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https://www.readbyqxmd.com/read/28432313/multiple-clinical-characteristics-separate-med12-mutation-positive-and-negative-uterine-leiomyomas
#1
Hanna-Riikka Heinonen, Annukka Pasanen, Oskari Heikinheimo, Tomas Tanskanen, Kimmo Palin, Jaana Tolvanen, Pia Vahteristo, Jari Sjöberg, Esa Pitkänen, Ralf Bützow, Netta Mäkinen, Lauri A Aaltonen
Up to 86% of uterine leiomyomas harbour somatic mutations in mediator complex subunit 12 (MED12). These mutations have been associated with conventional histology, smaller tumour size, and larger number of tumours within the uterus. Prior studies, with limited sample sizes, have failed to detect associations between other clinical features and MED12 mutations. Here, we prospectively collected 763 uterine leiomyomas and the corresponding normal myometrial tissue from 244 hysterectomy patients, recorded tumour characteristics, collected clinical data from medical records, and screened the tissue samples for MED12 mutations to assess potential associations between clinical variables and mutation status...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28432085/acute-myeloid-leukaemia-in-a-case-with-tatton-brown-rahman-syndrome-the-peculiar-dnmt3a-r882-mutation
#2
Iris H I M Hollink, Ans M W van den Ouweland, H Berna Beverloo, Susan T C J M Arentsen-Peters, C Michel Zwaan, Anja Wagner
BACKGROUND: Recently a novel syndromic form of overgrowth with intellectual disability and distinct facial features was identified caused by constitutional mutations in the epigenetic regulator DNA-methyltransferase 3A (DNMT3A), referred to as Tatton-Brown-Rahman syndrome (TBRS). Somatically acquired mutations in DNMT3A occur in haematological malignancies and are frequently present in acute myeloid leukaemia (AML) affecting in more than 50% the arginine residue at position 882 (R882)...
April 21, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28431268/assessment-of-mutagenicity-of-water-from-lake-sevan-armenia-with-application-of-tradescantia-clone-02
#3
R E Avalyan, E A Aghajanyan, A Khosrovyan, A L Atoyants, A E Simonyan, R M Aroutiounian
For many decades water resources in Armenia have been affected by anthropogenic activity, therefore, a regular bioindication of genotoxic effects of the water bodies is desirable. The genotoxicity of water samples collected from different parts of Lake Sevan were assessed by means of Trad-SHM (stamen hair mutation) assay using Tradescantia (clone 02). Here we report a significant increase in the frequency of somatic mutations and morphological changes in the Tradescantia inflorescences exposed to the water samples compared to the control...
March 31, 2017: Mutation Research
https://www.readbyqxmd.com/read/28431188/t-cell-receptor-%C3%AE-chain-repertoire-analysis-reveals-the-association-between-neoantigens-and-tumour-infiltrating-lymphocytes-in-multifocal-papillary-thyroid-carcinoma
#4
Zheming Lu, Chaoting Zhang, Jindong Sheng, Jing Shen, Baoguo Liu
To explore whether a few non-synonymous somatic mutations could induce activation and proliferation of neoantigen-specific tumour-infiltrating lymphocytes (TILs) in tumours with low mutation rates, we analysed a patient with multifocal papillary thyroid carcinoma (seven non-contiguous cancer foci) to investigate the relationship between neoantigens and TILs. These seven foci had a few or no non-synonymous somatic mutations; moreover, multiple loci had similar or different spectra of mutations. We used high-throughput sequencing of the rearranged genes in T cell receptor β-chain (TCRβ) to reveal the basic characteristics of T cells in seven tumour foci and matched adjacent normal tissue...
April 21, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28429735/phylogenetic-analysis-of-metastatic-progression-in-breast-cancer-using-somatic-mutations-and-copy-number-aberrations
#5
David Brown, Dominiek Smeets, Borbála Székely, Denis Larsimont, A Marcell Szász, Pierre-Yves Adnet, Françoise Rothé, Ghizlane Rouas, Zsófia I Nagy, Zsófia Faragó, Anna-Mária Tőkés, Magdolna Dank, Gyöngyvér Szentmártoni, Nóra Udvarhelyi, Gabriele Zoppoli, Lajos Pusztai, Martine Piccart, Janina Kulka, Diether Lambrechts, Christos Sotiriou, Christine Desmedt
Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression...
April 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28429085/the-role-of-rna-alternative-splicing-in-regulating-cancer-metabolism
#6
REVIEW
Itamar Kozlovski, Zahava Siegfried, Adi Amar-Schwartz, Rotem Karni
Tumor cells alter their metabolism by a wide array of mechanisms to promote growth and proliferation. Dysregulated expression and/or somatic mutations of key components of the glycolytic pathway/TCA cycle as well as other metabolic pathways allow tumor cells to improve their ability to survive harsh conditions such as hypoxia and the presence of reactive oxygen species, as well as the ability to obtain nutrients to increase lipids, protein, and nucleic acids biogenesis. Approximately 95% of the human protein encoding genes undergo alternative splicing (AS), a regulated process of gene expression that greatly diversifies the proteome by creating multiple proteins from a single gene...
April 20, 2017: Human Genetics
https://www.readbyqxmd.com/read/28429069/mupexi-prediction-of-neo-epitopes-from-tumor-sequencing-data
#7
Anne-Mette Bjerregaard, Morten Nielsen, Sine Reker Hadrup, Zoltan Szallasi, Aron Charles Eklund
Personalization of immunotherapies such as cancer vaccines and adoptive T cell therapy depends on identification of patient-specific neo-epitopes that can be specifically targeted. MuPeXI, the mutant peptide extractor and informer, is a program to identify tumor-specific peptides and assess their potential to be neo-epitopes. The program input is a file with somatic mutation calls, a list of HLA types, and optionally a gene expression profile. The output is a table with all tumor-specific peptides derived from nucleotide substitutions, insertions, and deletions, along with comprehensive annotation, including HLA binding and similarity to normal peptides...
April 20, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28428277/immune-gene-expression-is-associated-with-genomic-aberrations-in-breast-cancer
#8
Anton Safonov, Tingting Jiang, Giampaolo Bianchini, Balázs Győrffy, Thomas Karn, Christos Hatzis, Lajos Pusztai
The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the 3 major breast cancer subtypes...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28427592/pathologic-active-mtor-mutation-in-brain-malformation-with-intractable-epilepsy-leads-to-cell-autonomous-migration-delay
#9
Sae Hanai, Sayuri Sukigara, Hongmei Dai, Tomoo Owa, Shin-Ichi Horike, Taisuke Otsuki, Takashi Saito, Eiji Nakagawa, Naoki Ikegaya, Takanobu Kaido, Noriko Sato, Akio Takahashi, Kenji Sugai, Yuko Saito, Masayuki Sasaki, Mikio Hoshino, Yu-Ichi Goto, Schuichi Koizumi, Masayuki Itoh
The activation of phosphatidylinositol 3-kinase-AKTs-mammalian target of rapamycin cell signaling pathway leads to cell overgrowth and abnormal migration and results in various types of cortical malformations, such as hemimegalencephaly (HME), focal cortical dysplasia, and tuberous sclerosis complex. However, the pathomechanism underlying abnormal cell migration remains unknown. With the use of fetal mouse brain, we performed causative gene analysis of the resected brain tissues from a patient with HME and investigated the pathogenesis...
May 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28427513/polymerase-proofreading-domain-mutations-new-opportunities-for-immunotherapy-in-hypermutated-colorectal-cancer-beyond-mmr-deficiency
#10
REVIEW
Rémi Bourdais, Benoît Rousseau, Anaïs Pujals, Helene Boussion, Charlotte Joly, Aude Guillemin, Isabelle Baumgaertner, Cindy Neuzillet, Christophe Tournigand
Immune checkpoint inhibition is a new therapeutic strategy that has shown promising efficacy in many cancer types. Significant activity associated with mismatch repair (MMR) deficiency has been observed in hypermutated, microsatellite unstable (MSI) metastatic colorectal cancer (CRC). Beyond deficient-MMR tumors, somatic or germline DNA polymerase D1 (POLD1) or DNA polymerase E (POLE) alterations cause a hypermutated phenotype in CRC. This recently identified and rare subgroup of proficient-MMR tumors may also benefit from immunotherapy...
May 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28427458/whole-exome-sequencing-identifies-novel-candidate-predisposition-genes-for-familial-polycythemia-vera
#11
Elina A M Hirvonen, Esa Pitkänen, Kari Hemminki, Lauri A Aaltonen, Outi Kilpivaara
BACKGROUND: Polycythemia vera (PV), characterized by massive production of erythrocytes, is one of the myeloproliferative neoplasms. Most patients carry a somatic gain-of-function mutation in JAK2, c.1849G > T (p.Val617Phe), leading to constitutive activation of JAK-STAT signaling pathway. Familial clustering is also observed occasionally, but high-penetrance predisposition genes to PV have remained unidentified. RESULTS: We studied the predisposition to PV by exome sequencing (three cases) in a Finnish PV family with four patients...
April 20, 2017: Human Genomics
https://www.readbyqxmd.com/read/28427202/clinical-implications-of-genomic-profiles-in-metastatic-breast-cancer-with-a-focus-on-tp53-and-pik3ca-the-most-frequently-mutated-genes
#12
Ji-Yeon Kim, Eunjin Lee, Kyunghee Park, Woong-Yang Park, Hae Hyun Jung, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park
Breast cancer (BC) has been genetically profiled through large-scale genome analyses. However, the role and clinical implications of genetic alterations in metastatic BC (MBC) have not been evaluated. Therefore, we conducted whole-exome sequencing (WES) and RNA-Seq of 37 MBC samples and targeted deep sequencing of another 29 MBCs. We evaluated somatic mutations from WES and targeted sequencing and assessed gene expression and performed pathway analysis from RNA-Seq. In this analysis, PIK3CA was the most commonly mutated gene in estrogen receptor (ER)-positive BC, while in ER-negative BC, TP53 was the most commonly mutated gene (p = 0...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427185/transcriptional-landscape-of-human-cancers
#13
Mengyuan Li, Qingrong Sun, Xiaosheng Wang
The homogeneity and heterogeneity in somatic mutations, copy number alterations and methylation across different cancer types have been extensively explored. However, the related exploration based on transcriptome data is lacking. In this study we explored gene expression profiles across 33 human cancer types using The Cancer Genome Atlas (TCGA) data. We identified consistently upregulated genes (such as E2F1, EZH2, FOXM1, MYBL2, PLK1, TTK, AURKA/B and BUB1) and consistently downregulated genes (such as SCARA5, MYOM1, NKAPL, PEG3, USP2, SLC5A7 and HMGCLL1) across various cancers...
March 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28426938/high-throughput-screening-to-identify-inhibitors-of-dead-box-helicase-ddx41
#14
Mariko Yoneyama-Hirozane, Mitsuyo Kondo, Shin-Ichi Matsumoto, Akiko Morikawa-Oki, Daisuke Morishita, Atsushi Nakanishi, Tomohiro Kawamoto, Masaharu Nakayama
The human DEAD (Asp-Glu-Ala-Asp) box protein DDX41, a member of the DEXDc helicase family, has nucleic acid-dependent ATPase and RNA and DNA translocase and unwinding activities. DDX41 is affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. The R525H mutation in DDX41 is thought to play important roles in the development of hereditary myelodysplastic syndrome and acute myelocytic leukemia. In this study, human DDX41 and its R525H mutant (R525H) were expressed in Escherichia coli and purified...
April 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28426665/oncodomains-a-protein-domain-centric-framework-for-analyzing-rare-variants-in-tumor-samples
#15
Thomas A Peterson, Iris Ivy M Gauran, Junyong Park, DoHwan Park, Maricel G Kann
The fight against cancer is hindered by its highly heterogeneous nature. Genome-wide sequencing studies have shown that individual malignancies contain many mutations that range from those commonly found in tumor genomes to rare somatic variants present only in a small fraction of lesions. Such rare somatic variants dominate the landscape of genomic mutations in cancer, yet efforts to correlate somatic mutations found in one or few individuals with functional roles have been largely unsuccessful. Traditional methods for identifying somatic variants that drive cancer are 'gene-centric' in that they consider only somatic variants within a particular gene and make no comparison to other similar genes in the same family that may play a similar role in cancer...
April 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28426276/integrative-epigenetic-and-genetic-pan-cancer-somatic-alteration-portraits
#16
Lucas A Salas, Kevin C Johnson, Devin C Koestler, Dylan E O'Sullivan, Brock C Christensen
Genetic and epigenetic alterations are required for carcinogenesis and the mutation burden across tumor types has been investigated. Here, we investigate epigenetic alterations with a novel measure of global DNA methylation dysregulation, the methylation dysregulation index (MDI), across 14 cancer types in The Cancer Genome Atlas (TCGA) database. DNA methylation data-obtained using Illumina HumanMethylation450 BeadChip-was accessed from TCGA. We calculated the MDI in 14 tumor types (n = 5,592 tumors), using adjacent normal tissues (n = 701) from each tumor site...
April 20, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28425306/therapeutic-targeting-and-patient-selection-for-cancers-with-homologous-recombination-defects
#17
Francien Talens, Mathilde Jalving, Jourik A Gietema, Marcel A T M van Vugt
DNA double-strand breaks (DSBs) are toxic DNA lesions that can be repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR). Mutations in HR genes elicit a predisposition to cancer; yet, they also result in increased sensitivity to certain DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. To optimally implement PARP inhibitor treatment, it is important that patients with HR-deficient tumors are adequately selected. Areas covered: Herein, the authors describe the HR pathway mechanistically and review the treatment of HR-deficient cancers, with a specific focus on PARP inhibition for BRCA1/2-mutated breast and ovarian cancer...
April 20, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28424201/pik3ca-mutations-contribute-to-acquired-cetuximab-resistance-in-metastatic-colorectal-cancer-patients
#18
Jian Ming Xu, Yan Wang, You-Liang Wang, Yan Wang, Tao Liu, Ming Ni, Man-Sheng Li, Li Lin, Fei-Jiao Ge, Chun Gong, Jun-Yan Gu, Ru Jia, He-Fei Wang, Yu Ling Chen, Rong-Rui Liu, Chuan-Hua Zhao, Zhao-Li Tan, Yang Jin, Yunping Zhu, Shuji Ogino, Zhi Rong Qian
<p>Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential roles of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.</p> <br /><br />Experimental Design: <p>Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway...
April 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28424200/whole-exome-sequencing-of-metaplastic-breast-carcinoma-indicates-monoclonality-with-associated-ductal-carcinoma-component
#19
Bracha Avigdor, Katie Beierl, Christopher D Gocke, Daniel Zabransky, Karen Cravero, Kelly Kyker-Snowman, Berry Button, David Chu, Sarah Croessmann, Rory L Cochran, Roisin Connolly, Ben Ho Park, Ashley Cimino-Mathews, Sarah J Wheelan
Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogenous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) amplification/overexpression...
April 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28424163/clinical-significance-of-somatic-mutation-in-unexplained-blood-cytopenia
#20
Luca Malcovati, Anna Gallì, Erica Travaglino, Ilaria Ambaglio, Ettore Rizzo, Elisabetta Molteni, Chiara Elena, Virginia Valeria Ferretti, Silvia Catricalà, Elisa Bono, Gabriele Todisco, Antonio Bianchessi, Elisa Rumi, Silvia Zibellini, Daniela Pietra, Emanuela Boveri, Clara Camaschella, Daniela Toniolo, Elli Papaemmanuil, Seishi Ogawa, Mario Cazzola
Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm...
April 19, 2017: Blood
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