSTS, which proved to be useful very recently in clear cell renal cell carcinoma...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28319088/reference-component-analysis-of-single-cell-transcriptomes-elucidates-cellular-heterogeneity-in-human-colorectal-tumors
#3
Huipeng Li, Elise T Courtois, Debarka Sengupta, Yuliana Tan, Kok Hao Chen, Jolene Jie Lin Goh, Say Li Kong, Clarinda Chua, Lim Kiat Hon, Wah Siew Tan, Mark Wong, Paul Jongjoon Choi, Lawrence J K Wee, Axel M Hillmer, Iain Beehuat Tan, Paul Robson, Shyam Prabhakar
Intratumoral heterogeneity is a major obstacle to cancer treatment and a significant confounding factor in bulk-tumor profiling. We performed an unbiased analysis of transcriptional heterogeneity in colorectal tumors and their microenvironments using single-cell RNA-seq from 11 primary colorectal tumors and matched normal mucosa. To robustly cluster single-cell transcriptomes, we developed reference component analysis (RCA), an algorithm that substantially improves clustering accuracy. Using RCA, we identified two distinct subtypes of cancer-associated fibroblasts (CAFs)...
March 20, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28316008/cytogenetic-analysis-of-metaplastic-squamous-cell-carcinoma-of-the-breast-inter-and-intratumoral-heterogeneity
#4
Masahiro Oikawa, Akiko Igawa, Kenichi Taguchi, Kimiko Baba, Mayumi Ishida, Sayuri Akiyoshi, Hiroshi Yano, Takeshi Nagayasu, Shinji Ohno, Eriko Tokunaga
BACKGROUND: Squamous cell carcinoma (SCC) of the breast is a rare and generally aggressive disease that accounts for less than 0.1% of all breast carcinomas. Although SCCs have distinct morphological features, their origin and cytogenetic profile are not well understood. METHODS: Five patients with SCC were studied. The tumor area that was predominantly composed of SCC components was macrodissected and DNA was extracted. In three cases, an invasive or noninvasive ductal carcinoma of no special type (NST) component was also present...
March 18, 2017: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/28314739/intratumorous-heterogeneity-for-ras-mutations-in-a-treatment-na%C3%A3-ve-colorectal-tumour
#5
Sebastian Lunke, Belinda Lee, Sevastjan Kranz, Peter Gibbs, Paul Waring, Michael Christie
Activating mutations in KRAS and NRAS genes in patients with colorectal cancer (CRC) are associated with a lack of response to treatment with anti-epidermal growth factor receptor (EGFR) therapies. Mutations in these genes are thought to be mutually exclusive, however reports have described CRCs with two activating rat sarcoma (RAS) mutations. This has fuelled discussion about whether these mutations are the result of intratumorous heterogeneity, or if they are co-occurring in the same cancer cell clone. We present a case of a colorectal tumour with three RAS mutations detected during routine diagnostic testing...
March 17, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28302680/genomic-and-epigenomic-heterogeneity-of-hepatocellular-carcinoma
#6
De-Chen Lin, Anand Mayakonda, Huy Q Dinh, Pinbo Huang, Lehang Lin, Xiaoping Liu, Ling-Wen Ding, Jie Wang, Benjamin Berman, Erwei Song, Dong Yin, H Phillip Koeffler
Understanding the intratumoral heterogeneity of hepatocellular carcinoma (HCC) is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 HCC cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions i...
February 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28302144/a-dosimetric-model-for-the-heterogeneous-delivery-of-radioactive-nanoparticles-in-vivo-a-feasibility-study
#7
Andrew B Satterlee, Peter Attayek, Bentley Midkiff, Leaf Huang
ᅟ: Accurate and quantitative dosimetry for internal radiation therapy can be especially challenging, given the heterogeneity of patient anatomy, tumor anatomy, and source deposition. Internal radiotherapy sources such as nanoparticles and monoclonal antibodies require high resolution imaging to accurately model the heterogeneous distribution of these sources in the tumor. The resolution of nuclear imaging modalities is not high enough to measure the heterogeneity of intratumoral nanoparticle deposition or intratumoral regions, and mathematical models do not represent the actual heterogeneous dose or dose response...
March 17, 2017: Radiation Oncology
https://www.readbyqxmd.com/read/28299887/fibroepithelial-lesions-in-the-breast-of-adolescent-females-a-clinicopathological-study-of-54-cases
#8
Dara S Ross, Dilip D Giri, Muzaffar M Akram, Jeffrey P Catalano, Cristina Olcese, Kimberly J Van Zee, Edi Brogi
Fibroepithelial lesions (FELs) are the most frequent breast tumors in adolescent females. The pubertal hormonal surge could impact the growth and microscopic appearance of FELs in this age group. In this study, we evaluate the morphology and clinical behavior of FELs in adolescents. We searched the 1992-2012 pathology data base for FELs in females 18 years old or younger (F ≤18 years). Seven FELs from 1975 to 1983 were also included. Three pathologists reviewed all available material. Patient (pt) characteristics and follow-up information were obtained from electronic medical records...
March 2017: Breast Journal
https://www.readbyqxmd.com/read/28297623/clinical-implications-of-novel-genomic-discoveries-in-chronic-lymphocytic-leukemia
#9
Gregory Lazarian, Romain Guièze, Catherine J Wu
Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy with a remarkably heterogeneous course, ranging from indolent disease with no need for immediate therapy to rapidly progressive disease associated with therapeutic resistance. The recent US Food and Drug Administration approvals of novel targeted therapies such as inhibitors of B-cell receptor signaling and B-cell lymphoma 2 have opened up new opportunities in the clinical management of patients with CLL and heralded a new era in the clinical treatment of this disease...
March 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28289245/treatment-induced-mutagenesis-and-selective-pressures-sculpt-cancer-evolution
#10
Subramanian Venkatesan, Charles Swanton, Barry S Taylor, Joseph F Costello
Despite the great progress in our understanding of the molecular basis of human cancer, the heterogeneity of individual tumors and the evolutionary pressures imposed by therapy have hampered our ability to effectively eradicate and control this disease. How, therefore, do cancers evolve under the selective pressures of cancer therapy? Recent studies have linked both primary (or de novo) and acquired treatment resistance to intratumor heterogeneity and clonal evolution. Resistance to targeted therapies often includes mutation of the drug target itself and aberrations of pathways upstream of, downstream from, or parallel to the drug target...
March 13, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28287634/immune-microenvironment-of-gliomas
#11
Anna Gieryng, Dominika Pszczolkowska, Kacper A Walentynowicz, Wenson D Rajan, Bozena Kaminska
High-grade gliomas are rapidly progressing tumors of the central nervous system (CNS) with a very poor prognosis despite extensive resection combined with radiation and/or chemotherapy. Histopathological and flow cytometry analyses of human and rodent experimental gliomas revealed heterogeneity of a tumor and its niche, composed of reactive astrocytes, endothelial cells, and numerous immune cells. Infiltrating immune cells consist of CNS resident (microglia) and peripheral macrophages, granulocytes, myeloid-derived suppressor cells (MDSCs), and T lymphocytes...
March 13, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28285687/met-exon-14-skipping-mutation-in-triple-negative-pulmonary-adenocarcinomas-and-pleomorphic-carcinomas-an-analysis-of-intratumoral-met-status-heterogeneity-and-clinicopathological-characteristics
#12
Dohee Kwon, Jaemoon Koh, Sehui Kim, Heounjeong Go, Young A Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Yoon Kyung Jeon, Doo Hyun Chung
OBJECTIVES: MET mutations leading to exon 14 skipping rarely occur in non-small cell lung cancer (NSCLC). Recently, small molecule inhibitors targeting MET mutations showed clinical benefit. However, the clinicopathological characteristics of NSCLC harboring MET mutations, and the correlation among mutations, protein expression, and gene copy number of MET in NSCLC remain unclear. Therefore, we address these issues. MATERIALS AND METHODS: MET exon 14 skipping mutations were evaluated using real-time quantitative reverse-transcription-PCR (qRT-PCR) in 102 triple-negative (i...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28284891/loss-of-bap1-protein-expression-in-the-first-metastatic-site-predicts-prognosis-in-patients-with-clear-cell-renal-cell-carcinoma
#13
Yuji Miura, Naoko Inoshita, Masaomi Ikeda, Yu Miyama, Ryosuke Oki, Suguru Oka, Chihiro Kondoh, Yukinori Ozaki, Yuko Tanabe, Kazuhiro Kurosawa, Shinji Urakami, Tadasu Kohno, Toshikazu Okaneya, Toshimi Takano
OBJECTIVES: To investigate the intratumoral heterogeneity of BAP1 and PBRM1 expression at the primary site and metastatic sites and to evaluate whether BAP1 and PBRM1 expression in metastatic sites of clear cell renal cell carcinoma (ccRCC) has prognostic value. METHODS AND MATERIALS: We collected paired samples from the primary site and the first metastatic site in 41 patients with ccRCC. Immunohistochemistry analyses were performed for the expression of BAP1 and PBRM1 proteins...
March 8, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28280617/identifying-prognostic-intratumor-heterogeneity-using-pre-and-post-radiotherapy-18f-fdg-pet-images-for-pancreatic-cancer-patients
#14
Yong Yue, Arsen Osipov, Benedick Fraass, Howard Sandler, Xiao Zhang, Nicholas Nissen, Andrew Hendifar, Richard Tuli
BACKGROUND: To stratify risks of pancreatic adenocarcinoma (PA) patients using pre- and post-radiotherapy (RT) PET/CT images, and to assess the prognostic value of texture variations in predicting therapy response of patients. METHODS: Twenty-six PA patients treated with RT from 2011-2013 with pre- and post-treatment 18F-FDG-PET/CT scans were identified. Tumor locoregional texture was calculated using 3D kernel-based approach, and texture variations were identified by fitting discrepancies of texture maps of pre- and post-treatment images...
February 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28280521/resistance-to-mtorc1-inhibitors-in-cancer-therapy-from-kinase-mutations-to-intratumoral-heterogeneity-of-kinase-activity
#15
REVIEW
Seraina Faes, Nicolas Demartines, Olivier Dormond
Targeting mTORC1 has been thoroughly explored in cancer therapy. Following encouraging preclinical studies, mTORC1 inhibitors however failed to provide substantial benefits in cancer patients. Several resistance mechanisms have been identified including mutations of mTOR and activation of alternate proliferation pathways. Moreover, emerging evidence discloses intratumoral heterogeneity of mTORC1 activity that further contributes to a reduced anticancer efficacy of mTORC1 inhibitors. Genetic heterogeneity as well as heterogeneous conditions of the tumor environment such as hypoxia profoundly modifies mTORC1 activity in tumors and hence influences the response of tumors to mTORC1 inhibitors...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28280388/alternative-therapies-for-metastatic-breast-cancer-multimodal-approach-targeting-tumor-cell-heterogeneity
#16
REVIEW
Manpreet Sambi, Sabah Haq, Vanessa Samuel, Bessi Qorri, Fiona Haxho, Kelli Hill, William Harless, Myron R Szewczuk
One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol...
2017: Breast Cancer: Targets and Therapy
https://www.readbyqxmd.com/read/28277923/3d-culture-as-a-clinically-relevant-model-for-personalized-medicine
#17
Eliza Li Shan Fong, Tan Boon Toh, Hanry Yu, Edward Kai-Hua Chow
Advances in understanding many of the fundamental mechanisms of cancer progression have led to the development of molecular targeted therapies. While molecular targeted therapeutics continue to improve the outcome for cancer patients, tumor heterogeneity among patients, as well as intratumoral heterogeneity, limits the efficacy of these drugs to specific patient subtypes, as well as contributes to relapse. Thus, there is a need for a more personalized approach toward drug development and diagnosis that takes into account the diversity of cancer patients, as well as the complex milieu of tumor cells within a single patient...
March 1, 2017: SLAS Technol
https://www.readbyqxmd.com/read/28270234/genetic-and-epigenetic-stability-of-oligodendrogliomas-at-recurrence
#18
Koki Aihara, Akitake Mukasa, Genta Nagae, Masashi Nomura, Shogo Yamamoto, Hiroki Ueda, Kenji Tatsuno, Junji Shibahara, Miwako Takahashi, Toshimitsu Momose, Shota Tanaka, Shunsaku Takayanagi, Shunsuke Yanagisawa, Takahide Nejo, Satoshi Takahashi, Mayu Omata, Ryohei Otani, Kuniaki Saito, Yoshitaka Narita, Motoo Nagane, Ryo Nishikawa, Keisuke Ueki, Hiroyuki Aburatani, Nobuhito Saito
Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients...
March 7, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28264865/gatekeeper-mutations-and-intratumoral-heterogeneity-in-fgfr2-translocated-cholangiocarcinoma
#19
Elizabeth C Smyth, Irina S Babina, Nicholas C Turner
FGFR2 genetic translocations are frequent in cholangiocarcinoma, yet despite initial sensitivity to FGFR inhibitors in clinic, patients quickly become resistant to targeted therapies. The work published by Goyal and colleagues demonstrates that acquisition of gatekeeper mutations in FGFR2 and intratumoral heterogeneity drive resistance in patients with FGFR2-translocated intrahepatic cholangiocarcinoma, which will have important implications for management of the disease in clinic. Cancer Discov; 7(3); 248-9...
March 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28257429/early-mutation-bursts-in-colorectal-tumors
#20
Junsong Zhao, Matthew P Salomon, Darryl Shibata, Christina Curtis, Kimberly Siegmund, Paul Marjoram
Tumor growth is an evolutionary process involving accumulation of mutations, copy number alterations, and cancer stem cell (CSC) division and differentiation. As direct observation of this process is impossible, inference regarding when mutations occur and how stem cells divide is difficult. However, this ancestral information is encoded within the tumor itself, in the form of intratumoral heterogeneity of the tumor cell genomes. Here we present a framework that allows simulation of these processes and estimation of mutation rates at the various stages of tumor development and CSC division patterns for single-gland sequencing data from colorectal tumors...
2017: PloS One
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