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Journal of Thoracic Disease Nov 2023Lung cancer is the most common malignant tumor in the world, and its prognosis is still not optimistic. The aim of this study was to establish an immune-related gene...
BACKGROUND
Lung cancer is the most common malignant tumor in the world, and its prognosis is still not optimistic. The aim of this study was to establish an immune-related gene (IRG) prognostic index (IRGPI) for lung adenocarcinoma (LUAD) based on IRGs, and to explore the prognosis, molecular and immune features, and response to immune checkpoint inhibitor (ICI) therapy in IRGPI-classified different subgroups of LUAD.
METHODS
Based on the LUAD transcriptome RNA-sequencing data in TCGA database, the differentially expressed genes (DEGs) were selected. Subsequently, DEGs were intersected with IRGs to obtain differentially expressed immune-related genes (DEIRGs). Weighted gene co-expression network analysis (WGCNA) identified hub genes in DEIRGs. Finally, univariate and multivariate Cox regression analyses were used to build an IRGPI model. Subsequently, TCGA patients were divided into high- and low-risk groups, and the survival of patients in different groups was further analyzed. Besides, we validated the molecular and immune characteristics, relationship with immune checkpoints, angiogenesis-related genes, and immune subtypes distribution in different subgroups. Meanwhile, we further validated the response to ICI therapy in different subgroups.
RESULTS
The IRGPI was constructed based on 13 DEIRGs. Compared with the low-risk group, overall survival (OS) was lower in the high-risk group, and the high-risk score was independently associated with poorer OS. Besides, the high-risk score was associated with cell cycle pathway, high mutation rate of and , high infiltration of M0 macrophages, and immunosuppressive state, and these patients had poorer prognosis but the TIDE score of the high-risk group was lower than that of the other group, which means that the high-risk group could benefit more from ICI treatment. In contrast, the low-risk score was related to low mutation rate of and , high infiltration of plasma cells, and immunoactive state, and these patients had better prognosis but the low-risk group less benefit from ICI treatment based on the results of TIDE score.
CONCLUSIONS
IRGPI is a prospective biomarker based on IRGs that can distinguish high- and low-risk groups to predict patient prognosis, help characterize the tumor immune microenvironment, and evaluate the benefit of ICI therapy in LUAD.
PubMed: 38090291
DOI: 10.21037/jtd-23-1374 -
Environmental Health Insights 2023Viral diseases pose a significant threat to public health around the world. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) was originally identified in... (Review)
Review
Viral diseases pose a significant threat to public health around the world. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) was originally identified in Wuhan, China, in 2019. Throughout the epidemic, SARS-CoV-2 has continually changed genetically, giving rise to variants that are distinct from the original virus. SARS-CoV-2 has a high-frequency mutation rate, resulting in more genetic diversity. EG.5/Eris is a subvariant and descendant of Omicron, which remains the world's most prevalent coronavirus strain of current concern. The percentage of EG.5 recorded has steadily increased across the board. Epidemiological week 29 (17-23 July 2023) saw a 17.4% global prevalence of EG.5. Mutations in the virus's genome can cause false-negative results in molecular detection and cause increased transmissibility, morbidity, and mortality due to a reduction in vaccine efficiency. Furthermore, these changes in S-protein structure alter the neutralising ability of neutralising antibodies (Nabs), resulting in a reduction in vaccine efficiency. Therefore, all countries should take efficient infection prevention and control measures as per the guidelines of the world, continental, and their country's health organisations, along with vaccine and treatment investigations.
PubMed: 38084254
DOI: 10.1177/11786302231217805 -
Proceedings of the National Academy of... Aug 2023RNA viruses rapidly adapt to selective conditions due to the high intrinsic mutation rates of their RNA-dependent RNA polymerases (RdRps). Insertions and deletions...
RNA viruses rapidly adapt to selective conditions due to the high intrinsic mutation rates of their RNA-dependent RNA polymerases (RdRps). Insertions and deletions (indels) in viral genomes are major contributors to both deleterious mutational load and evolutionary novelty, but remain understudied. To characterize the mechanistic details of their formation and evolutionary dynamics during infection, we developed a hybrid experimental-bioinformatic approach. This approach, called MultiMatch, extracts insertions and deletions from ultradeep sequencing experiments, including those occurring at extremely low frequencies, allowing us to map their genomic distribution and quantify the rates at which they occur. Mapping indel mutations in adapting poliovirus and dengue virus populations, we determine the rates of indel generation and identify mechanistic and functional constraints shaping indel diversity. Using poliovirus RdRp variants of distinct fidelity and genome recombination rates, we demonstrate tradeoffs between fidelity and Indel generation. Additionally, we show that maintaining translation frame and viral RNA structures constrain the Indel landscape and that, due to these significant fitness effects, Indels exert a significant deleterious load on adapting viral populations. Conversely, we uncover positively selected Indels that modulate RNA structure, generate protein variants, and produce defective interfering genomes in viral populations. Together, our analyses establish the kinetic and mechanistic tradeoffs between misincorporation, recombination, and Indel rates and reveal functional principles defining the central role of Indels in virus evolution, emergence, and the regulation of viral infection.
Topics: Evolution, Molecular; Genome; Mutation Rate; INDEL Mutation; RNA, Viral; RNA Viruses
PubMed: 37487061
DOI: 10.1073/pnas.2304667120 -
Genetics Aug 2023The mutation rate plays an important role in adaptive evolution. It can be modified by mutator and anti-mutator alleles. Recent empirical evidence hints that the...
The mutation rate plays an important role in adaptive evolution. It can be modified by mutator and anti-mutator alleles. Recent empirical evidence hints that the mutation rate may vary among genetically identical individuals: evidence from bacteria suggests that the mutation rate can be affected by expression noise of a DNA repair protein and potentially also by translation errors in various proteins. Importantly, this non-genetic variation may be heritable via a transgenerational epigenetic mode of inheritance, giving rise to a mutator phenotype that is independent from mutator alleles. Here, we investigate mathematically how the rate of adaptive evolution is affected by the rate of mutation rate phenotype switching. We model an asexual population with two mutation rate phenotypes, non-mutator and mutator. An offspring may switch from its parental phenotype to the other phenotype. We find that switching rates that correspond to so-far empirically described non-genetic systems of inheritance of the mutation rate lead to higher rates of adaptation on both artificial and natural fitness landscapes. These switching rates can maintain within the same individuals both a mutator phenotype and intermediary mutations, a combination that facilitates adaptation. Moreover, non-genetic inheritance increases the proportion of mutators in the population, which in turn increases the probability of hitchhiking of the mutator phenotype with adaptive mutations. This in turns facilitates the acquisition of additional adaptive mutations. Our results rationalize recently observed noise in the expression of proteins that affect the mutation rate and suggest that non-genetic inheritance of this phenotype may facilitate evolutionary adaptive processes.
Topics: Mutation Rate; Mutation; Phenotype; Adaptation, Physiological; Bacteria
PubMed: 37293818
DOI: 10.1093/genetics/iyad111 -
Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia.Frontiers in Endocrinology 2023Hypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on...
INTRODUCTION
Hypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys.
METHODS
There were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure.
RESULTS
There were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as "pathogenic", "likely pathogenic", and "variants of uncertain significance". Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters.
DISCUSSION
We present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases.
Topics: Adult; Humans; Hypophosphatasia; Phylogeny; Computational Biology; Diagnosis, Differential; Italy; Rare Diseases
PubMed: 37600704
DOI: 10.3389/fendo.2023.1205977 -
Nucleic Acids Research Aug 2023Single nucleotide mutation rates have critical implications for human evolution and genetic diseases. Importantly, the rates vary substantially across the genome and the...
Single nucleotide mutation rates have critical implications for human evolution and genetic diseases. Importantly, the rates vary substantially across the genome and the principles underlying such variations remain poorly understood. A recent model explained much of this variation by considering higher-order nucleotide interactions in the 7-mer sequence context around mutated nucleotides. This model's success implicates a connection between DNA shape and mutation rates. DNA shape, i.e. structural properties like helical twist and tilt, is known to capture interactions between nucleotides within a local context. Thus, we hypothesized that changes in DNA shape features at and around mutated positions can explain mutation rate variations in the human genome. Indeed, DNA shape-based models of mutation rates showed similar or improved performance over current nucleotide sequence-based models. These models accurately characterized mutation hotspots in the human genome and revealed the shape features whose interactions underlie mutation rate variations. DNA shape also impacts mutation rates within putative functional regions like transcription factor binding sites where we find a strong association between DNA shape and position-specific mutation rates. This work demonstrates the structural underpinnings of nucleotide mutations in the human genome and lays the groundwork for future models of genetic variations to incorporate DNA shape.
Topics: Humans; Mutation Rate; Genome, Human; Mutation; DNA; Nucleotides
PubMed: 37395403
DOI: 10.1093/nar/gkad551 -
Bioinformatics (Oxford, England) Jun 2023Modern methods for computation-intensive tasks in sequence analysis (e.g. read mapping, sequence alignment, genome assembly, etc.) often first transform each sequence...
MOTIVATION
Modern methods for computation-intensive tasks in sequence analysis (e.g. read mapping, sequence alignment, genome assembly, etc.) often first transform each sequence into a list of short, regular-length seeds so that compact data structures and efficient algorithms can be employed to handle the ever-growing large-scale data. Seeding methods using kmers (substrings of length k) have gained tremendous success in processing sequencing data with low mutation/error rates. However, they are much less effective for sequencing data with high error rates as kmers cannot tolerate errors.
RESULTS
We propose SubseqHash, a strategy that uses subsequences, rather than substrings, as seeds. Formally, SubseqHash maps a string of length n to its smallest subsequence of length k, k < n, according to a given order overall length-k strings. Finding the smallest subsequence of a string by enumeration is impractical as the number of subsequences grows exponentially. To overcome this barrier, we propose a novel algorithmic framework that consists of a specifically designed order (termed ABC order) and an algorithm that computes the minimized subsequence under an ABC order in polynomial time. We first show that the ABC order exhibits the desired property and the probability of hash collision using the ABC order is close to the Jaccard index. We then show that SubseqHash overwhelmingly outperforms the substring-based seeding methods in producing high-quality seed-matches for three critical applications: read mapping, sequence alignment, and overlap detection. SubseqHash presents a major algorithmic breakthrough for tackling the high error rates and we expect it to be widely adapted for long-reads analysis.
AVAILABILITY AND IMPLEMENTATION
SubseqHash is freely available at https://github.com/Shao-Group/subseqhash.
Topics: Algorithms; Mutation Rate; Probability; Sequence Alignment
PubMed: 37387132
DOI: 10.1093/bioinformatics/btad218 -
Life Science Alliance Jan 2024Germline pathogenic variants in the exonuclease domain of the replicative DNA polymerase Pol ε encoded by the gene, predispose essentially to colorectal and... (Review)
Review
Germline pathogenic variants in the exonuclease domain of the replicative DNA polymerase Pol ε encoded by the gene, predispose essentially to colorectal and endometrial tumors by inducing an ultramutator phenotype. It is still unclear whether all the alterations influence similar strength tumorigenesis, immune microenvironment, and treatment response. In this review, we summarize the current understanding of the mechanisms and consequences of mutations in human malignancies; we highlight the heterogeneity of mutation rate and cancer aggressiveness among POLE variants, propose some mechanistic basis underlining such heterogeneity, and discuss novel considerations for the choice and efficacy of therapies of POLE tumors.
Topics: Female; Humans; DNA Polymerase II; DNA Replication; Endometrial Neoplasms; Germ-Line Mutation; Mutation; Tumor Microenvironment; Poly-ADP-Ribose Binding Proteins; Colorectal Neoplasms
PubMed: 37891003
DOI: 10.26508/lsa.202302290 -
Virulence Dec 2023Mother-to-child transmission (MTCT) is still the main route of hepatitis B virus (HBV) infection. However, the virological factors affecting HBV MTCT have not been fully...
Mother-to-child transmission (MTCT) is still the main route of hepatitis B virus (HBV) infection. However, the virological factors affecting HBV MTCT have not been fully elucidated. In this study, based on a prospective cohort of mother-infant pairs with positive maternal hepatitis B surface antigen (HBsAg), we found that the average nucleotide mutation rate of HBV preS1 promoter (SPI) region in the immunoprophylaxis success group was significantly higher than that in the immunoprophylaxis failure group. Among the nucleotide mutations of the HBV SPI region, the C2729T mutation had the highest frequency. Next, we found that the C2729T mutation promoted HBsAg release but reduced HBV production by suppressing the expression of large hepatitis B surface antigen (LHBs), and overexpressing LHBs could rescue this phenomenon. Based on the fact that the C2729T mutation could alter the binding site of hepatocyte nuclear factor 1 (HNF1) in the HBV SPI region, we uncovered that such an alteration could downregulate the transcriptional activity of SPI by attenuating the binding ability of HNF1 and HBV SPI region. This study suggests that HBV C2729T mutation may contribute to the immunoprophylaxis success of HBV MTCT by reducing HBV production, which supplements the virological factors affecting HBV MTCT.
Topics: Pregnancy; Infant; Humans; Female; Hepatitis B virus; Hepatitis B Surface Antigens; Infectious Disease Transmission, Vertical; Prospective Studies; Pregnancy Complications, Infectious; Hepatitis B e Antigens; Hepatitis B; Mutation; Nucleotides; DNA, Viral
PubMed: 36919573
DOI: 10.1080/21505594.2023.2189676 -
Frontiers in Oncology 2024The detection rate of ground glass nodules (GGNs) has increased in recent years because of their malignant potential but relatively indolent biological behavior; thus,... (Review)
Review
The detection rate of ground glass nodules (GGNs) has increased in recent years because of their malignant potential but relatively indolent biological behavior; thus, correct GGN recognition and management has become a research focus. Many scholars have explored the underlying mechanism of the indolent progression of GGNs from several perspectives, such as pathological type, genomic mutational characteristics, and immune microenvironment. GGNs have different major mutated genes at different stages of development; mutation is the most common mutation in GGNs, and mutation is the most abundant mutation in the invasive stage of GGNs. Pure GGNs have fewer genomic alterations and a simpler genomic profile and exhibit a gradually evolving genomic mutation profile as the pathology progresses. Compared to advanced lung adenocarcinoma, GGN lung adenocarcinoma has a higher immune cell percentage, is under immune surveillance, and has less immune escape. However, as the pathological progression and solid component increase, negative immune regulation and immune escape increase gradually, and a suppressive immune environment is established gradually. Currently, regular computer tomography monitoring and surgery are the main treatment strategies for persistent GGNs. Stereotactic body radiotherapy and radiofrequency ablation are two local therapeutic alternatives, and systemic therapy has been progressively studied for lung cancer with GGNs. In the present review, we discuss the characterization of the multidimensional molecular evolution of GGNs that could facilitate more precise differentiation of such highly heterogeneous lesions, laying a foundation for the development of more effective individualized treatment plans.
PubMed: 38841161
DOI: 10.3389/fonc.2024.1380527