Articles

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

Reconstruction of full-length circular RNAs enables isoform-level quantification

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 th...

Authors: Yi Zheng, Peifeng Ji, Shuai Chen, Lingling Hou and Fangqing Zhao

Next Generation-Targeted Amplicon Sequencing (NG-TAS): an optimised protocol and computational pipeline for cost-effective profiling of circulating tumour DNA

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 simultaneousl...

Authors: 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 and Carlos Caldas

Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response

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. Recen...

Authors: Paola Francica and Sven Rottenberg

Polygenic risk scores: a biased prediction?

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 work...

Authors: Francisco M. De La Vega and Carlos D. Bustamante

Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls

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...

Authors: 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…

Emerging evidence linking the gut microbiome to neurologic disorders

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...

Authors: Jessica A. Griffiths and Sarkis K. Mazmanian

Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations

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 th...

Authors: 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 and Javier Martín

An integrative approach for building personalized gene regulatory networks for precision medicine

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-individu...

Authors: Monique G. P. van der Wijst, Dylan H. de Vries, Harm Brugge, Harm-Jan Westra and Lude Franke

Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

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 whol...

Authors: 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…

Integrated proteotranscriptomics of breast cancer reveals globally increased protein-mRNA concordance associated with subtypes and survival

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 bi...

Authors: Wei Tang, Ming Zhou, Tiffany H. Dorsey, DaRue A. Prieto, Xin W. Wang, Eytan Ruppin, Timothy D. Veenstra and Stefan Ambs

Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer

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 resist...

Authors: Maki Tanioka, Kevin R. Mott, Daniel P. Hollern, Cheng Fan, David B. Darr and Charles M. Perou

Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine

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 ...

Authors: Jake R. Conway, Eric Kofman, Shirley S. Mo, Haitham Elmarakeby and Eliezer Van Allen

Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations

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 ...

Authors: 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…

Inactivation of DNA repair—prospects for boosting cancer immune surveillance

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 involv...

Authors: Anna Truini, Giovanni Germano and Alberto Bardelli

A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers

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 tr...

Authors: Tonći Šuštić, Sake van Wageningen, Evert Bosdriesz, Robert J. D. Reid, John Dittmar, Cor Lieftink, Roderick L. Beijersbergen, Lodewyk F. A. Wessels, Rodney Rothstein and René Bernards

The ins and outs of telomere crisis in cancer

Telomere crisis is linked with many of the genomic alterations found in cancer genomes. A new understanding of how these alterations arise points towards an active role for innate immune sensors during crisis ...

Authors: Patrick von Morgen and John Maciejowski

Early life immunity in the era of systems biology: understanding development and disease

Systems immunology has the potential to offer invaluable insights into the development of the immune system. Two recent studies offer an in-depth view of both the dynamics of immune system development and the ...

Authors: Steven Schaffert and Purvesh Khatri

Acquired mechanisms of immune escape in cancer following immunotherapy

Immunotherapy has revolutionized the management of numerous cancers; however, a substantial proportion that initially respond subsequently acquire means of immune escape and relapse. Analysis of recent clinica...

Authors: J. Bryan Iorgulescu, David Braun, Giacomo Oliveira, Derin B. Keskin and Catherine J. Wu

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potent...

Authors: Markus Mayrhofer, Bram De Laere, Tom Whitington, Peter Van Oyen, Christophe Ghysel, Jozef Ampe, Piet Ost, Wim Demey, Lucien Hoekx, Dirk Schrijvers, Barbara Brouwers, Willem Lybaert, Els Everaert, Daan De Maeseneer, Michiel Strijbos, Alain Bols…

Footprints of antigen processing boost MHC class II natural ligand predictions

Major histocompatibility complex class II (MHC-II) molecules present peptide fragments to T cells for immune recognition. Current predictors for peptide to MHC-II binding are trained on binding affinity data, ...

Authors: Carolina Barra, Bruno Alvarez, Sinu Paul, Alessandro Sette, Bjoern Peters, Massimo Andreatta, Søren Buus and Morten Nielsen

Computational analysis reveals histotype-dependent molecular profile and actionable mutation effects across cancers

Comprehensive mutational profiling data now available on all major cancers have led to proposals of novel molecular tumor classifications that modify or replace the established organ- and tissue-based tumor ty...

Authors: Daniel Heim, Grégoire Montavon, Peter Hufnagl, Klaus-Robert Müller and Frederick Klauschen

Whole-genome epidemiology, characterisation, and phylogenetic reconstruction of Staphylococcus aureus strains in a paediatric hospital

Staphylococcus aureus is an opportunistic pathogen and a leading cause of nosocomial infections. It can acquire resistance to all the antibiotics that entered the clinics to date, and the World Health Organizatio...

Authors: Serena Manara, Edoardo Pasolli, Daniela Dolce, Novella Ravenni, Silvia Campana, Federica Armanini, Francesco Asnicar, Alessio Mengoni, Luisa Galli, Carlotta Montagnani, Elisabetta Venturini, Omar Rota-Stabelli, Guido Grandi, Giovanni Taccetti and Nicola Segata

Landscape of genomic alterations in high-grade serous ovarian cancer from exceptional long- and short-term survivors

Patients diagnosed with high-grade serous ovarian cancer (HGSOC) who received initial debulking surgery followed by platinum-based chemotherapy can experience highly variable clinical responses. A small percen...

Authors: S. Y. Cindy Yang, Stephanie Lheureux, Katherine Karakasis, Julia V. Burnier, Jeffery P. Bruce, Derek L. Clouthier, Arnavaz Danesh, Rene Quevedo, Mark Dowar, Youstina Hanna, Tiantian Li, Lin Lu, Wei Xu, Blaise A. Clarke, Pamela S. Ohashi, Patricia A. Shaw…

Recent advances in immunotherapies: from infection and autoimmunity, to cancer, and back again

For at least 300 years the immune system has been targeted to improve human health. Decades of work advancing immunotherapies against infection and autoimmunity paved the way for the current explosion in cance...

Authors: Samantha L. Bucktrout, Jeffrey A. Bluestone and Fred Ramsdell

Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

Links between colorectal cancer (CRC) and the gut microbiome have been established, but the specific microbial species and their role in carcinogenesis remain an active area of inquiry. Our understanding would...

Authors: Vanessa L. Hale, Patricio Jeraldo, Jun Chen, Michael Mundy, Janet Yao, Sambhawa Priya, Gary Keeney, Kelly Lyke, Jason Ridlon, Bryan A. White, Amy J. French, Stephen N. Thibodeau, Christian Diener, Osbaldo Resendis-Antonio, Jaime Gransee, Tumpa Dutta…

Targeting the microbiome: from probiotics to fecal microbiota transplantation

The modern techniques of microbiome science can be applied to the development and evaluation of all microbiota-directed products, including probiotics and fecal microbiota transplantation.

Authors: Alexander Khoruts

Tracking key virulence loci encoding aerobactin and salmochelin siderophore synthesis in Klebsiella pneumoniae

Klebsiella pneumoniae is a recognised agent of multidrug-resistant (MDR) healthcare-associated infections; however, individual strains vary in their virulence potential due to the presence of mobile accessory gen...

Authors: Margaret M. C. Lam, Kelly L. Wyres, Louise M. Judd, Ryan R. Wick, Adam Jenney, Sylvain Brisse and Kathryn E. Holt

Genome-wide analyses reveal the IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation

The IRE1a-XBP1 pathway is a conserved adaptive mediator of the unfolded protein response. The pathway is indispensable for the development of secretory cells by facilitating protein folding and enhancing secre...

Authors: Jhuma Pramanik, Xi Chen, Gozde Kar, Johan Henriksson, Tomás Gomes, Jong-Eun Park, Kedar Natarajan, Kerstin B. Meyer, Zhichao Miao, Andrew N. J. McKenzie, Bidesh Mahata and Sarah A. Teichmann

Genotype effects contribute to variation in longitudinal methylome patterns in older people

DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals.

Authors: Qian Zhang, Riccardo E Marioni, Matthew R Robinson, Jon Higham, Duncan Sproul, Naomi R Wray, Ian J Deary, Allan F McRae and Peter M Visscher

Advanced model systems and tools for basic and translational human immunology

There are fundamental differences between humans and the animals we typically use to study the immune system. We have learned much from genetically manipulated and inbred animal models, but instances in which ...

Authors: Lisa E. Wagar, Robert M. DiFazio and Mark M. Davis