Gene Summary

Gene:MARS1; methionyl-tRNA synthetase 1
Summary:This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. The encoded protein is a component of the multi-tRNA synthetase complex and catalyzes the ligation of methionine to tRNA molecules. [provided by RefSeq, Jan 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:methionine--tRNA ligase, cytoplasmic
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (10)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Translocation
  • Ovarian Cancer
  • Myeloid Leukemia
  • Chromosome Mapping
  • Cell Line
  • Liver Cancer
  • Nuclear Matrix
  • Tumor Suppressor Proteins
  • Genetic Predisposition
  • Single Nucleotide Polymorphism
  • Immunohistochemistry
  • Chromosome 12
  • Apoptosis
  • Urea
  • Gene Expression Regulation
  • Leukaemia
  • Breast Cancer
  • Transcriptome
  • Chromosome Aberrations
  • Protein-Serine-Threonine Kinases
  • Mutation
  • FISH
  • Lung Cancer
  • Polymerase Chain Reaction
  • DNA
  • Cancer DNA
  • Cancer Gene Expression Regulation
  • Nucleic Acid Hybridization
  • Disease Models, Animal
  • MicroRNAs
  • Gene Regulatory Networks
  • DNA-Binding Proteins
  • Matrix Attachment Regions
  • DNA Sequence Analysis
  • Cancer RNA
  • RNA
  • Neoplastic Cell Transformation
  • Biomarkers, Tumor
  • Gene Expression Profiling
  • Trans-Activators
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MARS (cancer-related)

Loyez M, Larrieu JC, Chevineau S, et al.
In situ cancer diagnosis through online plasmonics.
Biosens Bioelectron. 2019; 131:104-112 [PubMed] Related Publications
Most cancer diagnoses rely on biomarkers detection. This could be improved if directly conducted in suspicious cancer spots, preventing the need for biopsy. Lung cancer remains a perfect study-case for such a development, as it is generally detected at advanced stage and is in the need for early diagnosis techniques. To this aim, we have designed a minimally invasive catheter-embedded biosensor. It combines a specific grating structure photo-imprinted in a telecommunication-grade optical fiber and an overlay made of a thin metal coating on which receptors are grafted, yielding plasmonic coupling. Our optrode targets a type of cytokeratins, overexpressed at the surface of cancer cells. It was assayed ex vivo in resected lung tissues collected from a dozen of patients. Biosensing responses were confirmed by immunohistochemistry, conducted on the same samples. In addition to accurate biosensing, our gratings inherently enable force-sensing features, which also allow a fine positioning of the probe in the tissue. Finally, the in vivo navigation of the bronchoscope-embedded sensor was validated into pig lungs. These achievements are a critical milestone towards the development of this micro/nano biosensor as a cost-effective and weakly invasive diagnostic tool for applications in areas of critical access such as brain, liver or prostate.

Valiollahi E, Ribera JM, Genescà E, Behravan J
Genome-wide identification of microRNA signatures associated with stem/progenitor cells in Philadelphia chromosome-positive acute lymphoblastic leukemia.
Mol Biol Rep. 2019; 46(1):1295-1306 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is a malignant transformation with uncontrolled proliferation of lymphoid precursor cells within bone marrow including a dismal prognosis after relapse. Survival of a population of quiescent leukemia stem cells (LSCs, also termed leukemia-initiating cells (LICs)) after treatment is one of the relapse reasons in Ph

Kalyvianaki K, Panagiotopoulos AA, Malamos P, et al.
Membrane androgen receptors (OXER1, GPRC6A AND ZIP9) in prostate and breast cancer: A comparative study of their expression.
Steroids. 2019; 142:100-108 [PubMed] Related Publications
Accumulating evidence during the last decades revealed that androgens exert membrane-initiated actions leading to the modulation of significant cellular processes, important for cancer cell growth and metastasis (including prostate and breast), that involve signaling via specific kinases. Collectively, many nonclassical, cell surface-initiated androgen actions are mediated by novel membrane androgen receptors (mARs), unrelated to nuclear androgen receptors. Recently, our group identified the G protein coupled oxo-eicosanoid receptor 1 (OXER1) (a receptor of the arachidonic acid metabolite, 5-oxoeicosatetraenoic acid, 5-oxoETE) as a novel mAR involved in the rapid effects of androgens. However, two other membrane proteins, G protein-coupled receptor family C group 6 member A (GPRC6A) and zinc transporter member 9 (ZIP9) have also been portrayed as mARs, related to the extranuclear action of androgens. In the present work, we present a comparative study of in silico pharmacology, gene expression and immunocytochemical data of the three receptors in various prostate and breast cancer cell lines. Furthermore, we analyzed the immunohistochemical expression of these receptors in human tumor and non-tumoral specimens and provide a pattern of expression and intracellular distribution.

Guilhamon P, Lupien M
SMuRF: a novel tool to identify regulatory elements enriched for somatic point mutations.
BMC Bioinformatics. 2018; 19(1):454 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Single Nucleotide Variants (SNVs), including somatic point mutations and Single Nucleotide Polymorphisms (SNPs), in noncoding cis-regulatory elements (CREs) can affect gene regulation and lead to disease development. Several approaches have been developed to identify highly mutated regions, but these do not take into account the specific genomic context, and thus likelihood of mutation, of CREs.
RESULTS: Here, we present SMuRF (Significantly Mutated Region Finder), a user-friendly command-line tool to identify these significantly mutated regions from user-defined genomic intervals and SNVs. We demonstrate this using publicly available datasets in which SMuRF identifies 72 significantly mutated CREs in liver cancer, including known mutated gene promoters as well as previously unreported regions.
CONCLUSIONS: SMuRF is a helpful tool to allow the simple identification of significantly mutated regulatory elements. It is open-source and freely available on GitHub ( ).

Patel R, Zhang L, Desai A, et al.
Mlh1 deficiency increases the risk of hematopoietic malignancy after simulated space radiation exposure.
Leukemia. 2019; 33(5):1135-1147 [PubMed] Free Access to Full Article Related Publications
Cancer-causing genome instability is a major concern during space travel due to exposure of astronauts to potent sources of high-linear energy transfer (LET) ionizing radiation. Hematopoietic stem cells (HSCs) are particularly susceptible to genotoxic stress, and accumulation of damage can lead to HSC dysfunction and oncogenesis. Our group recently demonstrated that aging human HSCs accumulate microsatellite instability coincident with loss of MLH1, a DNA Mismatch Repair (MMR) protein, which could reasonably predispose to radiation-induced HSC malignancies. Therefore, in an effort to reduce risk uncertainty for cancer development during deep space travel, we employed an Mlh1

Milpied P, Cervera-Marzal I, Mollichella ML, et al.
Human germinal center transcriptional programs are de-synchronized in B cell lymphoma.
Nat Immunol. 2018; 19(9):1013-1024 [PubMed] Related Publications
Most adult B cell lymphomas originate from germinal center (GC) B cells, but it is unclear to what extent B cells in overt lymphoma retain the functional dynamics of GC B cells or are blocked at a particular stage of the GC reaction. Here we used integrative single-cell analysis of phenotype, gene expression and variable-region sequence of the immunoglobulin heavy-chain locus to track the characteristic human GC B cell program in follicular lymphoma B cells. By modeling the cyclic continuum of GC B cell transitional states, we identified characteristic patterns of synchronously expressed gene clusters. GC-specific gene-expression synchrony was lost in single lymphoma B cells. However, distinct follicular lymphoma-specific cell states co-existed within single patient biopsies. Our data show that lymphoma B cells are not blocked in a GC B cell state but might adopt new dynamic modes of functional diversity, which opens the possibility of novel definitions of lymphoma identity.

Shah T, Krishnamachary B, Wildes F, et al.
Molecular causes of elevated phosphoethanolamine in breast and pancreatic cancer cells.
NMR Biomed. 2018; 31(8):e3936 [PubMed] Free Access to Full Article Related Publications
Elevated phosphoethanolamine (PE) is frequently observed in MRS studies of human cancers and xenografts. The role of PE in cell survival and the molecular causes underlying this increase are, however, relatively underexplored. In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells. We investigated the effect of silencing Etnk-1 and Etnk-2 on cell viability as a potential therapeutic strategy. Both breast and pancreatic cancer cells showed higher PE compared with their nonmalignant counterparts. We identified Etnk-1 as a major cause of the elevated PE levels in these cancer cells, with little or no contribution from Chk-α, Chk-β, or Etnk-2. The increase of PE observed in pancreatic cancer cells in culture was replicated in the corresponding tumor xenografts. Downregulation of Etnk-1 with siRNA resulted in cell cytotoxicity that correlated with PE levels in breast and pancreatic cancer cells. Etnk-1 may provide a potential therapeutic target in breast and pancreatic cancers.

Li Y, Ji F, Jiang Y, et al.
Correlation analysis of expressions of PTEN and p53 with the value obtained by magnetic resonance spectroscopy and apparent diffusion coefficient in the tumor and the tumor-adjacent area in magnetic resonance imaging for glioblastoma.
J BUON. 2018 Mar-Apr; 23(2):391-397 [PubMed] Related Publications
PURPOSE: To explore the correlation of the expression levels of phosphate and tension homology deleted on chromosome ten (PTEN) and p53 of glioblastoma multiforme (GBM) with the value obtained by magnetic resonance spectroscopy (MRS) and apparent diffusion coefficient (ADC) in the tumor and the tumor-adjacent area in magnetic resonance imaging (MRI).
METHODS: A total of 38 patients were operated for GBM. All the patients had received diffusion-weighted imaging (DWI) and MRS prior to surgery. ADC of water molecules and values of metabolite indexes of MRS, including n-acetyl aspartate (NAA), choline (Cho) and creatine (Cr), were recorded, and the ratios of Cho/NAA, Cho/Cr and NAA/Cr were calculated. Hematoxylin-eosin (H&E) staining was done to examine the morphology of tumor and of tumor-adjacent tissues; immunohistochemistry (IHC) was performed to examine the expressions of PTEN and p53 in the tumor and the tumor-adjacent area. Finally, the correlations of the expressions of PTEN and p53 with ADC, Cho/NAA, Cho/Cr and NAA/Cr of the tumor and the tumor-adjacent area were analyzed.
RESULTS: H&E staining showed that GBM tissues had disordered morphology, different sizes of cells, large cell nuclei and significant cell heterogeneity. IHC indicated that the expression level of p53 protein in the tumor was significantly higher than in the tumor-adjacent tissues (p<0.05). The expression level of PTEN protein was high in the tumor-adjacent tissues, but significantly deficient in the tumor. DWI showed that the signal of DWI in the tumor was significantly increased, but ADC was decreased compared with the tumor-adjacent area. MRS indicated that the wave band of Cho in the tumor was significantly increased, NAA was significantly lowered, and Cr section was decreased compared with the tumor-adjacent area, while NAA/Cr in the tumor was significantly decreased compared with the tumoradjacent area (p<0.05). Correlation analysis indicated that PTEN levels in the tumor and the tumor-adjacent area were positively correlated with ADC in the corresponding area, while p53 in the tumor and the tumor-adjacent area was negatively correlated with ADC in the corresponding area. Cho/NAA and Cho/Cr in the tumor were positively correlated with p53 in the tumor, but negatively correlated with PTEN in the tumor. However, NAA/Cr of the tumor was irrelevant to the levels of PTEN and p53.
CONCLUSIONS: The test results of DWI and MRS of patients with GBM can accurately reflect the inactivation or mutation of PTEN and p53.

Stuursma A, van Driel CMG, Wessels NJ, et al.
Severity and duration of menopausal symptoms after risk-reducing salpingo-oophorectomy.
Maturitas. 2018; 111:69-76 [PubMed] Related Publications
OBJECTIVES: To reduce the risk of ovarian cancer, women with BRCA1/2 mutations are advised to undergo risk-reducing salpingo-oophorectomy (RRSO) at a premenopausal age. Premenopausal RRSO results in acute menopause and is associated with various menopausal symptoms. This study investigates the severity and duration of subjective menopausal symptoms after premenopausal RRSO and associated factors.
METHODS: We included 199 women who had undergone RRSO before age 52 in this cross-sectional study. The Menopause Rating Scale (MRS) was used to measure the level of psychological, somato-vegetative and urogenital symptoms (no/little, mild, moderate, or severe). Uni- and multivariate logistic regressions were performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for having moderate or severe symptoms as compared to having no or mild symptoms. Duration of symptoms was investigated by calculating the time since RRSO.
RESULTS: Sixty-nine percent (137/199) of the included women reported moderate or severe symptoms on the MRS, a mean of 7.9 years after RRSO. Fifty-seven percent (94/137) of these women reported severe urogenital symptoms, and about one-quarter reported severe psychological and/or somato-vegetative symptoms. Only psychological symptoms tended to improve over time (>=10 years). A personal history of breast cancer was independently associated with having moderate or severe menopausal symptoms (OR = 3.4; 95%CI = 1.6-7.1).
CONCLUSIONS: The majority of women report moderate or severe menopausal symptoms, even 10 years after surgical menopause, and breast cancer survivors especially. To improve quality of life, follow-up care after RRSO should focus on these symptoms and be accessible for many years after RRSO.

Andronesi OC, Arrillaga-Romany IC, Ly KI, et al.
Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate.
Nat Commun. 2018; 9(1):1474 [PubMed] Free Access to Full Article Related Publications
Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. Mutant IDH1 produces high levels of 2-hydroxyglurate (2HG), thought to initiate oncogenesis through epigenetic modifications of gene expression. In this study, we show the initial evidence of the pharmacodynamics of a new mutant IDH1 inhibitor in glioma patients, using non-invasive 3D MR spectroscopic imaging of 2HG. Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0.019) after 1 week of treatment. Importantly, inhibition of mutant IDH1 may lead to the reprogramming of tumor metabolism, suggested by simultaneous changes in glutathione, glutamine, glutamate, and lactate. An inverse correlation between metabolic changes and diffusion MRI indicates an effect on the tumor-cell density. We demonstrate a feasible radiopharmacodynamics approach to support the rapid clinical translation of rationally designed drugs targeting IDH1/2 mutations for personalized and precision medicine of glioma patients.

Roerink SF, Sasaki N, Lee-Six H, et al.
Intra-tumour diversification in colorectal cancer at the single-cell level.
Nature. 2018; 556(7702):457-462 [PubMed] Related Publications
Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.

Chong T, Sarac A, Yao CQ, et al.
Deregulation of the spindle assembly checkpoint is associated with paclitaxel resistance in ovarian cancer.
J Ovarian Res. 2018; 11(1):27 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer is the leading gynecologic cancer diagnosed in North America and because related symptoms are not disease specific, this often leads to late detection, an advanced disease state, and the need for chemotherapy. Ovarian cancer is frequently sensitive to chemotherapy at diagnosis but rapid development of drug resistance leads to disease progression and ultimately death in the majority of patients.
RESULTS: We have generated paclitaxel resistant ovarian cell lines from their corresponding native cell lines to determine driver mechanisms of drug resistance using gene expression arrays. These paclitaxel resistant ovarian cells demonstrate: (1) Increased IC
CONCLUSIONS: We have generated model systems to explore drug resistance in ovarian cancer, which have revealed a key pathway related to the spindle assembly checkpoint underlying paclitaxel resistance in ovarian cell lines.

Lu H, Yang S, Zhu H, et al.
Targeted next generation sequencing identified clinically actionable mutations in patients with esophageal sarcomatoid carcinoma.
BMC Cancer. 2018; 18(1):251 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Esophageal sarcomatoid carcinoma (ESC) is a rare disease with a mixture of both carcinomatous and sarcomatous components in the tumor. Its genetic background and mechanisms of oncogenesis remain largely unknown.
METHODS: Here we performed targeted next generation sequencing (NGS) on a pan-cancer gene panel in 15 ESC tumors to explore their genetic alterations, and aimed to identify clinically actionable mutations for future treatment instructions.
RESULTS: TP53 alterations were identified in all patients. Alterations in receptor tyrosine kinases (RTK) were identified in 10 out of 15 patients. Members of downstream RAS and PI3-kinase pathways are also mutated in 10 patients, and PIK3CA is the top mutated gene in these pathways. In addition, we identified mutations on histone modification genes in 5 patients, including histone acetyltransferase gene EP300 and its homologue CREBBP, lysine methyltransferase genes KMT2A and KMT2B, and lysine demethylase gene KDM5A. Finally, mismatch repair (MMR) genes and proofreading gene POLE all together were mutated in one third of the ESC patients.
CONCLUSIONS: This is the first study to unravel the mutational profile of ESC tumors. Our findings could match 9 patients to the targeted therapies currently available in clinical practice or in active clinical trials, suggesting the potential utility of targeted therapies for this rare disease in the future.

Lai M, Vassallo I, Lanz B, et al.
In vivo characterization of brain metabolism by
Int J Cancer. 2018; 143(1):127-138 [PubMed] Related Publications
Glioblastoma are notorious for their highly invasive growth, diffusely infiltrating adjacent brain structures that precludes complete resection, and is a major obstacle for cure. To characterize this "invisible" tumor part, we designed a high resolution multimodal imaging approach assessing in vivo the metabolism of invasively growing glioma xenografts in the mouse brain. Animals were subjected longitudinally to magnetic resonance imaging (MRI) and

Berrington A, Voets NL, Larkin SJ, et al.
A comparison of 2-hydroxyglutarate detection at 3 and 7 T with long-TE semi-LASER.
NMR Biomed. 2018; 31(3) [PubMed] Related Publications
Abnormally high levels of the 'oncometabolite' 2-hydroxyglutarate (2-HG) occur in many grade II and III gliomas, and correlate with mutations in the genes of isocitrate dehydrogenase (IDH) isoforms. In vivo measurement of 2-HG in patients, using magnetic resonance spectroscopy (MRS), has largely been carried out at 3 T, yet signal overlap continues to pose a challenge for 2-HG detection. To combat this, several groups have proposed MRS methods at ultra-high field (≥7 T) where theoretical increases in signal-to-noise ratio and spectral resolution could improve 2-HG detection. Long echo time (long-TE) semi-localization by adiabatic selective refocusing (semi-LASER) (TE = 110 ms) is a promising method for improved 2-HG detection in vivo at either 3 or 7 T owing to the use of broad-band adiabatic localization. Using previously published semi-LASER methods at 3 and 7 T, this study directly compares the detectability of 2-HG in phantoms and in vivo across nine patients. Cramér-Rao lower bounds (CRLBs) of 2-HG fitting were found to be significantly lower at 7 T (6 ± 2%) relative to 3 T (15 ± 7%) (p = 0.0019), yet were larger at 7 T in an IDH wild-type patient. Although no increase in SNR was detected at 7 T (77 ± 26) relative to 3 T (77 ± 30), the detection of 2-HG was greatly enhanced through an improved spectral profile and increased resolution at 7 T. 7 T had a large effect on pairwise fitting correlations between γ-aminobutyric acid (GABA) and 2-HG (p = 0.004), and resulted in smaller coefficients. The increased sensitivity for 2-HG detection using long-TE acquisition at 7 T may allow for more rapid estimation of 2-HG (within a few spectral averages) together with other associated metabolic markers in glioma.

Lawler M, Alsina D, Adams RA, et al.
Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer.
Gut. 2018; 67(1):179-193 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes.
DESIGN: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants.
RESULTS: Fifteen critical RGs are summarised below:
CONCLUSION: Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.

Bien SA, Auer PL, Harrison TA, et al.
Enrichment of colorectal cancer associations in functional regions: Insight for using epigenomics data in the analysis of whole genome sequence-imputed GWAS data.
PLoS One. 2017; 12(11):e0186518 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The evaluation of less frequent genetic variants and their effect on complex disease pose new challenges for genomic research. To investigate whether epigenetic data can be used to inform aggregate rare-variant association methods (RVAM), we assessed whether variants more significantly associated with colorectal cancer (CRC) were preferentially located in non-coding regulatory regions, and whether enrichment was specific to colorectal tissues.
METHODS: Active regulatory elements (ARE) were mapped using data from 127 tissues and cell-types from NIH Roadmap Epigenomics and Encyclopedia of DNA Elements (ENCODE) projects. We investigated whether CRC association p-values were more significant for common variants inside versus outside AREs, or 2) inside colorectal (CR) AREs versus AREs of other tissues and cell-types. We employed an integrative epigenomic RVAM for variants with allele frequency <1%. Gene sets were defined as ARE variants within 200 kilobases of a transcription start site (TSS) using either CR ARE or ARE from non-digestive tissues. CRC-set association p-values were used to evaluate enrichment of less frequent variant associations in CR ARE versus non-digestive ARE.
RESULTS: ARE from 126/127 tissues and cell-types were significantly enriched for stronger CRC-variant associations. Strongest enrichment was observed for digestive tissues and immune cell types. CR-specific ARE were also enriched for stronger CRC-variant associations compared to ARE combined across non-digestive tissues (p-value = 9.6 × 10-4). Additionally, we found enrichment of stronger CRC association p-values for rare variant sets of CR ARE compared to non-digestive ARE (p-value = 0.029).
CONCLUSIONS: Integrative epigenomic RVAM may enable discovery of less frequent variants associated with CRC, and ARE of digestive and immune tissues are most informative. Although distance-based aggregation of less frequent variants in CR ARE surrounding TSS showed modest enrichment, future association studies would likely benefit from joint analysis of transcriptomes and epigenomes to better link regulatory variation with target genes.

Szymiczek A, Carbone M, Pastorino S, et al.
Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma.
Oncogene. 2017; 36(46):6501-6507 [PubMed] Free Access to Full Article Related Publications
Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients' outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo, CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care. Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.

Kim EY, Jung JY, Kim A, et al.
Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer.
BMC Cancer. 2017; 17(1):467 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Methionyl-tRNA synthetase (MRS) plays a critical role in initiating translation by transferring Met to the initiator tRNA (tRNA
METHODS: Immunoblot and immunohistochemical (IHC) analyses were performed using tissue lysates and formalin-fixed paraffin embedded (FFPE) tissue blocks from wild type C57BL/6, LSL-Kras G12D, and LSL-Kras G12D:p53
RESULTS: MRS was weakly expressed in the spleen and intestinal epithelium and only marginally expressed in the kidney, liver, and lungs of wild type C57BL/6 mice. On the other hand, MRS was strongly expressed in the neoplastic region of lung tissue from LSL-Kras G12D and LSL-Kras G12D:p53
CONCLUSIONS: Taken together, MRS is frequently overexpressed in NSCLC. Moreover, MRS is related to mTORC1 activity and its overexpression is associated with poor clinical outcomes, indicating that it has potential as a putative therapeutic target.

Cheng M, Rizwan A, Jiang L, et al.
Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer.
Neoplasia. 2017; 19(8):617-627 [PubMed] Free Access to Full Article Related Publications
Abnormal choline phospholipid metabolism is a hallmark of cancer. The magnetic resonance spectroscopy (MRS) detected total choline (tCho) signal can serve as an early noninvasive imaging biomarker of chemotherapy response in breast cancer. We have quantified the individual components of the tCho signal, glycerophosphocholine (GPC), phosphocholine (PC) and free choline (Cho), before and after treatment with the commonly used chemotherapeutic drug doxorubicin in weakly metastatic human MCF7 and triple-negative human MDA-MB-231 breast cancer cells. While the tCho concentration did not change following doxorubicin treatment, GPC significantly increased and PC decreased. Of the two phosphatidylcholine-specific PLD enzymes, only PLD1, but not PLD2, mRNA was down-regulated by doxorubicin treatment. For the two reported genes encoding GPC phosphodiesterase, the mRNA of GDPD6, but not GDPD5, decreased following doxorubicin treatment. mRNA levels of choline kinase α (ChKα), which converts Cho to PC, were reduced following doxorubicin treatment. PLD1 and ChKα protein levels decreased following doxorubicin treatment in a concentration dependent manner. Treatment with the PLD1 specific inhibitor VU0155069 sensitized MCF7 and MDA-MB-231 breast cancer cells to doxorubicin-induced cytotoxicity. Low concentrations of 100 nM of doxorubicin increased MDA-MB-231 cell migration. GDPD6, but not PLD1 or ChKα, silencing by siRNA abolished doxorubicin-induced breast cancer cell migration. Doxorubicin induced GPC increase and PC decrease are caused by reductions in PLD1, GDPD6, and ChKα mRNA and protein expression. We have shown that silencing or inhibiting these genes/proteins can promote drug effectiveness and reduce adverse drug effects. Our findings emphasize the importance of detecting PC and GPC individually.

Sun R, Hu Z, Sottoriva A, et al.
Between-region genetic divergence reflects the mode and tempo of tumor evolution.
Nat Genet. 2017; 49(7):1015-1024 [PubMed] Free Access to Full Article Related Publications
Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. By simulating spatial tumor growth under different evolutionary modes and examining patterns of between-region subclonal genetic divergence from multiregion sequencing (MRS) data, we demonstrate that it is feasible to distinguish tumors driven by strong positive subclonal selection from those evolving neutrally or under weak selection, as the latter fail to dramatically alter subclonal composition. We developed a classifier based on measures of between-region subclonal genetic divergence and projected patient data into model space, finding different modes of evolution both within and between solid tumor types. Our findings have broad implications for how human tumors progress, how they accumulate intratumoral heterogeneity, and ultimately how they may be more effectively treated.

Agarwal K, Hariprasad G, Rani K, et al.
Is there an association between enhanced choline and β-catenin pathway in breast cancer? A pilot study by MR Spectroscopy and ELISA.
Sci Rep. 2017; 7(1):2221 [PubMed] Free Access to Full Article Related Publications
Total choline (tCho) was documented as a biomarker for breast cancer diagnosis by in vivo MRS. To understand the molecular mechanisms behind elevated tCho in breast cancer, an association of tCho with β-catenin and cyclin D1 was evaluated. Hundred fractions from 20 malignant, 10 benign and 20 non-involved breast tissues were isolated. Cytosolic and nuclear expressions of β-catenin and cyclin D1 were estimated using ELISA. Higher tCho was seen in malignant compared to benign tissues. Malignant tissues showed higher cytosolic and nuclear β-catenin expressions than benign and non-involved tissues. Within malignant tissues, β-catenin and cyclin D1 expressions were higher in the nucleus than cytosol. Cyclin D1 expression was higher in the cytosolic fractions of benign and non-involved than malignant tissues. Furthermore, in malignant tissues, tCho showed a positive correlation with the cytosolic and nuclear expression of β-catenin and cyclin D1 and also a correlation between nuclear expressions of both these proteins was seen. Higher cytosolic β-catenin expression was seen in progesterone receptor negative than positive patients. Results provide an evidence of correlation between non-invasive biomarker, tCho and the Wnt/β-catenin pathway. The findings explain the molecular mechanism of tCho elevation which may facilitate exploration of additional therapeutic targets for breast cancer.

Loo LWM, Lemire M, Le Marchand L
In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants.
BMC Genomics. 2017; 18(1):381 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genome-wide association studies have identified 55 genetic variants associated with colorectal cancer risk to date. However, potential causal genes and pathways regulated by these risk variants remain to be characterized. Therefore, we performed gene ontology enrichment and pathway analyses to determine if there was an enrichment of genes in proximity to the colorectal cancer risk variants that could further elucidate the probable causal genes and pathways involved in colorectal cancer biology.
RESULTS: For the 65 unique genes that either contained, or were immediately neighboring up- and downstream, of these variants there was a significant enrichment for the KEGG pathway, Pathways in Cancer (p-value = 2.67 × 10
CONCLUSIONS: Our data reaffirm the potential to identify an enrichment for biological processes and candidate causal genes based on expression profiles correlated with genetic risk alleles of colorectal cancer, however, the identification of these significant cis-eQTLs is context and tissue specific.

Earl HM, Hiller L, Dunn JA, et al.
Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial.
Ann Oncol. 2017; 28(8):1817-1824 [PubMed] Free Access to Full Article Related Publications
Background: The ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review.
Patients and methods: Patients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class.
Results: A total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2-4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89-1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90-1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23-0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24-0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group.
Conclusions: The addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer. number: NCT01093235.

Yu Z, Zhao J, Hua Z, et al.
Chem Biol Drug Des. 2017; 90(5):719-729 [PubMed] Related Publications
In this study, we propose a novel molecular platform-integrated fluorinated antitumor nitrogen mustards for

Medrano M, Communal L, Brown KR, et al.
Interrogation of Functional Cell-Surface Markers Identifies CD151 Dependency in High-Grade Serous Ovarian Cancer.
Cell Rep. 2017; 18(10):2343-2358 [PubMed] Related Publications
The degree of genetic aberrations characteristic of high-grade serous ovarian cancer (HGSC) makes identification of the molecular features that drive tumor progression difficult. Here, we perform genome-wide RNAi screens and comprehensive expression analysis of cell-surface markers in a panel of HGSC cell lines to identify genes that are critical to their survival. We report that the tetraspanin CD151 contributes to survival of a subset of HGSC cell lines associated with a ZEB transcriptional program and supports the growth of HGSC tumors. Moreover, we show that high CD151 expression is prognostic of poor clinical outcome. This study reveals cell-surface vulnerabilities associated with HGSC, provides a framework for identifying therapeutic targets, and reports a role for CD151 in HGSC.

Guillaumet-Adkins A, Rodríguez-Esteban G, Mereu E, et al.
Single-cell transcriptome conservation in cryopreserved cells and tissues.
Genome Biol. 2017; 18(1):45 [PubMed] Free Access to Full Article Related Publications
A variety of single-cell RNA preparation procedures have been described. So far, protocols require fresh material, which hinders complex study designs. We describe a sample preservation method that maintains transcripts in viable single cells, allowing one to disconnect time and place of sampling from subsequent processing steps. We sequence single-cell transcriptomes from >1000 fresh and cryopreserved cells using 3'-end and full-length RNA preparation methods. Our results confirm that the conservation process did not alter transcriptional profiles. This substantially broadens the scope of applications in single-cell transcriptomics and could lead to a paradigm shift in future study designs.

Choi C, Raisanen JM, Ganji SK, et al.
Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma.
J Clin Oncol. 2016; 34(33):4030-4039 [PubMed] Free Access to Full Article Related Publications
Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration > 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.

Gorczynski RM, Zhu F, Chen Z, et al.
A comparison of serum miRNAs influencing metastatic growth of EMT6 vs 4THM tumor cells in wild-type and CD200R1KO mice.
Breast Cancer Res Treat. 2017; 162(2):255-266 [PubMed] Related Publications
PURPOSE: We investigated whether miRNAs in exosomes from EMT6 or 4THM tumor-bearing mice played a role in regulating inflammatory cytokine expression and/or metastasis in WT mice injected with EMT6 and/or 4THM tumor cells.
METHODS: EMT6 tumors in BALB/c CD200R1KO mice resolve following surgical resection of localized tumor and immunization with irradiated EMT6 cells along with CpG as adjuvant. Wild-type (WT) animals treated in the same fashion develop pulmonary and liver metastases within 20 days of surgery. DLNs from CD200R1KO mice contain no tumor cells detectable at limiting dilution. In contrast, 4THM tumor cells injected into CD200R1KO show increased metastasis compared with WT mice. Transfer of serum exosomes from 4THM tumor-bearing mice to WT animals increased metastasis of EMT6 tumors, an effect attenuated by anti-IL-6 antibody. We compared miRNA expression in exosomes from the serum of 4THM/EMT6 WT or CD200R1KO tumor-bearing mice, and the effects of antagomirs to miRNAs on tumor growth.
RESULTS: Complex changes in miRNA expression were observed in the isolated exosomes. Some miRNAs, including miR155, have been reported to potentiate inflammatory responses and augment inflammatory cytokine expression. Expression of miR155 increased in exosomes from 4THM relative to EMT6 tumor bearers, and antagomirs to miR155 attenuated tumor growth and metastasis, and improved survival, following infusion into WT mice. Antagomirs to the miR205 family were thought to affect metastasis by targeting epithelial-to-mesenchymal transition (EMT), increased growth and metastasis in both 4THM and EMT6 tumor-bearing mice, and decreased survival, with some modulation of inflammatory cytokine production.
CONCLUSIONS: Multiple pathways are implicated in differential metastasis of EMT6/4THM, and targeting these may have clinical utility in human breast cancer.

Wasąg P, Lenartowski R
Nuclear matrix - structure, function and pathogenesis.
Postepy Hig Med Dosw (Online). 2016; 70(0):1206-1219 [PubMed] Related Publications
The nuclear matrix (NM), or nuclear skeleton, is the non-chromatin, ribonucleoproteinaceous framework that is resistant to high ionic strength buffers, nonionic detergents, and nucleolytic enzymes. The NM fulfills a structural role in eukaryotic cells and is responsible for maintaining the shape of the nucleus and the spatial organization of chromatin. Moreover, the NM participates in several cellular processes, such as DNA replication/repair, gene expression, RNA transport, cell signaling and differentiation, cell cycle regulation, apoptosis and carcinogenesis. Short nucleotide sequences called scaffold/matrix attachment regions (S/MAR) anchor the chromatin loops to the NM proteins (NMP). The NMP composition is dynamic and depends on the cell type and differentiation stage or metabolic activity. Alterations in the NMP composition affect anchoring of the S/MARs and thus alter gene expression. This review aims to systematize information about the skeletal structure of the nucleus, with particular emphasis on the organization of the NM and its role in selected cellular processes. We also discuss several diseases that are caused by aberrant NM structure or dysfunction of individual NM elements.

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