Articles

Identifying chemogenetic interactions from CRISPR screens with drugZ

Chemogenetic profiling enables the identification of gene mutations that enhance or suppress the activity of chemical compounds. This knowledge provides insights into drug mechanism of action, genetic vulnerab...

Authors: Medina Colic, Gang Wang, Michal Zimmermann, Keith Mascall, Megan McLaughlin, Lori Bertolet, W. Frank Lenoir, Jason Moffat, Stephane Angers, Daniel Durocher and Traver Hart

A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases

Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across ...

Authors: Danuta R. Gawel, Jordi Serra-Musach, Sandra Lilja, Jesper Aagesen, Alex Arenas, Bengt Asking, Malin Bengnér, Janne Björkander, Sophie Biggs, Jan Ernerudh, Henrik Hjortswang, Jan-Erik Karlsson, Mattias Köpsen, Eun Jung Lee, Antonio Lentini, Xinxiu Li…

Advancing cancer immunotherapy: a vision for the field

Authors: Noel F. C. C. de Miranda and Zlatko Trajanoski

Correction to: Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data

It was highlighted that the original article [1] contained a typesetting mistake in the name of Noel Filipe da Cunha Carvalho de Miranda. This was incorrectly captured as Noel Filipe da Cunha Carvahlo de Miran...

Authors: Francesca Finotello, Clemens Mayer, Christina Plattner, Gerhard Laschober, Dietmar Rieder, Hubert Hackl, Anne Krogsdam, Zuzana Loncova, Wilfried Posch, Doris Wilflingseder, Sieghart Sopper, Marieke Ijsselsteijn, Thomas P. Brouwer, Douglas Johnson, Yaomin Xu, Yu Wang…

Hidden Markov models lead to higher resolution maps of mutation signature activity in cancer

Knowing the activity of the mutational processes shaping a cancer genome may provide insight into tumorigenesis and personalized therapy. It is thus important to characterize the signatures of active mutationa...

Authors: Damian Wojtowicz, Itay Sason, Xiaoqing Huang, Yoo-Ah Kim, Mark D. M. Leiserson, Teresa M. Przytycka and Roded Sharan

A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing

Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have ...

Authors: Ye Cao, Mari J. Tokita, Edward S. Chen, Rajarshi Ghosh, Tiansheng Chen, Yanming Feng, Elizabeth Gorman, Federica Gibellini, Patricia A. Ward, Alicia Braxton, Xia Wang, Linyan Meng, Rui Xiao, Weimin Bi, Fan Xia, Christine M. Eng…

Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series

A multi-disciplinary approach to promote engagement, inform decision-making and support clinicians and patients is increasingly advocated to realise the potential of genome-scale sequencing in the clinic for p...

Authors: John Taylor, Jude Craft, Edward Blair, Sarah Wordsworth, David Beeson, Saleel Chandratre, Judith Cossins, Tracy Lester, Andrea H. Németh, Elizabeth Ormondroyd, Smita Y. Patel, Alistair T. Pagnamenta, Jenny C. Taylor, Kate L. Thomson, Hugh Watkins, Andrew O. M. Wilkie…

Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges

Tuberculosis (TB) is a global infectious threat that is intensified by an increasing incidence of highly drug-resistant disease. Whole-genome sequencing (WGS) studies of Mycobacterium tuberculosis, the causative ...

Authors: Keira A. Cohen, Abigail L. Manson, Christopher A. Desjardins, Thomas Abeel and Ashlee M. Earl

Identification of intermediate-sized deletions and inference of their impact on gene expression in a human population

Next-generation sequencing has allowed for the identification of different genetic variations, which are known to contribute to diseases. Of these, insertions and deletions are the second most abundant type of...

Authors: Jing Hao Wong, Daichi Shigemizu, Yukiko Yoshii, Shintaro Akiyama, Azusa Tanaka, Hidewaki Nakagawa, Shu Narumiya and Akihiro Fujimoto

The good, the bad, and the ugly: hyperprogression in cancer patients following immune checkpoint therapy

Immune checkpoint blockade therapy can elicit robust and durable responses in a variety of cancer types. While many patients do not respond, recent reports highlight a distinct group of patients whose tumors u...

Authors: Erich Sabio and Timothy A. Chan

Evolving neoantigen profiles in colorectal cancers with DNA repair defects

Neoantigens that arise as a consequence of tumor-specific mutations can be recognized by T lymphocytes leading to effective immune surveillance. In colorectal cancer (CRC) and other tumor types, a high number ...

Authors: Giuseppe Rospo, Annalisa Lorenzato, Nabil Amirouchene-Angelozzi, Alessandro Magrì, Carlotta Cancelliere, Giorgio Corti, Carola Negrino, Vito Amodio, Monica Montone, Alice Bartolini, Ludovic Barault, Luca Novara, Claudio Isella, Enzo Medico, Andrea Bertotti, Livio Trusolino…

Integrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugs

Mycobacterium tuberculosis resistance to anti-tuberculosis drugs is a major threat to global public health. Whole genome sequencing (WGS) is rapidly gaining traction as a diagnostic tool for clinical tuberculosis...

Authors: Jody E. Phelan, Denise M. O’Sullivan, Diana Machado, Jorge Ramos, Yaa E. A. Oppong, Susana Campino, Justin O’Grady, Ruth McNerney, Martin L. Hibberd, Miguel Viveiros, Jim F. Huggett and Taane G. Clark

Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system

The expression of antigens that are recognized by self-reactive T cells is essential for immune-mediated tumor rejection by immune checkpoint blockade (ICB) therapy. Growing evidence suggests that mutation-ass...

Authors: Claire Lhuillier, Nils-Petter Rudqvist, Olivier Elemento, Silvia C. Formenti and Sandra Demaria

Mechanisms of immune-related adverse events associated with immune checkpoint blockade: using germline genetics to develop a personalized approach

Personalized care of cancer patients undergoing treatment with immune checkpoint inhibitors will require approaches that can predict their susceptibility to immune-related adverse events. Understanding the rol...

Authors: Zia Khan, Christian Hammer, Ellie Guardino, G. Scott Chandler and Matthew L. Albert

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of pa...

Authors: Peer Arts, Annet Simons, Mofareh S. AlZahrani, Elanur Yilmaz, Eman AlIdrissi, Koen J. van Aerde, Njood Alenezi, Hamza A. AlGhamdi, Hadeel A. AlJubab, Abdulrahman A. Al-Hussaini, Fahad AlManjomi, Alaa B. Alsaad, Badr Alsaleem, Abdulrahman A. Andijani, Ali Asery, Walid Ballourah…

Associating somatic mutations to clinical outcomes: a pan-cancer study of survival time

We developed subclone multiplicity allocation and somatic heterogeneity (SMASH), a new statistical method for intra-tumor heterogeneity (ITH) inference. SMASH is tailored to the purpose of large-scale associat...

Authors: Paul Little, Dan-Yu Lin and Wei Sun

Prognostic value of B cells in cutaneous melanoma

Measures of the adaptive immune response have prognostic and predictive associations in melanoma and other cancer types. Specifically, intratumoral T cell density and function have considerable prognostic and ...

Authors: Sara R. Selitsky, Lisle E. Mose, Christof C. Smith, Shengjie Chai, Katherine A. Hoadley, Dirk P. Dittmer, Stergios J. Moschos, Joel S. Parker and Benjamin G. Vincent

Somatic mutation and clonal expansions in human tissues

Recent sequencing studies on healthy skin and esophagus have found that, as we age, these tissues become colonized by mutant clones of cells carrying driver mutations in traditional cancer genes. This comment ...

Authors: Inigo Martincorena

Clinical utility of custom-designed NGS panel testing in pediatric tumors

Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved...

Authors: Lea F. Surrey, Suzanne P. MacFarland, Fengqi Chang, Kajia Cao, Komal S. Rathi, Gozde T. Akgumus, Daniel Gallo, Fumin Lin, Adam Gleason, Pichai Raman, Richard Aplenc, Rochelle Bagatell, Jane Minturn, Yael Mosse, Mariarita Santi, Sarah K. Tasian…

Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data

We introduce quanTIseq, a method to quantify the fractions of ten immune cell types from bulk RNA-sequencing data. quanTIseq was extensively validated in blood and tumor samples using simulated, flow cytometry...

Authors: Francesca Finotello, Clemens Mayer, Christina Plattner, Gerhard Laschober, Dietmar Rieder, Hubert Hackl, Anne Krogsdam, Zuzana Loncova, Wilfried Posch, Doris Wilflingseder, Sieghart Sopper, Marieke Ijsselsteijn, Thomas P. Brouwer, Douglas Johnson, Yaomin Xu, Yu Wang…

Dissecting lung development and fibrosis at single-cell resolution

Single-cell transcriptome profiling has enabled high-resolution analysis of cellular populations in tissues during development, health, and disease. Recent studies make innovative use of single-cell RNA sequen...

Authors: Donna L. Farber and Peter A. Sims

Points-to-consider on the return of results in epigenetic research

As epigenetic studies become more common and lead to new insights into health and disease, the return of individual epigenetic results to research participants, in particular in large-scale epigenomic studies,...

Authors: Stephanie O. M. Dyke, Katie M. Saulnier, Charles Dupras, Amy P. Webster, Karen Maschke, Mark Rothstein, Reiner Siebert, Jörn Walter, Stephan Beck, Tomi Pastinen and Yann Joly

Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases

Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains cha...

Authors: Avinash V. Dharmadhikari, Rajarshi Ghosh, Bo Yuan, Pengfei Liu, Hongzheng Dai, Sami Al Masri, Jennifer Scull, Jennifer E. Posey, Allen H. Jiang, Weimin He, Francesco Vetrini, Alicia A. Braxton, Patricia Ward, Theodore Chiang, Chunjing Qu, Shen Gu…

Discovery and characterization of actionable tumor antigens

The nature of the tumor antigens that are detectable by T cells remains unclear. In melanoma, T cells were shown to react against major histocompatibility complex (MHC)-associated peptides (MAPs) that are deri...

Authors: Grégory Ehx and Claude Perreault

Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma

Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach ...

Authors: Markus W. Löffler, Christopher Mohr, Leon Bichmann, Lena Katharina Freudenmann, Mathias Walzer, Christopher M. Schroeder, Nico Trautwein, Franz J. Hilke, Raphael S. Zinser, Lena Mühlenbruch, Daniel J. Kowalewski, Heiko Schuster, Marc Sturm, Jakob Matthes, Olaf Riess, Stefan Czemmel…

A modular transcriptome map of mature B cell lymphomas

Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this diseas...

Authors: Henry Loeffler-Wirth, Markus Kreuz, Lydia Hopp, Arsen Arakelyan, Andrea Haake, Sergio B. Cogliatti, Alfred C. Feller, Martin-Leo Hansmann, Dido Lenze, Peter Möller, Hans Konrad Müller-Hermelink, Erik Fortenbacher, Edith Willscher, German Ott, Andreas Rosenwald, Christiane Pott…

Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility

Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been id...

Authors: Ali Afrasiabi, Grant P. Parnell, Nicole Fewings, Stephen D. Schibeci, Monica A. Basuki, Ramya Chandramohan, Yuan Zhou, Bruce Taylor, David A. Brown, Sanjay Swaminathan, Fiona C. McKay, Graeme J. Stewart and David R. Booth

Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome

Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjace...

Authors: Claudia M. B. Carvalho, Zeynep Coban-Akdemir, Hadia Hijazi, Bo Yuan, Matthew Pendleton, Eoghan Harrington, John Beaulaurier, Sissel Juul, Daniel J. Turner, Rupa S. Kanchi, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, Pawel Stankiewicz, John W. Belmont, Chad A. Shaw…

Molecular basis for phenotypic similarity of genetic disorders

The contribution of distinct genes to overlapping phenotypes suggests that such genes share ancestral origins, membership of disease pathways, or molecular functions. A recent study by Liu and colleagues ident...

Authors: Vijay Kumar Pounraja and Santhosh Girirajan

TCF21 and AP-1 interact through epigenetic modifications to regulate coronary artery disease gene expression

Genome-wide association studies have identified over 160 loci that are associated with coronary artery disease. As with other complex human diseases, risk in coronary disease loci is determined primarily by al...

Authors: Quanyi Zhao, Robert Wirka, Trieu Nguyen, Manabu Nagao, Paul Cheng, Clint L. Miller, Juyong Brian Kim, Milos Pjanic and Thomas Quertermous

Designing circulating tumor DNA-based interventional clinical trials in oncology

Circulating tumor (ct) DNA is a powerful tool that can be used to track cancer beyond a single snapshot in space and time. It has potential applications in detecting minimal residual disease and predicting rel...

Authors: Daniel V. Araujo, Scott V. Bratman and Lillian L. Siu

CRISPR-SONIC: targeted somatic oncogene knock-in enables rapid in vivo cancer modeling

CRISPR/Cas9 has revolutionized cancer mouse models. Although loss-of-function genetics by CRISPR/Cas9 is well-established, generating gain-of-function alleles in somatic cancer models is still challenging beca...

Authors: Haiwei Mou, Deniz M. Ozata, Jordan L. Smith, Ankur Sheel, Suet-Yan Kwan, Soren Hough, Alper Kucukural, Zachary Kennedy, Yueying Cao and Wen Xue

Translating insights into tumor evolution to clinical practice: promises and challenges

Accelerating technological advances have allowed the widespread genomic profiling of tumors. As yet, however, the vast catalogues of mutations that have been identified have made only a modest impact on clinic...

Authors: Matthew W. Fittall and Peter Van Loo

Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data

Genome-wide association studies (GWAS) have identified several hundred susceptibility loci for type 2 diabetes (T2D). One critical, but unresolved, issue concerns the extent to which the mechanisms through whi...

Authors: Juan Fernández-Tajes, Kyle J. Gaulton, Martijn van de Bunt, Jason Torres, Matthias Thurner, Anubha Mahajan, Anna L. Gloyn, Kasper Lage and Mark I. McCarthy

Loss of BAP1 as a candidate predictive biomarker for immunotherapy of mesothelioma

As trials of immune checkpoint inhibitor (ICI) therapies demonstrate responses in only a minority of pleural mesotheliomas (PlMs) and largely exclude patients with the related peritoneal mesothelioma (PeM), cl...

Authors: Marc Ladanyi, Francisco Sanchez Vega and Marjorie Zauderer

Encircling the regions of the pharmacogenomic landscape that determine drug response

The integration of large-scale drug sensitivity screens and genome-wide experiments is changing the field of pharmacogenomics, revealing molecular determinants of drug response without the need for previous kn...

Authors: Adrià Fernández-Torras, Miquel Duran-Frigola and Patrick Aloy

Correction to: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The ...

Authors: Francesco Vetrini, Shane McKee, Jill A. Rosenfeld, Mohnish Suri, Andrea M. Lewis, Kimberly Margaret Nugent, Elizabeth Roeder, Rebecca O. Littlejohn, Sue Holder, Wenmiao Zhu, Joseph T. Alaimo, Brett Graham, Jill M. Harris, James B. Gibson, Matthew Pastore, Kim L. McBride…

Circular RNAs as promising biomarkers in cancer: detection, function, and beyond

Circular RNAs (circRNAs) are 3′–5′ covalently closed RNA rings produced from back-splicing of precursor mRNA in eukaryotes. Recent studies, using both computational and experimental approaches, have allowed ad...

Authors: Shengli Li and Leng Han

Correction to: NSAID use and somatic exomic mutations in Barrett’s esophagus

It was highlighted that in the original article [1] the Availability of data and materials section was incorrect.

Authors: Patricia C. Galipeau, Kenji M. Oman, Thomas G. Paulson, Carissa A. Sanchez, Qing Zhang, Jerry A. Marty, Jeffrey J. Delrow, Mary K. Kuhner, Thomas L. Vaughan, Brian J. Reid and Xiaohong Li

A decade of Genome Medicine: toward precision medicine

Authors: Rabia Begum

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormaliti...

Authors: Francesco Vetrini, Shane McKee, Jill A. Rosenfeld, Mohnish Suri, Andrea M. Lewis, Kimberly Margaret Nugent, Elizabeth Roeder, Rebecca O. Littlejohn, Sue Holder, Wenmiao Zhu, Joseph T. Alaimo, Brett Graham, Jill M. Harris, James B. Gibson, Matthew Pastore, Kim L. McBride…

Predispositional genome sequencing in healthy adults: design, participant characteristics, and early outcomes of the PeopleSeq Consortium

Increasing numbers of healthy individuals are undergoing predispositional personal genome sequencing. Here we describe the design and early outcomes of the PeopleSeq Consortium, a multi-cohort collaboration of...

Authors: Emilie S. Zoltick, Michael D. Linderman, Molly A. McGinniss, Erica Ramos, Madeleine P. Ball, George M. Church, Debra G. B. Leonard, Stacey Pereira, Amy L. McGuire, C. Thomas Caskey, Saskia C. Sanderson, Eric E. Schadt, Daiva E. Nielsen, Scott D. Crawford and Robert C. Green

Impact of the gut microbiome on the genome and epigenome of colon epithelial cells: contributions to colorectal cancer development

In recent years, the number of studies investigating the impact of the gut microbiome in colorectal cancer (CRC) has risen sharply. As a result, we now know that various microbes (and microbial communities) ar...

Authors: Jawara Allen and Cynthia L. Sears

Translating genomic medicine to the clinic: challenges and opportunities

Genomic medicine has considerable potential to provide novel diagnostic and therapeutic solutions for patients who have molecularly complex diseases and who are not responding to existing therapies. To bridge ...

Authors: Huan Zhang, Lars Klareskog, Andreas Matussek, Stefan M. Pfister and Mikael Benson

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma

Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, ...

Authors: Raunak Shrestha, Noushin Nabavi, Yen-Yi Lin, Fan Mo, Shawn Anderson, Stanislav Volik, Hans H. Adomat, Dong Lin, Hui Xue, Xin Dong, Robert Shukin, Robert H. Bell, Brian McConeghy, Anne Haegert, Sonal Brahmbhatt, Estelle Li…

Ten years of Genome Medicine

Authors: Charles Auffray, Julian L. Griffin, Muin J. Khoury, James R. Lupski and Matthias Schwab

Prioritizing putative influential genes in cardiovascular disease susceptibility by applying tissue-specific Mendelian randomization

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 inte...

Authors: Kurt Taylor, George Davey Smith, Caroline L. Relton, Tom R. Gaunt and Tom G. Richardson

Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy

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...

Authors: 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…

From genome integrity to cancer

Authors: Serena Nik-Zainal

Single-cell analysis reveals congruence between kidney organoids and human fetal kidney

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...

Authors: Alexander N. Combes, Luke Zappia, Pei Xuan Er, Alicia Oshlack and Melissa H. Little