Mutation Research-Reviews in Mutation Research最新文献

Background

GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes G_sα, the α subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in GNAS are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that G_sα serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, β₂- and β₃-adrenoceptors, and corticotropin-releasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic GNAS changes.

Scope of review

This review examines the structure and function of GNAS and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying G_sα deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition.

Major conclusions

G_sα deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for GNAS defects is recommended, to enhance the molecular diagnosis and management of this condition.

Neutropenia is a hematological condition characterized by a decrease in absolute neutrophil count (ANC) in peripheral blood, typically classified in adults as mild (1–1.5 × 10⁹/L), moderate (0.5–1 × 10⁹/L), or severe (< 0.5 × 10⁹/L). It can be categorized into two types: congenital and acquired. Congenital severe chronic neutropenia (SCN) arises from mutations in various genes, with different inheritance patterns, including autosomal recessive, autosomal dominant, and X-linked forms, often linked to mitochondrial diseases. The most common genetic cause is alterations in the ELANE gene. Some cases exist as non-syndromic neutropenia within the SCN spectrum, where genetic origins remain unidentified. The clinical consequences of congenital neutropenia depend on granulocyte levels and dysfunction. Infants with this condition often experience recurrent bacterial infections, with approximately half facing severe infections within their first six months of life. These infections commonly affect the respiratory system, digestive tract, and skin, resulting in symptoms like fever, abscesses, and even sepsis. The severity of these symptoms varies, and the specific organs and systems affected depend on the genetic defect. Congenital neutropenia elevates the risk of developing acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), particularly with certain genetic variants. SCN patients may acquire CSF3R and RUNX1 mutations, which can predict the development of leukemia. It is important to note that high-dose granulocyte colony-stimulating factor (G-CSF) treatment may have the potential to promote leukemogenesis. Treatment for neutropenia involves antibiotics, drugs that boost neutrophil production, or bone marrow transplants. Immediate treatment is essential due to the heightened risk of severe infections. In severe congenital or cyclic neutropenia (CyN), the primary therapy is G-CSF, often combined with antibiotics. The G-CSF dosage is gradually increased to normalize neutrophil counts. Hematopoietic stem cell transplants are considered for non-responders or those at risk of AML/MDS. In cases of WHIM syndrome, CXCR4 inhibitors can be effective. Future treatments may involve gene editing and the use of the diabetes drug empagliflozin to alleviate neutropenia symptoms.

Background

Head and neck cancer is the seventh most common malignancy globally. Head and neck squamous cell carcinoma (HNSCC) originates from squamous cells and 90% of HNC are HNSCC. The gold standard for diagnosing HNSCC is tissue biopsy. However, given tumour heterogeneity, biopsies may miss important cancer-associated molecular signatures, and more importantly, after the tumour is excised, there is no means of tracking response to treatment in patients. Captured under liquid biopsy, circulating tumour DNA (ctDNA), may identify in vivo molecular genotypes and complements tumour tissue analysis in cancer management. A systematic search was conducted in PubMed, Embase, Scopus and the Cochran Library between 2012 to early 2023 on ctDNA in HNSCC using publications written in English. We summarise 20 studies that compared mutational profiles between tumour tissue DNA (tDNA) and ctDNA, using a cohort of 631 HNSCC patients and 139 controls. Among these studies, the concordance rates varied greatly and the most mutated and the most concordant gene was TP53, followed by PIK3CA, CDKN2A, NOTCH1 and FAT1. Concordant variants were mainly found in Stage IV tumours, and the mutation type is mostly single nucleotide variants (SNV). We conclude that, as a biomarker for HNSCC, ctDNA demonstrates great promise as it recapitulates tumour genotypes, however additional multi-central trials are needed.

Mutations, the irreversible changes in an organism’s DNA sequence, are present in tissues at a variant allele frequency (VAF) ranging from ∼10^-8 per bp for a founder mutation to ∼10^-3 for a histologically normal tissue sample containing several independent clones – compared to 1%− 50% for a heterozygous tumor mutation or a polymorphism. The rarity of these events poses a challenge for accurate clinical diagnosis and prognosis, toxicology, and discovering new disease etiologies. Standard Next-Generation Sequencing (NGS) technologies report VAFs as low as 0.5% per nt, but reliably observing rarer precursor events requires additional sophistication to measure ultralow-frequency mutations. We detail the challenge; define terms used to characterize the results, which vary between laboratories and sometimes conflict between biologists and bioinformaticists; and describe recent innovations to improve standard NGS methodologies including: single-strand consensus sequence methods such as Safe-SeqS and SiMSen-Seq; tandem-strand consensus sequence methods such as o2n-Seq and SMM-Seq; and ultrasensitive parent-strand consensus sequence methods such as DuplexSeq, PacBio HiFi, SinoDuplex, OPUSeq, EcoSeq, BotSeqS, Hawk-Seq, NanoSeq, SaferSeq, and CODEC. Practical applications are also noted. Several methods quantify VAF down to 10^-5 at a nt and mutation frequency (MF) in a target region down to 10^-7 per nt. By expanding to > 1 Mb of sites never observed twice, thus forgoing VAF, other methods quantify MF < 10^-9 per nt or < 15 errors per haploid genome. Clonal expansion cannot be directly distinguished from independent mutations by sequencing, so it is essential for a paper to report whether its MF counted only different mutations – the minimum independent-mutation frequency MF_minI – or all mutations observed including recurrences – the larger maximum independent-mutation frequency MF_maxI which may reflect clonal expansion. Ultrasensitive methods reveal that, without their use, even mutations with VAF 0.5–1% are usually spurious.

Breeding is the most important and efficient method for crop improvement involving repeated modification of the genetic makeup of a plant population over many generations. In this review, various accessible breeding approaches, such as conventional breeding and mutation breeding (physical and chemical mutagenesis and insertional mutagenesis), are discussed with respect to the actual impact of research on the economic improvement of tomato agriculture. Tomatoes are among the most economically important fruit crops consumed worldwide because of their high nutritional content and health-related benefits. Additionally, we summarize mutation-based mapping approaches, including Mutmap and MutChromeSeq, for the efficient mapping of several genes identified by random indel mutations that are beneficial for crop improvement. Difficulties and challenges in the adaptation of new genome editing techniques that provide opportunities to demonstrate precise mutations are also addressed. Lastly, this review focuses on various effective and convenient genome editing tools, such as RNA interference (RNAi), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), and their potential for the improvement of numerous desirable traits to allow the development of better varieties of tomato and other horticultural crops.

Error-corrected Next Generation Sequencing (ecNGS) is rapidly emerging as a valuable, highly sensitive and accurate method for detecting and characterizing mutations in any cell type, tissue or organism from which DNA can be isolated. Recent mutagenicity and carcinogenicity studies have used ecNGS to quantify drug-/chemical-induced mutations and mutational spectra associated with cancer risk. ecNGS has potential applications in genotoxicity assessment as a new readout for traditional models, for mutagenesis studies in 3D organotypic cultures, and for detecting off-target effects of gene editing tools. Additionally, early data suggest that ecNGS can measure clonal expansion of mutations as a mechanism-agnostic early marker of carcinogenic potential and can evaluate mutational load directly in human biomonitoring studies. In this review, we discuss promising applications, challenges, limitations, and key data initiatives needed to enable regulatory testing and adoption of ecNGS – including for advancing safety assessment, augmenting weight-of-evidence for mutagenicity and carcinogenicity mechanisms, identifying early biomarkers of cancer risk, and managing human health risk from chemical exposures.

The aim of this review is to discuss how aneuploidy contributes to the aging process, and to identify plausible strategies for its prevention. After an overview of mechanisms leading to aneuploidy and the major features of cellular senescence, we discuss the link between (i) aneuploidy and cellular senescence; (ii) aneuploidy and aging; and (iii) cellular senescence and aging. We also consider (i) interactions between aneuploidy, micronuclei, cellular senescence and aging, (ii) the potential of nutritional treatments to prevent aneuploidy-associated senescence and aging, and (iii) knowledge and technological gaps. Evidence for a causal link between aneuploidy, senescence and aging is emerging. In vitro, aneuploidy accompanies the entry into cellular senescence and can itself induce senescence. How aneuploidy contributes in vivo to cellular senescence is less clear. Several routes depending on aneuploidy and/or senescence converge towards chronic inflammation, the major driver of unhealthy aging. Aneuploidy can induce the pro-inflammatory Senescence Associated Secretory Phenotype (SASP), either directly or as a result of micronucleus (MN) induction leading to leakage of DNA into the cytoplasm and triggering of the cGAS-STING pathway of innate immune response. A major difficulty in understanding the impact of aneuploidy on senescence and aging in vivo, results from the heterogeneity of cellular senescence in different tissues at the cytological and molecular level. Due to this complexity, there is at the present time no biomarker or biomarker combination characteristic for all types of senescent cells. In conclusion, a deeper understanding of the critical role aneuploidy plays in cellular senescence and aging is essential to devise practical strategies to protect human populations from aneuploidy-associated pathologies. We discuss emerging evidence, based on in vitro and in vivo studies, that adequate amounts of specific micronutrients are essential for prevention of aneuploidy in humans and that precise nutritional intervention may be essential to help avoid the scourge of aneuploidy-driven diseases.

The Wnt signaling pathway is known to play a crucial role in cancer, and WNT5A is a member of this pathway that binds to the Frizzled (FZD) and Receptor Tyrosine Kinase-Like Orphan Receptor (ROR) family members to activate non-canonical Wnt signaling pathways. The WNT5A pathway is involved in various cellular processes, such as proliferation, differentiation, migration, adhesion, and polarization. In the case of colorectal cancer (CRC), abnormal activation or inhibition of WNT5A signaling can lead to both oncogenic and antitumor effects. Moreover, WNT5A is associated with inflammation, metastasis, and altered metabolism in cancer cells. This article aims to discuss the molecular mechanisms and dual roles of WNT5A in CRC.

The development of resistance by tumor cells to various types of therapy is a significant problem that decreases the effectiveness of oncology treatments. For more than two decades, comparative transcriptomic studies of tumor cells with different sensitivities to ionizing radiation and chemotherapeutic agents have been conducted in order to identify the causes and mechanisms underlying this phenomenon. However, the results of such studies have little in common and often contradict each other. We have assumed that a systematic analysis of a large number of such studies will provide new knowledge about the mechanisms of development of therapeutic resistance in tumor cells. Our comparison of 123 differentially expressed gene (DEG) lists published in 98 papers suggests a very low degree of consistency between the study results. Grouping the data by type of genotoxic agent and tumor type did not increase the similarity. The most frequently overexpressed genes were found to be those encoding the transport protein ABCB1 and the antiviral defense protein IFITM1. We put forward a hypothesis that the role played by the overexpression of the latter in the development of resistance may be associated not only with the stimulation of proliferation, but also with the limitation of exosomal communication and, as a result, with a decrease in the bystander effect. Among down regulated DEGs, BNIP3 was observed most frequently. The expression of BNIP3, together with BNIP3L, is often suppressed in cells resistant to non-platinum genotoxic chemotherapeutic agents, whereas it is increased in cells resistant to ionizing radiation. These observations are likely to be mediated by the binary effects of these gene products on survival, and regulation of apoptosis and autophagy. The combined data also show that even such obvious mechanisms as inhibition of apoptosis and increase of proliferation are not universal but show multidirectional changes.

In the context of the increasing environmental and sanitary crisis, it is accepted that soil pollution can cause health alterations and disturb natural population dynamics. Consequently, the assessment of the genotoxic potential of compounds found in contaminated soils is important. Indeed, the alteration of genomic integrity may increase the risk of cancer development and may impair reproduction and long-term population dynamics. Among the methodologies to assess terrestrial genotoxic potential, there has been growing interest during the last decade in monitoring alterations of the genome in bioindicators of soil quality. As some land snail species are recognized bioindicators of soil quality, especially to assess the environmental and toxicological bioavailability of compounds, this review focuses on current knowledge regarding the genotoxicology of land snails. Classical biomarkers to assess genotoxic effects have been used (e.g., DNA breakage, micronuclei, random amplification polymorphic DNA) at various stages of the life cycle, including embryos. The studies were performed in vitro, in vivo, in situ and ex situ and covered a diverse set of contaminants (nanoparticles, metal(loid)s, pesticides, polycyclic aromatic hydrocarbons) and snail species (Cantareus aspersus, Eobania vermiculata, Theba pisana, Helix lucorum). Based on recent studies reviewed here, the use of land snails to map soil genotoxic potential is promising due to their ability to reveal pollution and subsequent environmental risks. Moreover, the position of snails in the trophic chain and the existing bridges between contaminant bioavailability to snails and bioaccessibility to humans reinforce the value of land snail-based ecotoxicological assessment.