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The mutational constraint spectrum quantified from variation in 141,456 humans Open
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in na…
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COSMIC: the Catalogue Of Somatic Mutations In Cancer Open
This FAIRsharing record describes: The Catalogue of Somatic Mutations in Cancer (COSMIC) is a database of manually-curated somatic mutation information relating to human cancers. The COSMIC database combines manually-curated data and genom…
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Genomic Classification and Prognosis in Acute Myeloid Leukemia Open
The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.…
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The repertoire of mutational signatures in human cancer Open
Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the Intern…
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Risks of Breast, Ovarian, and Contralateral Breast Cancer for <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers Open
These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.
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Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England Open
UK variant transmission Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the capacity to generate variants with major genomic changes. The UK variant B.1.1.7 (also known as VOC 202012/01) has many mutations that alter virus…
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Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma Open
Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC c…
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Maintenance Olaparib for Germline <i>BRCA</i> -Mutated Metastatic Pancreatic Cancer Open
Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195…
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Efficient generation of mouse models of human diseases via ABE- and BE-mediated base editing Open
A recently developed adenine base editor (ABE) efficiently converts A to G and is potentially useful for clinical applications. However, its precision and efficiency in vivo remains to be addressed. Here we achieve A-to-G conversion in viv…
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COSMIC: somatic cancer genetics at high-resolution Open
COSMIC, the Catalogue of Somatic Mutations in Cancer (http://cancer.sanger.ac.uk) is a high-resolution resource for exploring targets and trends in the genetics of human cancer. Currently the broadest database of mutations in cancer, the i…
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Mechanisms of DNA damage, repair, and mutagenesis Open
Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease‐states. However, robust DNA repair and damage‐bypass mechanisms faithfully protect the DNA by either removing or toler…
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Detection of a SARS-CoV-2 variant of concern in South Africa Open
Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known…
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A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma Open
A trial of autologous T cells redirected to a specific mutation in glioblastoma patients illustrates mechanisms of resistance.
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Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation Open
In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 Clini…
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Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer Open
In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate …
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<i>STK11/LKB1</i> Mutations and PD-1 Inhibitor Resistance in <i>KRAS</i>-Mutant Lung Adenocarcinoma Open
KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in…
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Adjuvant Olaparib for Patients with <i>BRCA1</i> - or <i>BRCA2</i> -Mutated Breast Cancer Open
Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was assoc…
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Integrated genomic and molecular characterization of cervical cancer Open
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical can…
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Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice Open
Faulty blood cells and heart disease Recent studies have shown that elderly people's blood cells often harbor mutations in genes encoding certain epigenetic regulators. These mutations can lead to clonal expansion of the mutant blood cells…
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The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies Open
The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited disease. At the time of writing (March 2017), th…
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Encorafenib, Binimetinib, and Cetuximab in <i>BRAF</i> V600E–Mutated Colorectal Cancer Open
A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded…
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AMRFinderPlus and the Reference Gene Catalog facilitate examination of the genomic links among antimicrobial resistance, stress response, and virulence Open
Antimicrobial resistance (AMR) is a significant public health threat. With the rise of affordable whole genome sequencing, in silico approaches to assessing AMR gene content can be used to detect known resistance mechanisms and potentially…
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Primary Resistance to PD-1 Blockade Mediated by <i>JAK1/2</i> Mutations Open
Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti–PD-1 therapy. JAK1/2-inactivating mutations we…
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The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients Open
Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cy…
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FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing Open
Allele-specific copy number analysis (ASCN) from next generation sequencing (NGS) data can greatly extend the utility of NGS beyond the identification of mutations to precisely annotate the genome for the detection of homozygous/heterozygo…
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Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers Open
This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.
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Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa Open
Summary Continued uncontrolled transmission of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in many parts of the world is creating the conditions for significant virus evolution. Here, we describe a new SARS-CoV…
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Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer Open
Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated wit…
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Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in <i>ALK</i> -Rearranged Lung Cancer Open
Advanced, anaplastic lymphoma kinase (ALK)–positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progress…
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DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability Open
Proteins are highly dynamic molecules, whose function is intrinsically linked to their molecular motions. Despite the pivotal role of protein dynamics, their computational simulation cost has led to most structure-based approaches for asse…