Search

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Clare Turnbull and colleagues identify three new risk loci for testicular germ cell cancer. The newly discovered risk variants reside near the telomere regulator genes TERT and ATF7IP and the sex determination gene DMRT1.

Clare Turnbull and colleagues identify nine new susceptibility loci for testicular germ-cell tumor. The newly identified risk regions include variants near DAZL and PRDM14, genes known to be important for germ cell development.

Tissue-preserving focal therapies that target individual cancer lesions rather than the whole prostate have emerged as potential interventions for localized prostate cancer. In this article, the Prostate Cancer RCT Consensus Group recommends the development of a cohort-embedded randomized controlled trial methodology to evaluate focal therapy use in men with clinically significant localized disease. The importance for a randomized controlled trial design to provide cost-efficient practice-changing data is highlighted.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Clare Turnbull and colleagues report discovery of 19 new susceptibility loci for testicular germ cell tumor (TGCT) and provide evidence for a network of physical interactions between TGCT risk variants and candidate causal genes. Their findings implicate widespread disruption of developmental transcriptional regulators in TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis.

A rare variant burden analytical framework for Mendelian diseases was developed and applied to data from the 100,000 Genomes Project, identifying 69 probable new disease–gene associations.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Clinical classification of genomic variants identified on sequencing is often challenging, with many variants classified as Variants of Uncertain Significance (VUS) on account of insufficient evidence. Advances in sequencing and gene synthesis has made feasible multiplexed assays of variant effect (MAVEs), which quantify the functional impact of many thousands of genomic variants in a single experiment. These assays and the functional evidence they generate have the potential to empower more accurate clinical variant classification. However, there are many outstanding challenges and opportunities that require joint resolution and specification, thus necessitating communication between the research scientists who have designed and performed MAVEs and the clinicians and diagnostic scientists who will apply their data to clinical variant classification. In the ‘Clinical Application of MAVE Data’ workshop, held on 12th July 2023 at the Wellcome Connecting Science Conference Centre in between two relevant research meetings, ‘Curating the Clinical Genome 2023’ and the ‘Mutational Scanning Symposium 2023’, 44 key scientific and/or clinical stakeholders were brought together to consider important questions relating to clinical application of MAVE data, such as quantitative validation, variant truth-sets, platforms and standards for dissemination of MAVE data. The outcomes and possible next steps that were discussed encompassed development of focused workshops to develop consensus recommendations, creating a MAVE evaluation working group, and collaboration of ClinVar and MaveDB to enact software changes that support enhanced functional data submission.

In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.

Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here, the authors sequence the whole exomes of 42 TGCTs, and characterize the mutational profile of this tumour type.

There is some evidence of a hereditary risk for developing testicular germ cell tumours. Here, the authors use whole-exome sequencing and identify a risk variant for the disease in DNAAF1, a gene involved in microtubule-based cilia.

This genome-wide association study identifies four novel risk loci for testicular germ cell tumour, and provides functional correlation between a disease-associated variant and gene expression in patient samples for one of the identified loci.

Our biological understanding of TGCTs has been improved using sequencing, and molecular profiles associated with the genomic evolution and development of cisplatin resistance have been identified. The genomics of variants underpinning TGCT predisposition is being delineated. Studies of circulating microRNAs have demonstrated their potential for noninvasive diagnosis and disease monitoring.

Most testicular germ-cell tumours are exquisitely sensitive to platinum-based chemotherapies, but little is known about why 10% are resistant. Here, the authors explore the potential underlying mechanisms by probing the genomic landscape of platinum-resistant disease.

The genomic landscape of testicular germ cell tumour (TGCT) risk is dominated by inherited genetic factors, which are highly polygenic in nature. Here, the authors discuss results from genome-wide association studies that have identified risk loci associated with TGCT risk.KIT–KITLGsignalling is currently the major pathway that is implicated in TGCT formation.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Saturation genome editing characterizes BAP1 variants and their association with disease presentation. A phenome-wide association analysis in the UK finds that BAP1 variants identified as deleterious in the study are associated with higher serum IGF-1 levels.

The first report from the Cancer Programme of the 100,000 Genomes Project presents whole-genome sequencing profiles of 13,880 solid tumors spanning 33 cancer types, combined with real-world clinical data, providing insights for precision oncology.

Michael Stratton and colleagues report a genome-wide association study for testicular germ cell tumor (TGCT) in a UK population, identifying three associated loci.

Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

Douglas Easton, Per Hall and colleagues report meta-analyses of genome-wide association studies for breast cancer, including 10,052 cases and 12,575 controls, followed by genotyping using the iCOGS array in an additional 52,675 cases and 49,436 controls from studies within the Breast Cancer Association Consortium (BCAC). They identify 41 loci newly associated with susceptibility to breast cancer.

Doug Easton and colleagues report the results of a large-scale genome-wide association study of breast cancer. They discover 15 new susceptibility loci and highlight likely target genes in several of the newly associated regions.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Katherine Nathanson and colleagues report four new susceptibility loci for testicular germ cell tumor identified through a meta-analysis of genome-wide association studies with follow-up replication. The newly discovered risk regions include genes important for male germ cell development, chromosomal segregation and the DNA damage response.

Katherine Nathanson, Peter Kanetsky and colleagues present a meta-analysis of five genome-wide association studies of testicular germ cell tumor (TGCT). They identify eight new susceptibility loci and new independent signals at two previously reported loci, providing further clues to the etiology of TGCT.

Nazneen Rahman and colleagues show that germline inactivating mutations in RAD51D confer susceptibility to ovarian cancer. They further show that RAD51D-deficient cells are sensitive to PARP inhibition, suggesting a possible strategy for treating cancers arising in RAD51D mutation carriers.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

This proposal calls for the initiation of national population-screening programs to identify carriers of cancer gene mutations for long-term, large-scale analysis of longitudinal clinical data to aid in prevention and early detection of disease.

The identification of individuals carrying cancer susceptibility genetic variants could be improved by peridiagnostic cancer genetic testing and cascade testing of the relatives of patients diagnosed with cancer. Herein we discuss two studies that highlight the importance of active involvement of the medical team, both in informing the relatives and offering pre-test telephone genetic counselling.

Montserrat Garcia-Closas and colleagues report a meta-analysis of three genome-wide association studies for estrogen receptor (ER)-negative breast cancer, including 4,193 ER-negative breast cancer cases and 35,194 controls, with replication using the iCOGS custom genotyping array in 40 studies, including 6,514 cases and 41,455 controls. They identify four loci associated with ER-negative but not ER-positive breast cancer.