Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.
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ABSTRACT:
SUBMITTER: Mandelker D
PROVIDER: S-EPMC6683854 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe use of next-generation sequencing technologies has enabled the rapid identification of non-synonymous somatic mutations in cancer cells. Neoantigens are mutated peptides derived from somatic mutations not present in normal tissues that may result in the presentation of tumour-specific peptides capable of eliciting antitumour T-cell responses. Personalised neoantigen-based cancer vaccines and adoptive T-cell therapies have been shown to prime host immunity against tumour cells and are under clinical trial development. However, the optimisation and standardisation of neoantigen identification, as well as its delivery as immunotherapy are needed to increase tumour-specific T-cell responses and, thus, the clinical efficacy of current cancer immunotherapies.MethodsIn this recommendation article, launched by the European Society for Medical Oncology (ESMO), we outline and discuss the available framework for neoantigen prediction and present a systematic review of the current scientific evidence.ResultsA number of computational pipelines for neoantigen prediction are available. Most of them provide peptide major histocompatibility complex (MHC) binding affinity predictions, but more recent approaches incorporate additional features like variant allele fraction, gene expression, and clonality of mutations. Neoantigens can be predicted in all cancer types with high and low tumour mutation burden, in part by exploiting tumour-specific aberrations derived from mutational frameshifts, splice variants, gene fusions, endogenous retroelements and other tumour-specific processes that could yield more potently immunogenic tumour neoantigens. Ongoing clinical trials will highlight those cancer types and combinations of immune therapies that would derive the most benefit from neoantigen-based immunotherapies.ConclusionsImproved identification, selection and prioritisation of tumour-specific neoantigens are needed to increase the scope of benefit from cancer vaccines and adoptive T-cell therapies. Novel pipelines are being developed to resolve the challenges posed by high-throughput sequencing and to predict immunogenic neoantigens.
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Project description:Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease specific to pregnancy. The cardinal symptom of pruritus and a concomitant elevated level of bile acids in the serum and/or alanine aminotransferase (ALT) are suggestive for the diagnosis. Overall, the maternal prognosis is good. The fetal outcome depends on the bile acid level. ICP is associated with increased risks for adverse perinatal outcomes, including preterm delivery, meconium-stained amniotic fluid, and stillbirth. Acute fetal asphyxia and not chronic uteroplacental dysfunction leads to stillbirth. Therefore, predictive fetal monitoring is not possible. While medication with ursodeoxycholic acid (UDCA) improves pruritus, it has not been shown to affect fetal outcome. The indication for induction of labour depends on bile acid levels and gestational age. There is a high risk of recurrence in subsequent pregnancies.
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Project description:Advances in tumor genome sequencing have enabled discovery of actionable alterations leading to novel therapies. Currently, there are approved targeted therapies across various tumors that can be matched to genomic alterations, such as point mutations, gene amplification, and translocations. Tools to detect these genomic alterations have emerged as a result of decreasing costs and improved throughput enabled by next-generation sequencing (NGS) technologies. NGS has been successfully utilized for developing biomarkers to assess susceptibility, diagnosis, prognosis, and treatment of cancers. However, clinical application presents some potential challenges in terms of tumor specimen acquisition, analysis, privacy, interpretation, and drug development in rare cancer subsets. Although whole-genome sequencing offers the most complete strategy for tumor analysis, its present utility in clinical care is limited. Consequently, targeted gene capture panels are more commonly employed by academic institutions and commercial vendors for clinical grade cancer genomic testing to assess molecular eligibility for matching therapies, whereas whole-exome and transcriptome (RNASeq) sequencing are being utilized for discovery research. This review discusses the strategies, clinical challenges, and opportunities associated with the application of cancer genomic testing for precision cancer medicine.
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Project description:In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
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Project description:Immunotherapy strategies targeting immune checkpoints such as the CTLA4 and CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, HLA genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.
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Project description:Background: An early etiological diagnosis of hearing loss positively impacts children's quality of life including language and cognitive development. Even though hearing loss associates with extremely high genetic and allelic heterogeneity, several studies have proven that Next-Generation Sequencing (NGS)-based gene panel testing significantly reduces the time between onset and diagnosis. Methods: In order to assess the clinical utility of our custom NGS GHELP panel, the prevalence of pathogenic single nucleotide variants, indels or copy number variants was assessed by sequencing 171 nuclear and 8 mitochondrial genes in 155 Spanish individuals with hearing loss. Results: A genetic diagnosis of hearing loss was achieved in 34% (52/155) of the individuals (5 out of 52 were syndromic). Among the diagnosed cases, 87% (45/52) and 12% (6/52) associated with autosomal recessive and dominant inheritance patterns respectively; remarkably, 2% (1/52) associated with mitochondrial inheritance pattern. Although the most frequently mutated genes in this cohort were consistent with those described in the literature (GJB2, OTOF or MYO7A), causative variants in less frequent genes such as TMC1, FGF3 or mitCOX1 were also identified. Moreover, 5% of the diagnosed cases (3/52) were associated with pathogenic copy number variants. Conclusion: The clinical utility of NGS panels that allows identification of different types of pathogenic variants-not only single nucleotide variants/indels in both nuclear and mitochondrial genes but also copy number variants-has been demonstrated to reduce the clinical diagnostic odyssey in hearing loss. Thus, clinical implementation of genomic strategies within the regular clinical practice, and, more significantly, within the newborn screening protocols, is warranted.
| S-EPMC10557071 | biostudies-literature
Project description:Autopsy has been a foundation of pathology training for many years, but hospital autopsy rates are notoriously low. At the 2014 meeting of the Association of Pathology Chairs, some pathologists suggested removing autopsy from the training curriculum of pathology residents to provide additional months for training in newer disciplines, such as molecular genetics and informatics. At the same time, the American Board of Pathology received complaints that newly hired pathologists recently certified in anatomic pathology are unable to perform an autopsy when called upon to do so. In response to a call to abolish autopsy from pathology training on the one hand and for more rigorous autopsy training on the other, the Association of Pathology Chairs formed the Autopsy Working Group to examine the role of autopsy in pathology residency training. After 2 years of research and deliberation, the Autopsy Working Group recommends the following:Autopsy should remain a component of anatomic pathology training.A training program must have an autopsy service director with defined responsibilities, including accountability to the program director to record every autopsy performed by every resident.Specific entrustable activities should be defined that a resident must master in order to be deemed competent in autopsy practice, as well as criteria for gaining the trust to perform the tasks without direct supervision.Technical standardization of autopsy performance and reporting must be improved.The current minimum number of 50 autopsies should not be reduced until the changes recommended above have been implemented.
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Project description: Not available
| S-EPMC6555597 | biostudies-literature
Project description:BackgroundTargeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response.MethodsA panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms.ResultsAdequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy.ConclusionsPGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.
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Project description:BACKGROUND:Recent advances in molecular biology, sensors, and digital medicine have led to an explosion of products and services for high-resolution monitoring of individual health. The N-of-1 study has emerged as an important methodological tool for harnessing these new data sources, enabling researchers to compare the effectiveness of health interventions at the level of a single individual. OBJECTIVE:N-of-1 studies are susceptible to several design flaws. We developed a model that generates realistic data for N-of-1 studies to enable researchers to optimize study designs in advance. METHODS:Our stochastic time-series model simulates an N-of-1 study, incorporating all study-relevant effects, such as carryover and wash-in effects, as well as various sources of noise. The model can be used to produce realistic simulated data for a near-infinite number of N-of-1 study designs, treatment profiles, and patient characteristics. RESULTS:Using simulation, we demonstrate how the number of treatment blocks, ordering of treatments within blocks, duration of each treatment, and sampling frequency affect our ability to detect true differences in treatment efficacy. We provide a set of recommendations for study designs on the basis of treatment, outcomes, and instrument parameters, and make our simulation software publicly available for use by the precision medicine community. CONCLUSIONS:Simulation can facilitate rapid optimization of N-of-1 study designs and increase the likelihood of study success while minimizing participant burden.
| S-EPMC6462889 | biostudies-literature