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  • Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy
    Genome Med. (IF 10.886) Pub Date : 2020-03-30
    Anna Reustle; Moreno Di Marco; Carolin Meyerhoff; Annika Nelde; Juliane S. Walz; Stefan Winter; Siahei Kandabarau; Florian Büttner; Mathias Haag; Linus Backert; Daniel J. Kowalewski; Steffen Rausch; Jörg Hennenlotter; Viktoria Stühler; Marcus Scharpf; Falko Fend; Arnulf Stenzl; Hans-Georg Rammensee; Jens Bedke; Stefan Stevanović; Matthias Schwab; Elke Schaeffeler

    Clear cell renal cell carcinoma (ccRCC) is the dominant subtype of renal cancer. With currently available therapies, cure of advanced and metastatic ccRCC is achieved only in rare cases. Here, we developed a workflow integrating different -omics technologies to identify ccRCC-specific HLA-presented peptides as potential drug targets for ccRCC immunotherapy. We analyzed HLA-presented peptides by MS-based

  • Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival
    Genome Med. (IF 10.886) Pub Date : 2020-03-30
    Mary A. Wood; Benjamin R. Weeder; Julianne K. David; Abhinav Nellore; Reid F. Thompson

    Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized. Using a standardized approach, we quantify the robustness

  • Tracking cancer progression: from circulating tumor cells to metastasis
    Genome Med. (IF 10.886) Pub Date : 2020-03-19
    Francesc Castro-Giner; Nicola Aceto

    The analysis of circulating tumor cells (CTCs) is an outstanding tool to provide insights into the biology of metastatic cancers, to monitor disease progression and with potential for use in liquid biopsy-based personalized cancer treatment. These goals are ambitious, yet recent studies are already allowing a sharper understanding of the strengths, challenges, and opportunities provided by liquid biopsy

  • Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders
    Genome Med. (IF 10.886) Pub Date : 2020-03-17
    Dennis Lal; Patrick May; Eduardo Perez-Palma; Kaitlin E. Samocha; Jack A. Kosmicki; Elise B. Robinson; Rikke S. Møller; Roland Krause; Peter Nürnberg; Sarah Weckhuysen; Peter De Jonghe; Renzo Guerrini; Lisa M. Niestroj; Juliana Du; Carla Marini; James S. Ware; Mitja Kurki; Padhraig Gormley; Sha Tang; Sitao Wu; Saskia Biskup; Annapurna Poduri; Bernd A. Neubauer; Bobby P. C. Koeleman; Katherine L. Helbig;

    Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery

  • Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL
    Genome Med. (IF 10.886) Pub Date : 2020-03-18
    Justyna A. Wierzbinska; Reka Toth; Naveed Ishaque; Karsten Rippe; Jan-Philipp Mallm; Lara C. Klett; Daniel Mertens; Thorsten Zenz; Thomas Hielscher; Marc Seifert; Ralf Küppers; Yassen Assenov; Pavlo Lutsik; Stephan Stilgenbauer; Philipp M. Roessner; Martina Seiffert; John Byrd; Christopher C. Oakes; Christoph Plass; Daniel B. Lipka

    In cancer, normal epigenetic patterns are disturbed and contribute to gene expression changes, disease onset, and progression. The cancer epigenome is composed of the epigenetic patterns present in the tumor-initiating cell at the time of transformation, and the tumor-specific epigenetic alterations that are acquired during tumor initiation and progression. The precise dissection of these two components

  • Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma
    Genome Med. (IF 10.886) Pub Date : 2020-03-18
    Gabriel J. Starrett; Manisha Thakuria; Tianqi Chen; Christina Marcelus; Jingwei Cheng; Jason Nomburg; Aaron R. Thorner; Michael K. Slevin; Winslow Powers; Robert T. Burns; Caitlin Perry; Adriano Piris; Frank C. Kuo; Guilherme Rabinowits; Anita Giobbie-Hurder; Laura E. MacConaill; James A. DeCaprio

    Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet-induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types

  • Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex.
    Genome Med. (IF 10.886) Pub Date : 2020-03-06
    Matthias Merker,Thomas A Kohl,Ivan Barilar,Sönke Andres,Philip W Fowler,Erja Chryssanthou,Kristian Ängeby,Pontus Jureen,Danesh Moradigaravand,Julian Parkhill,Sharon J Peacock,Thomas Schön,Florian P Maurer,Timothy Walker,Claudio Köser,Stefan Niemann

    BACKGROUND A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST). METHODS We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes

  • A reference profile-free deconvolution method to infer cancer cell-intrinsic subtypes and tumor-type-specific stromal profiles.
    Genome Med. (IF 10.886) Pub Date : 2020-02-28
    Li Wang,Robert P Sebra,John P Sfakianos,Kimaada Allette,Wenhui Wang,Seungyeul Yoo,Nina Bhardwaj,Eric E Schadt,Xin Yao,Matthew D Galsky,Jun Zhu

    BACKGROUND Patient stratification based on molecular subtypes is an important strategy for cancer precision medicine. Deriving clinically informative cancer molecular subtypes from transcriptomic data generated on whole tumor tissue samples is a non-trivial task, especially given the various non-cancer cellular elements intertwined with cancer cells in the tumor microenvironment. METHODS We developed

  • Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.
    Genome Med. (IF 10.886) Pub Date : 2020-03-02
    Simon Kebede Merid,Alexei Novoloaca,Gemma C Sharp,Leanne K Küpers,Alvin T Kho,Ritu Roy,Lu Gao,Isabella Annesi-Maesano,Pooja Jain,Michelle Plusquin,Manolis Kogevinas,Catherine Allard,Florianne O Vehmeijer,Nabila Kazmi,Lucas A Salas,Faisal I Rezwan,Hongmei Zhang,Sylvain Sebert,Darina Czamara,Sheryl L Rifas-Shiman,Phillip E Melton,Debbie A Lawlor,Göran Pershagen,Carrie V Breton,Karen Huen,Nour Baiz,Luigi

    BACKGROUND Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. METHODS We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational

  • Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer.
    Genome Med. (IF 10.886) Pub Date : 2020-02-28
    Kyungsoo Kim,Seyeon Park,Seong Yong Park,Gamin Kim,Su Myeong Park,Jae-Won Cho,Da Hee Kim,Young Min Park,Yoon Woo Koh,Hye Ryun Kim,Sang-Jun Ha,Insuk Lee

    BACKGROUND T cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T cell exhaustion could serve as potential targets for delaying the process

  • Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors.
    Genome Med. (IF 10.886) Pub Date : 2020-02-28
    Christopher G Smith,Tina Moser,Florent Mouliere,Johanna Field-Rayner,Matthew Eldridge,Anja L Riediger,Dineika Chandrananda,Katrin Heider,Jonathan C M Wan,Anne Y Warren,James Morris,Irena Hudecova,Wendy N Cooper,Thomas J Mitchell,Davina Gale,Andrea Ruiz-Valdepenas,Tobias Klatte,Stephan Ursprung,Evis Sala,Antony C P Riddick,Tevita F Aho,James N Armitage,Samantha Perakis,Martin Pichler,Maximilian Seles

    BACKGROUND Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. METHODS Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. RESULTS Our data revealed

  • Large-scale public data reuse to model immunotherapy response and resistance.
    Genome Med. (IF 10.886) Pub Date : 2020-02-26
    Jingxin Fu,Karen Li,Wubing Zhang,Changxin Wan,Jing Zhang,Peng Jiang,X Shirley Liu

    Despite growing numbers of immune checkpoint blockade (ICB) trials with available omics data, it remains challenging to evaluate the robustness of ICB response and immune evasion mechanisms comprehensively. To address these challenges, we integrated large-scale omics data and biomarkers on published ICB trials, non-immunotherapy tumor profiles, and CRISPR screens on a web platform TIDE (http://tide

  • Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer.
    Genome Med. (IF 10.886) Pub Date : 2020-02-22
    Qing Zhou,Samantha O Perakis,Peter Ulz,Sumitra Mohan,Jakob M Riedl,Emina Talakic,Sigurd Lax,Martin Tötsch,Gerald Hoefler,Thomas Bauernhofer,Martin Pichler,Armin Gerger,Jochen B Geigl,Ellen Heitzer,Michael R Speicher

    BACKGROUND Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the

  • Comprehensive pharmacogenomic characterization of gastric cancer.
    Genome Med. (IF 10.886) Pub Date : 2020-02-18
    Jason K Sa,Jung Yong Hong,In-Kyoung Lee,Ju-Sun Kim,Moon-Hee Sim,Ha Jung Kim,Ji Yeong An,Tae Sung Sohn,Joon Ho Lee,Jae Moon Bae,Sung Kim,Kyoung-Mee Kim,Seung Tae Kim,Se Hoon Park,Joon Oh Park,Ho Yeong Lim,Won Ki Kang,Nam-Gu Her,Yeri Lee,Hee Jin Cho,Yong Jae Shin,Misuk Kim,Harim Koo,Mirinae Kim,Yun Jee Seo,Ja Yeon Kim,Min-Gew Choi,Do-Hyun Nam,Jeeyun Lee

    BACKGROUND Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development

  • Towards a European health research and innovation cloud (HRIC).
    Genome Med. (IF 10.886) Pub Date : 2020-02-19
    F M Aarestrup,A Albeyatti,W J Armitage,C Auffray,L Augello,R Balling,N Benhabiles,G Bertolini,J G Bjaalie,M Black,N Blomberg,P Bogaert,M Bubak,B Claerhout,L Clarke,B De Meulder,G D'Errico,A Di Meglio,N Forgo,C Gans-Combe,A E Gray,I Gut,A Gyllenberg,G Hemmrich-Stanisak,L Hjorth,Y Ioannidis,S Jarmalaite,A Kel,F Kherif,J O Korbel,C Larue,M Laszlo,A Maas,L Magalhaes,I Manneh-Vangramberen,E Morley-Fletcher

    The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrastructure. Creating a European Health Research and Innovation Cloud (HRIC) within this environment should enable data sharing and analysis for health research across the EU, in compliance with data

  • A chromosomal connectome for psychiatric and metabolic risk variants in adult dopaminergic neurons.
    Genome Med. (IF 10.886) Pub Date : 2020-02-19
    Sergio Espeso-Gil,Tobias Halene,Jaroslav Bendl,Bibi Kassim,Gabriella Ben Hutta,Marina Iskhakova,Neda Shokrian,Pavan Auluck,Behnam Javidfar,Prashanth Rajarajan,Sandhya Chandrasekaran,Cyril J Peter,Alanna Cote,Rebecca Birnbaum,Will Liao,Tyler Borrman,Jennifer Wiseman,Aaron Bell,Michael J Bannon,Panagiotis Roussos,John F Crary,Zhiping Weng,Stefano Marenco,Barbara Lipska,Nadejda M Tsankova,Laura Huckins

    BACKGROUND Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing

  • The pan-cancer landscape of prognostic germline variants in 10,582 patients
    Genome Med. (IF 10.886) Pub Date : 2020-02-17
    Ajay Chatrath; Roza Przanowska; Shashi Kiran; Zhangli Su; Shekhar Saha; Briana Wilson; Takaaki Tsunematsu; Ji-Hye Ahn; Kyung Yong Lee; Teressa Paulsen; Ewelina Sobierajska; Manjari Kiran; Xiwei Tang; Tianxi Li; Pankaj Kumar; Aakrosh Ratan; Anindya Dutta

    While clinical factors such as age, grade, stage, and histological subtype provide physicians with information about patient prognosis, genomic data can further improve these predictions. Previous studies have shown that germline variants in known cancer driver genes are predictive of patient outcome, but no study has systematically analyzed multiple cancers in an unbiased way to identify genetic loci

  • The paradox of cancer genes in non-malignant conditions: implications for precision medicine
    Genome Med. (IF 10.886) Pub Date : 2020-02-17
    Jacob J. Adashek; Shumei Kato; Scott M. Lippman; Razelle Kurzrock

    Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to

  • A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase.
    Genome Med. (IF 10.886) Pub Date : 2020-01-30
    Song Sun,Jochen Weile,Marta Verby,Yingzhou Wu,Yang Wang,Atina G Cote,Iosifina Fotiadou,Julia Kitaygorodsky,Marc Vidal,Jasper Rine,Pavel Ješina,Viktor Kožich,Frederick P Roth

    BACKGROUND For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective. METHODS Damaging CBS variants can be detected

  • A highly sensitive and specific workflow for detecting rare copy-number variants from exome sequencing data.
    Genome Med. (IF 10.886) Pub Date : 2020-01-30
    Ramakrishnan Rajagopalan,Jill R Murrell,Minjie Luo,Laura K Conlin

    BACKGROUND Exome sequencing (ES) is a first-tier diagnostic test for many suspected Mendelian disorders. While it is routine to detect small sequence variants, it is not a standard practice in clinical settings to detect germline copy-number variants (CNVs) from ES data due to several reasons relating to performance. In this work, we comprehensively characterized one of the most sensitive ES-based

  • Interactions between the gut microbiome and host gene regulation in cystic fibrosis.
    Genome Med. (IF 10.886) Pub Date : 2020-01-28
    Gargi Dayama,Sambhawa Priya,David E Niccum,Alexander Khoruts,Ran Blekhman

    BACKGROUND Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians. It is caused by mutations in the CFTR gene, leading to poor hydration of mucus and impairment of the respiratory, digestive, and reproductive organ functions. Advancements in medical care have led to markedly increased longevity of patients with cystic fibrosis, but new complications have emerged, such

  • Stepwise evolution and convergent recombination underlie the global dissemination of carbapenemase-producing Escherichia coli.
    Genome Med. (IF 10.886) Pub Date : 2020-01-20
    Rafael Patiño-Navarrete,Isabelle Rosinski-Chupin,Nicolas Cabanel,Lauraine Gauthier,Julie Takissian,Jean-Yves Madec,Monzer Hamze,Remy A Bonnin,Thierry Naas,Philippe Glaser

    BACKGROUND Carbapenem-resistant Enterobacteriaceae are considered by WHO as "critical" priority pathogens for which novel antibiotics are urgently needed. The dissemination of carbapenemase-producing Escherichia coli (CP-Ec) in the community is a major public health concern. However, the global molecular epidemiology of CP-Ec isolates remains largely unknown as well as factors contributing to the acquisition

  • Genomic surveillance for hypervirulence and multi-drug resistance in invasive Klebsiella pneumoniae from South and Southeast Asia.
    Genome Med. (IF 10.886) Pub Date : 2020-01-16
    Kelly L Wyres,To N T Nguyen,Margaret M C Lam,Louise M Judd,Nguyen van Vinh Chau,David A B Dance,Margaret Ip,Abhilasha Karkey,Clare L Ling,Thyl Miliya,Paul N Newton,Nguyen Phu Huong Lan,Amphone Sengduangphachanh,Paul Turner,Balaji Veeraraghavan,Phat Voong Vinh,Manivanh Vongsouvath,Nicholas R Thomson,Stephen Baker,Kathryn E Holt

    BACKGROUND Klebsiella pneumoniae is a leading cause of bloodstream infection (BSI). Strains producing extended-spectrum beta-lactamases (ESBLs) or carbapenemases are considered global priority pathogens for which new treatment and prevention strategies are urgently required, due to severely limited therapeutic options. South and Southeast Asia are major hubs for antimicrobial-resistant (AMR) K. pneumoniae

  • De novo variants in exomes of congenital heart disease patients identify risk genes and pathways.
    Genome Med. (IF 10.886) Pub Date : 2020-01-15
    Cigdem Sevim Bayrak,Peng Zhang,Martin Tristani-Firouzi,Bruce D Gelb,Yuval Itan

    BACKGROUND Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently. De novo variants are estimated to contribute to approximately 8% of sporadic CHD. METHODS CHD is genetically heterogeneous, making pathway enrichment analysis an effective approach

  • Molecular profiling for precision cancer therapies.
    Genome Med. (IF 10.886) Pub Date : 2020-01-14
    Eoghan R Malone,Marc Oliva,Peter J B Sabatini,Tracy L Stockley,Lillian L Siu

    The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation

  • An unsupervised learning approach to identify novel signatures of health and disease from multimodal data.
    Genome Med. (IF 10.886) Pub Date : 2020-01-10
    Ilan Shomorony,Elizabeth T Cirulli,Lei Huang,Lori A Napier,Robyn R Heister,Michael Hicks,Isaac V Cohen,Hung-Chun Yu,Christine Leon Swisher,Natalie M Schenker-Ahmed,Weizhong Li,Karen E Nelson,Pamila Brar,Andrew M Kahn,Timothy D Spector,C Thomas Caskey,J Craig Venter,David S Karow,Ewen F Kirkness,Naisha Shah

    BACKGROUND Modern medicine is rapidly moving towards a data-driven paradigm based on comprehensive multimodal health assessments. Integrated analysis of data from different modalities has the potential of uncovering novel biomarkers and disease signatures. METHODS We collected 1385 data features from diverse modalities, including metabolome, microbiome, genetics, and advanced imaging, from 1253 individuals

  • Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential.
    Genome Med. (IF 10.886) Pub Date : 2020-01-08
    Kara A Moser,Elliott F Drábek,Ankit Dwivedi,Emily M Stucke,Jonathan Crabtree,Antoine Dara,Zalak Shah,Matthew Adams,Tao Li,Priscila T Rodrigues,Sergey Koren,Adam M Phillippy,James B Munro,Amed Ouattara,Benjamin C Sparklin,Julie C Dunning Hotopp,Kirsten E Lyke,Lisa Sadzewicz,Luke J Tallon,Michele D Spring,Krisada Jongsakul,Chanthap Lon,David L Saunders,Marcelo U Ferreira,Myaing M Nyunt,Miriam K Laufer

    BACKGROUND Plasmodium falciparum (Pf) whole-organism sporozoite vaccines have been shown to provide significant protection against controlled human malaria infection (CHMI) in clinical trials. Initial CHMI studies showed significantly higher durable protection against homologous than heterologous strains, suggesting the presence of strain-specific vaccine-induced protection. However, interpretation

  • An epigenome-wide association study of sex-specific chronological ageing.
    Genome Med. (IF 10.886) Pub Date : 2019-12-31
    Daniel L McCartney,Futao Zhang,Robert F Hillary,Qian Zhang,Anna J Stevenson,Rosie M Walker,Mairead L Bermingham,Thibaud Boutin,Stewart W Morris,Archie Campbell,Alison D Murray,Heather C Whalley,David J Porteous,Caroline Hayward,Kathryn L Evans,Tamir Chandra,Ian J Deary,Andrew M McIntosh,Jian Yang,Peter M Visscher,Allan F McRae,Riccardo E Marioni

    BACKGROUND Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 individuals between

  • Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank.
    Genome Med. (IF 10.886) Pub Date : 2019-12-31
    Noura S Abul-Husn,Emily R Soper,Jacqueline A Odgis,Sinead Cullina,Dean Bobo,Arden Moscati,Jessica E Rodriguez,,,Ruth J F Loos,Judy H Cho,Gillian M Belbin,Sabrina A Suckiel,Eimear E Kenny

    BACKGROUND Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City

  • Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.
    Genome Med. (IF 10.886) Pub Date : 2019-12-31
    Sarah E Brnich,Ahmad N Abou Tayoun,Fergus J Couch,Garry R Cutting,Marc S Greenblatt,Christopher D Heinen,Dona M Kanavy,Xi Luo,Shannon M McNulty,Lea M Starita,Sean V Tavtigian,Matt W Wright,Steven M Harrison,Leslie G Biesecker,Jonathan S Berg,

    BACKGROUND The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for "well-established" functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they

  • Digital twins to personalize medicine.
    Genome Med. (IF 10.886) Pub Date : 2019-12-31
    Bergthor Björnsson,Carl Borrebaeck,Nils Elander,Thomas Gasslander,Danuta R Gawel,Mika Gustafsson,Rebecka Jörnsten,Eun Jung Lee,Xinxiu Li,Sandra Lilja,David Martínez-Enguita,Andreas Matussek,Per Sandström,Samuel Schäfer,Margaretha Stenmarker,X F Sun,Oleg Sysoev,Huan Zhang,Mikael Benson,

    Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.

  • Keeping up with the genomes: scaling genomic variant interpretation.
    Genome Med. (IF 10.886) Pub Date : 2019-12-31
    Heidi L Rehm,Douglas M Fowler

    In the past 10 years, we have seen major advances in our ability to read human genomic DNA and detect variation. The variants we find have the potential to improve the diagnosis and treatment of human disease and also to define our unique traits. Although slower to catch up, we are now seeing equally rapid advances in the strategies used to interpret these variants in both coding and non-coding regions

  • Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4.
    Genome Med. (IF 10.886) Pub Date : 2019-12-30
    Jitske van den Bulk,Els M E Verdegaal,Dina Ruano,Marieke E Ijsselsteijn,Marten Visser,Ruud van der Breggen,Thomas Duhen,Manon van der Ploeg,Natasja L de Vries,Jan Oosting,Koen C M J Peeters,Andrew D Weinberg,Arantza Farina-Sarasqueta,Sjoerd H van der Burg,Noel F C C de Miranda

    BACKGROUND The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for

  • Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression.
    Genome Med. (IF 10.886) Pub Date : 2019-12-23
    Anastasiya Kazachenka,George R Young,Jan Attig,Chrysoula Kordella,Eleftheria Lamprianidou,Emmanuela Zoulia,George Vrachiolias,Menelaos Papoutselis,Elsa Bernard,Elli Papaemmanuil,Ioannis Kotsianidis,George Kassiotis

    BACKGROUND Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs). Drugs that reverse epigenetic repression, such as 5-azacytidine (5-AZA), induce haematological improvement in half of treated patients. Although the mechanisms underlying therapy success are not yet clear

  • Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation.
    Genome Med. (IF 10.886) Pub Date : 2019-12-20
    Hannah Gelman,Jennifer N Dines,Jonathan Berg,Alice H Berger,Sarah Brnich,Fuki M Hisama,Richard G James,Alan F Rubin,Jay Shendure,Brian Shirts,Douglas M Fowler,Lea M Starita,

    Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously, are increasingly generating data that can be used as additional evidence for or against variant pathogenicity. Such assays have the potential to resolve variants of uncertain significance, thereby

  • FIREVAT: finding reliable variants without artifacts in human cancer samples using etiologically relevant mutational signatures.
    Genome Med. (IF 10.886) Pub Date : 2019-12-17
    Hyunbin Kim,Andy Jinseok Lee,Jongkeun Lee,Hyonho Chun,Young Seok Ju,Dongwan Hong

    BACKGROUND Accurate identification of real somatic variants is a primary part of cancer genome studies and precision oncology. However, artifacts introduced in various steps of sequencing obfuscate confidence in variant calling. Current computational approaches to variant filtering involve intensive interrogation of Binary Alignment Map (BAM) files and require massive computing power, data storage

  • Genomics of circadian rhythms in health and disease.
    Genome Med. (IF 10.886) Pub Date : 2019-12-17
    Filipa Rijo-Ferreira,Joseph S Takahashi

    Circadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including the regulation of sleep, metabolism, and the immune system. Here, we review advances in understanding the genetic regulation of sleep through the circadian system, as well as the impact of dysregulated

  • Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases.
    Genome Med. (IF 10.886) Pub Date : 2019-12-17
    Elias L Salfati,Emily G Spencer,Sarah E Topol,Evan D Muse,Manuel Rueda,Jonathan R Lucas,Glenn N Wagner,Steven Campman,Eric J Topol,Ali Torkamani

    BACKGROUND Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. METHODS Of the 101 WES cases, 51 were rare idiopathic disease

  • A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation.
    Genome Med. (IF 10.886) Pub Date : 2019-12-17
    Hannah Demond,Zahra Anvar,Bahia Namavar Jahromi,Angela Sparago,Ankit Verma,Maryam Davari,Luciano Calzari,Silvia Russo,Mojgan Akbarzadeh Jahromi,David Monk,Simon Andrews,Andrea Riccio,Gavin Kelsey

    BACKGROUND Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM)

  • Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants.
    Genome Med. (IF 10.886) Pub Date : 2019-12-09
    Vahid Bahrambeigi,Xiaofei Song,Karen Sperle,Christine R Beck,Hadia Hijazi,Christopher M Grochowski,Shen Gu,Pavel Seeman,Karen J Woodward,Claudia M B Carvalho,Grace M Hobson,James R Lupski

    BACKGROUND We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). We then compared our new data to previous structural variant mutagenesis studies involving the Xq22 region of the human genome. The aggregate data from 159 sequenced

  • Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants.
    Genome Med. (IF 10.886) Pub Date : 2019-12-04
    Sjors Middelkamp,Judith M Vlaar,Jacques Giltay,Jerome Korzelius,Nicolle Besselink,Sander Boymans,Roel Janssen,Lisanne de la Fonteijne,Ellen van Binsbergen,Markus J van Roosmalen,Ron Hochstenbach,Daniela Giachino,Michael E Talkowski,Wigard P Kloosterman,Edwin Cuppen

    BACKGROUND Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown. METHODS We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual

  • Text-mining clinically relevant cancer biomarkers for curation into the CIViC database.
    Genome Med. (IF 10.886) Pub Date : 2019-12-03
    Jake Lever,Martin R Jones,Arpad M Danos,Kilannin Krysiak,Melika Bonakdar,Jasleen K Grewal,Luka Culibrk,Obi L Griffith,Malachi Griffith,Steven J M Jones

    BACKGROUND Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic, prognostic, predisposing, and drug response markers is essential. Several knowledgebases have been created by different groups to collate evidence for these associations. These include

  • Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels
    Genome Med. (IF 10.886) Pub Date : 2019-11-29
    Dona M. Kanavy; Shannon M. McNulty; Meera K. Jairath; Sarah E. Brnich; Chris Bizon; Bradford C. Powell; Jonathan S. Berg

    The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that “well-established” functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and

  • Standard operating procedure for curation and clinical interpretation of variants in cancer.
    Genome Med. (IF 10.886) Pub Date : 2019-11-29
    Arpad M Danos,Kilannin Krysiak,Erica K Barnell,Adam C Coffman,Joshua F McMichael,Susanna Kiwala,Nicholas C Spies,Lana M Sheta,Shahil P Pema,Lynzey Kujan,Kaitlin A Clark,Amber Z Wollam,Shruti Rao,Deborah I Ritter,Dmitriy Sonkin,Gordana Raca,Wan-Hsin Lin,Cameron J Grisdale,Raymond H Kim,Alex H Wagner,Subha Madhavan,Malachi Griffith,Obi L Griffith

    Manually curated variant knowledgebases and their associated knowledge models are serving an increasingly important role in distributing and interpreting variants in cancer. These knowledgebases vary in their level of public accessibility, and the complexity of the models used to capture clinical knowledge. CIViC (Clinical Interpretation of Variants in Cancer - www.civicdb.org) is a fully open, free-to-use

  • Genomic screening and genomic diagnostic testing—two very different kettles of fish
    Genome Med. (IF 10.886) Pub Date : 2019-11-27
    Leslie G. Biesecker

    Genomic testing can be misunderstood as being determinative, when in reality it is the same as all other tests and context is essential for its correct interpretation. Two hypothetical cases of testing for Marfan syndrome demonstrate how clinicians should contextualize genomic test results and the implementation of Bayes theorem in clinical decision-making.

  • Immune receptor repertoires in pediatric and adult acute myeloid leukemia
    Genome Med. (IF 10.886) Pub Date : 2019-11-26
    Jian Zhang; Xihao Hu; Jin Wang; Avinash Das Sahu; David Cohen; Li Song; Zhangyi Ouyang; Jingyu Fan; Binbin Wang; Jingxin Fu; Shengqing Gu; Moshe Sade-Feldman; Nir Hacohen; Wuju Li; Xiaomin Ying; Bo Li; X. Shirley Liu

    Acute myeloid leukemia (AML), caused by the abnormal proliferation of immature myeloid cells in the blood or bone marrow, is one of the most common hematologic malignancies. Currently, the interactions between malignant myeloid cells and the immune microenvironment, especially T cells and B cells, remain poorly characterized. In this study, we systematically analyzed the T cell receptor and B cell

  • Low coverage whole genome sequencing enables accurate assessment of common variants and calculation of genome-wide polygenic scores
    Genome Med. (IF 10.886) Pub Date : 2019-11-26
    Julian R. Homburger; Cynthia L. Neben; Gilad Mishne; Alicia Y. Zhou; Sekar Kathiresan; Amit V. Khera

    Inherited susceptibility to common, complex diseases may be caused by rare, pathogenic variants (“monogenic”) or by the cumulative effect of numerous common variants (“polygenic”). Comprehensive genome interpretation should enable assessment for both monogenic and polygenic components of inherited risk. The traditional approach requires two distinct genetic testing technologies—high coverage sequencing

  • Is 'likely pathogenic' really 90% likely? Reclassification data in ClinVar.
    Genome Med. (IF 10.886) Pub Date : 2019-11-21
    Steven M Harrison,Heidi L Rehm

    In 2015, professional guidelines defined the term 'likely pathogenic' to mean with a 90% chance of pathogenicity. To determine whether current practice reflects this definition, ClinVar classifications were tracked from 2016 to 2019. During that period, between 83.8 and 99.1% of likely pathogenic classifications were reclassified as pathogenic, depending on whether LP to VUS reclassifications are included

  • Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response.
    Genome Med. (IF 10.886) Pub Date : 2019-11-20
    Elaine R Mardis

    The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clearly lies in the genomic alterations that are associated with cancer onset and progression, including those that contribute to genomic instability and the resulting creation of novel peptide sequences

  • Artificial intelligence in clinical and genomic diagnostics.
    Genome Med. (IF 10.886) Pub Date : 2019-11-19
    Raquel Dias,Ali Torkamani

    Artificial intelligence (AI) is the development of computer systems that are able to perform tasks that normally require human intelligence. Advances in AI software and hardware, especially deep learning algorithms and the graphics processing units (GPUs) that power their training, have led to a recent and rapidly increasing interest in medical AI applications. In clinical diagnostics, AI-based computer

  • Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension.
    Genome Med. (IF 10.886) Pub Date : 2019-11-14
    Na Zhu,Michael W Pauciulo,Carrie L Welch,Katie A Lutz,Anna W Coleman,Claudia Gonzaga-Jauregui,Jiayao Wang,Joseph M Grimes,Lisa J Martin,Hua He,,Yufeng Shen,Wendy K Chung,William C Nichols

    BACKGROUND Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial

  • From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
    Genome Med. (IF 10.886) Pub Date : 2019-11-07
    Anna Lindstrand; Jesper Eisfeldt; Maria Pettersson; Claudia M. B. Carvalho; Malin Kvarnung; Giedre Grigelioniene; Britt-Marie Anderlid; Olof Bjerin; Peter Gustavsson; Anna Hammarsjö; Patrik Georgii-Hemming; Erik Iwarsson; Maria Johansson-Soller; Kristina Lagerstedt-Robinson; Agne Lieden; Måns Magnusson; Marcel Martin; Helena Malmgren; Magnus Nordenskjöld; Ameli Norling; Ellika Sahlin; Henrik Stranneheim;

    Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test. We analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants

  • Advancing cancer immunotherapy: a vision for the field.
    Genome Med. (IF 10.886) Pub Date : 2019-07-29
    Noel F C C de Miranda,Zlatko Trajanoski

  • From genome integrity to cancer.
    Genome Med. (IF 10.886) Pub Date : 2019-01-31
    Serena Nik-Zainal

  • pVAC-Seq: A genome-guided in silico approach to identifying tumor neoantigens.
    Genome Med. (IF 10.886) Pub Date : 2016-01-31
    Jasreet Hundal,Beatriz M Carreno,Allegra A Petti,Gerald P Linette,Obi L Griffith,Elaine R Mardis,Malachi Griffith

    Cancer immunotherapy has gained significant momentum from recent clinical successes of checkpoint blockade inhibition. Massively parallel sequence analysis suggests a connection between mutational load and response to this class of therapy. Methods to identify which tumor-specific mutant peptides (neoantigens) can elicit anti-tumor T cell immunity are needed to improve predictions of checkpoint therapy

  • From genomic medicine to precision medicine: highlights of 2015.
    Genome Med. (IF 10.886) Pub Date : 2016-01-31
    Charles Auffray,Timothy Caulfield,Julian L Griffin,Muin J Khoury,James R Lupski,Matthias Schwab

  • Epigenetic impact of infection on carcinogenesis: mechanisms and applications.
    Genome Med. (IF 10.886) Pub Date : 2016-01-30
    Naoko Hattori,Toshikazu Ushijima

    Viral and bacterial infections are involved in the development of human cancers, such as liver, nasopharyngeal, cervical, head and neck, and gastric cancers. Aberrant DNA methylation is frequently present in these cancers, and some of the aberrantly methylated genes are causally involved in cancer development and progression. Notably, aberrant DNA methylation can be present even in non-cancerous or

  • Signatures of early frailty in the gut microbiota.
    Genome Med. (IF 10.886) Pub Date : 2016-01-30
    Matthew A Jackson,Matt Jackson,Ian B Jeffery,Michelle Beaumont,Jordana T Bell,Andrew G Clark,Ruth E Ley,Paul W O'Toole,Tim D Spector,Claire J Steves

    BACKGROUND Frailty is arguably the biggest problem associated with population ageing, and associates with gut microbiome composition in elderly and care-dependent individuals. Here we characterize frailty associations with the gut microbiota in a younger community dwelling population, to identify targets for intervention to encourage healthy ageing. METHOD We analysed 16S rRNA gene sequence data derived

  • Designing string-of-beads vaccines with optimal spacers.
    Genome Med. (IF 10.886) Pub Date : 2016-01-28
    Benjamin Schubert,Oliver Kohlbacher

    String-of-beads polypeptides allow convenient delivery of epitope-based vaccines. The success of a polypeptide relies on efficient processing: constituent epitopes need to be recovered while avoiding neo-epitopes from epitope junctions. Spacers between epitopes are employed to ensure this, but spacer selection is non-trivial.We present a framework to determine optimally the length and sequence of a

  • Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease.
    Genome Med. (IF 10.886) Pub Date : 2016-01-26
    Corey T Watson,Panos Roussos,Paras Garg,Daniel J Ho,Nidha Azam,Pavel L Katsel,Vahram Haroutunian,Andrew J Sharp

    BACKGROUND Alzheimer's disease affects ~13% of people in the United States 65 years and older, making it the most common neurodegenerative disorder. Recent work has identified roles for environmental, genetic, and epigenetic factors in Alzheimer's disease risk. METHODS We performed a genome-wide screen of DNA methylation using the Illumina Infinium HumanMethylation450 platform on bulk tissue samples

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全球疫情及响应:BMC Medicine专题征稿