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Genome Medicine

Charles Auffray, Julian L Griffin, Muin J Khoury, James R Lupski, Matthias Schwab
No abstract text is available yet for this article.
February 15, 2019: Genome Medicine
Kurt Taylor, George Davey Smith, Caroline L Relton, Tom R Gaunt, Tom G Richardson
BACKGROUND: The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analysis pipeline that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from a genetic variant to a complex trait. METHODS: We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both nearby gene expression and cardiovascular traits...
January 31, 2019: Genome Medicine
Serena Nik-Zainal
No abstract text is available yet for this article.
January 29, 2019: Genome Medicine
Roddy Walsh, Francesco Mazzarotto, Nicola Whiffin, Rachel Buchan, William Midwinter, Alicja Wilk, Nicholas Li, Leanne Felkin, Nathan Ingold, Risha Govind, Mian Ahmad, Erica Mazaika, Mona Allouba, Xiaolei Zhang, Antonio de Marvao, Sharlene M Day, Euan Ashley, Steven D Colan, Michelle Michels, Alexandre C Pereira, Daniel Jacoby, Carolyn Y Ho, Kate L Thomson, Hugh Watkins, Paul J R Barton, Iacopo Olivotto, Stuart A Cook, James S Ware
BACKGROUND: International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework...
January 29, 2019: Genome Medicine
Alexander N Combes, Luke Zappia, Pei Xuan Er, Alicia Oshlack, Melissa H Little
BACKGROUND: Human kidney organoids hold promise for studying development, disease modelling and drug screening. However, the utility of stem cell-derived kidney tissues will depend on how faithfully these replicate normal fetal development at the level of cellular identity and complexity. METHODS: Here, we present an integrated analysis of single cell datasets from human kidney organoids and human fetal kidney to assess similarities and differences between the component cell types...
January 23, 2019: Genome Medicine
Yi Zheng, Peifeng Ji, Shuai Chen, Lingling Hou, Fangqing Zhao
Currently, circRNA studies are shifting from the identification of circular transcripts to understanding their biological functions. However, such endeavors have been limited by large-scale determination of their full-length sequences and also by the inability of accurate quantification at the isoform level. Here, we propose a new feature, reverse overlap (RO), for circRNA detection, which outperforms back-splice junction (BSJ)-based methods in identifying low-abundance circRNAs. By combining RO and BSJ features, we present a novel approach for effective reconstruction of full-length circRNAs and isoform-level quantification from the transcriptome...
January 19, 2019: Genome Medicine
Meiling Gao, Maurizio Callari, Emma Beddowes, Stephen-John Sammut, Marta Grzelak, Heather Biggs, Linda Jones, Abdelhamid Boumertit, Sabine C Linn, Javier Cortes, Mafalda Oliveira, Richard Baird, Suet-Feung Chin, Carlos Caldas
Circulating tumour DNA (ctDNA) detection and monitoring have enormous potential clinical utility in oncology. We describe here a fast, flexible and cost-effective method to profile multiple genes simultaneously in low input cell-free DNA (cfDNA): Next Generation-Targeted Amplicon Sequencing (NG-TAS). We designed a panel of 377 amplicons spanning 20 cancer genes and tested the NG-TAS pipeline using cell-free DNA from two HapMap lymphoblastoid cell lines. NG-TAS consistently detected mutations in cfDNA when mutation allele fraction was > 1%...
January 4, 2019: Genome Medicine
Paola Francica, Sven Rottenberg
Inhibitors of poly(ADP-ribose) polymerase (PARPi) have entered the clinic for the treatment of patients with cancers that lack homology-directed DNA repair, but drug resistance remains a clinical hurdle. Recent advances in the identification of PARPi resistance mechanisms have yielded a better understanding of DNA end protection and the relevance of endogenous poly(ADP-ribose) glycohydrolase, highlighting new vulnerabilities.
December 28, 2018: Genome Medicine
Francisco M De La Vega, Carlos D Bustamante
A new study highlights the biases and inaccuracies of polygenic risk scores (PRS) when predicting disease risk in individuals from populations other than those used in their derivation. The design bias of workhorse tools used for research, particularly genotyping arrays, contributes to these distortions. To avoid further inequities in health outcomes, the inclusion of diverse populations in research, unbiased genotyping, and methods of bias reduction in PRS are critical.
December 27, 2018: Genome Medicine
Jung Kim, Wen Luo, Mingyi Wang, Talia Wegman-Ostrosky, Megan N Frone, Jennifer J Johnston, Michael L Nickerson, Melissa Rotunno, Shengchao A Li, Maria I Achatz, Seth A Brodie, Michael Dean, Kelvin C de Andrade, Fernanda P Fortes, Matthew Gianferante, Payal Khincha, Mary L McMaster, Lisa J McReynolds, Alexander Pemov, Maisa Pinheiro, Karina M Santiago, Blanche P Alter, Neil E Caporaso, Shahinaz M Gadalla, Lynn R Goldin, Mark H Greene, Jennifer Loud, Xiaohong R Yang, Neal D Freedman, Susan M Gapstur, Mia M Gaudet, Donato Calista, Paola Ghiorzo, Maria Concetta Fargnoli, Eduardo Nagore, Ketty Peris, Susana Puig, Maria Teresa Landi, Belynda Hicks, Bin Zhu, Jia Liu, Joshua N Sampson, Stephen J Chanock, Lisa J Mirabello, Lindsay M Morton, Leslie G Biesecker, Margaret A Tucker, Sharon A Savage, Alisa M Goldstein, Douglas R Stewart
BACKGROUND: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982). METHODS: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS)...
December 24, 2018: Genome Medicine
Jessica A Griffiths, Sarkis K Mazmanian
The gut microbiome contributes to the development and function of the immune, metabolic, and nervous systems. Furthermore, commensal bacteria modulate symptoms and pathology in mouse models of neuropsychiatric and neurodevelopmental diseases. Uncovering mechanisms that are utilized by the microbiome to mediate gut-brain connections may provide novel opportunities to target therapies to the gut in order to treat neurologic disorders.
December 21, 2018: Genome Medicine
Ana Márquez, Martin Kerick, Alexandra Zhernakova, Javier Gutierrez-Achury, Wei-Min Chen, Suna Onengut-Gumuscu, Isidoro González-Álvaro, Luis Rodriguez-Rodriguez, Raquel Rios-Fernández, Miguel A González-Gay, Maureen D Mayes, Soumya Raychaudhuri, Stephen S Rich, Cisca Wijmenga, Javier Martín
BACKGROUND: In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. METHODS: For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET...
December 20, 2018: Genome Medicine
Monique G P van der Wijst, Dylan H de Vries, Harm Brugge, Harm-Jan Westra, Lude Franke
Only a small fraction of patients respond to the drug prescribed to treat their disease, which means that most are at risk of unnecessary exposure to side effects through ineffective drugs. This inter-individual variation in drug response is driven by differences in gene interactions caused by each patient's genetic background, environmental exposures, and the proportions of specific cell types involved in disease. These gene interactions can now be captured by building gene regulatory networks, by taking advantage of RNA velocity (the time derivative of the gene expression state), the ability to study hundreds of thousands of cells simultaneously, and the falling price of single-cell sequencing...
December 19, 2018: Genome Medicine
Alba Sanchis-Juan, Jonathan Stephens, Courtney E French, Nicholas Gleadall, Karyn Mégy, Christopher Penkett, Olga Shamardina, Kathleen Stirrups, Isabelle Delon, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Detelina Grozeva, Luca Stefanucci, Gavin Arno, Andrew R Webster, Trevor Cole, Topun Austin, Ricardo Garcia Branco, Willem H Ouwehand, F Lucy Raymond, Keren J Carss
BACKGROUND: Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. METHODS: We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients...
December 7, 2018: Genome Medicine
Wei Tang, Ming Zhou, Tiffany H Dorsey, DaRue A Prieto, Xin W Wang, Eytan Ruppin, Timothy D Veenstra, Stefan Ambs
BACKGROUND: Transcriptome analysis of breast cancer discovered distinct disease subtypes of clinical significance. However, it remains a challenge to define disease biology solely based on gene expression because tumor biology is often the result of protein function. Here, we measured global proteome and transcriptome expression in human breast tumors and adjacent non-cancerous tissue and performed an integrated proteotranscriptomic analysis. METHODS: We applied a quantitative liquid chromatography/mass spectrometry-based proteome analysis using an untargeted approach and analyzed protein extracts from 65 breast tumors and 53 adjacent non-cancerous tissues...
December 3, 2018: Genome Medicine
Maki Tanioka, Kevin R Mott, Daniel P Hollern, Cheng Fan, David B Darr, Charles M Perou
BACKGROUND: Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. Predictors of sensitivity and resistance, however, remain unknown. METHODS: A total of eight cell lines and nine mouse models of breast cancer were treated with entinostat. Luminal cell lines were treated with or without entinostat at their IC50 doses, and MMTV/Neu luminal mouse tumors were untreated or treated with entinostat until progression...
November 30, 2018: Genome Medicine
Elen Kristine Höglander, Silje Nord, David C Wedge, Ole Christian Lingjærde, Laxmi Silwal-Pandit, Hedda vdL Gythfeldt, Hans Kristian Moen Vollan, Thomas Fleischer, Marit Krohn, Ellen Schlitchting, Elin Borgen, Øystein Garred, Marit M Holmen, Erik Wist, Bjørn Naume, Peter Van Loo, Anne-Lise Børresen-Dale, Olav Engebraaten, Vessela Kristensen
BACKGROUND: Chemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its receptor interaction, thus obstructing the formation of new blood vessels. METHODS: A phase II randomized clinical trial of 123 patients with Her2-negative breast cancer was conducted, with patients treated with neoadjuvant chemotherapy (fluorouracil (5FU)/epirubicin/cyclophosphamide (FEC) and taxane), with or without bevacizumab...
November 29, 2018: Genome Medicine
Jake R Conway, Eric Kofman, Shirley S Mo, Haitham Elmarakeby, Eliezer Van Allen
Immune checkpoint blockade (ICB) therapies, which potentiate the body's natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient's tumor and immune system must be considered to maximize treatment efficacy...
November 29, 2018: Genome Medicine
Anna Truini, Giovanni Germano, Alberto Bardelli
The emergence of drug resistance depends on the ability of the genome of cancer cells to constantly mutate and evolve under selective pressures. The generation of new mutations is accelerated when genes involved in DNA repair pathways are altered. Notably, although the emergence of new mutations fosters drug resistance, new variants can nevertheless become novel antigens that promote immune surveillance and even restrict cancer growth.
November 28, 2018: Genome Medicine
Tonći Šuštić, Sake van Wageningen, Evert Bosdriesz, Robert J D Reid, John Dittmar, Cor Lieftink, Roderick L Beijersbergen, Lodewyk F A Wessels, Rodney Rothstein, René Bernards
BACKGROUND: Mutations in KRAS are frequent in human cancer, yet effective targeted therapeutics for these cancers are still lacking. Attempts to drug the MEK kinases downstream of KRAS have had limited success in clinical trials. Understanding the specific genomic vulnerabilities of KRAS-driven cancers may uncover novel patient-tailored treatment options. METHODS: We first searched for synthetic lethal (SL) genetic interactions with mutant RAS in yeast with the ultimate aim to identify novel cancer-specific targets for therapy...
November 27, 2018: Genome Medicine
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