Mutational Processes Research Articles

Mutational signatures and their association with cancer survival and gene expression in multiple cancer types.

Different endogenous and exogenous mutational processes cause specific patterns of somatic mutations and mutational signatures. Although their biological research has been intensive, there are only rare studies assessing the possible prognostic role of mutational signatures. We used data from The Cancer Genome Atlas to study the associations between the activity of the mutational signatures and four survival endpoints in 18 types of malignancies. We further explored the prognostic differences according to, for example, the HPV status in head and neck squamous cell carcinomas and smoking status in lung cancers. The predictive power of the signatures over time was evaluated with a dynamic area under the curve model, and the links between mutational signature activities and differences in gene expression patterns were analyzed. In 12 of 18 studied cancer types, we identified at least one mutational signature whose activity predicted survival outcomes after adjusting for the established prognostic factors. For example, overall survival was associated with the activity of mutational signatures in nine cancer types and disease-specific survival in seven cancer types. The clock-like signatures SBS5 and SBS40 were most commonly associated with survival endpoints. The genes of the myosin binding protein and melanoma antigen families were among the most substantially dysregulated genes between the signatures of low and high activity. The differences in gene expression also revealed various enriched pathways. Based on these data, specific mutational signatures associate with the gene expression and have the potential to serve as strong prognostic factors in several cancer types.

A comprehensive landscape analysis of autophagy in cancer development and drug resistance.

Autophagy plays important roles in cancer progression and therapeutic resistance, and the autophagy underlying the tumor pathogenesis and further mechanisms of chemoresistance emergence remains unknown. In this study, via the single-sample gene set enrichment analysis (ssGSEA) method, an autophagy 45-gene list was identified to evaluate samples' autophagy activity, verified through six GEO datasets with a confirmed autophagy phenotype. It was further utilized to distinguish tumors into autophagy score-high and score-low subtypes, and analyze their transcriptome landscapes, including survival analysis, correlation analysis of autophagy- and resistance-related genes, biological functional enrichment, and immune- and hypoxia-related and genomic heterogeneity comparison, in TCGA pan-cancer datasets. Furthermore, we performed an analysis of autophagy status in breast cancer chemoresistance combined with multiple GEO datasets and in vitro experiments to validate the mechanisms of potential anticancer drugs for reversing chemoresistance, including CCK-8 cell viability assays, RT-qPCR, and immunofluorescence. The 45-gene list was used to identify autophagy score-high and score-low subtypes and further analyze their multi-dimensional features. We demonstrated that cancer autophagy status correlated with significantly different prognoses, molecular alterations, biological process activations, immunocyte infiltrations, hypoxia statuses, and specific mutational processes. The autophagy score-low subtype displayed a more favorable prognosis compared with the score-high subtype, associated with their immune-activated features, manifested as high immunocyte infiltration, including high CD8+T, Tfh, Treg, NK cells, and tumor-associated macrophages M1/M2. The autophagy score-low subtype also showed a high hypoxia score, and hypoxic tumors showed a significantly differential prognosis in different autophagy statuses. Therefore, "double-edged" cell fates triggered by autophagy might be closely correlated with the immune microenvironment and hypoxia induction. Results demonstrated that dysregulated autophagy was involved in many cancers and their therapeutic resistance and that the autophagy was induced by the resistance-reversing drug response, in five breast cancer GEO datasets and validated by in vitro experiments. In vitro, dihydroartemisinin and artesunate could reverse breast cancer doxorubicin resistance, through inducing autophagy via upregulating LC3B and ATG7. Our study provided a comprehensive landscape of the autophagy-related molecular and tumor microenvironment patterns for cancer progression and resistance, and highlighted the promising potential of drug-induced autophagy in the activation of drug sensitivity and reversal of resistance.

Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations.

A multitude of exogenous and endogenous processes have the potential to result in DNA damage. While the repair mechanisms are typically capable of correcting this damage, errors in the repair process can result in mutations. The findings of research conducted in 2012 indicate that mutations do not occur randomly but rather follow specific patterns that can be attributed to known or inferred mutational processes. The process of mutational signature analysis allows for the inference of the predominant mutational process for a given cancer sample, with significant potential for clinical applications. A deeper comprehension of these mutational signatures in CRC could facilitate enhanced prevention strategies, facilitate the comprehension of genotoxic drug activity, predict responses to personalized treatments, and, in the future, inform the development of targeted therapies in the context of precision oncology. The efforts of numerous researchers have led to the identification of several mutational signatures, which can be categorized into different mutational signature references. In CRC, distinct mutational signatures are identified as correlating with mismatch repair deficiency, polymerase mutations, and chemotherapy treatment. In this context, a mutational signature analysis offers considerable potential for enhancing minimal residual disease (MRD) tests in stage II (high-risk) and stage III CRC post-surgery, stratifying CRC based on the impacts of genetic and epigenetic alterations for precision oncology, identifying potential therapeutic vulnerabilities, and evaluating drug efficacy and guiding therapy, as illustrated in a proof-of-concept clinical trial.

Long-Term Variation Patterns of Precipitations Driven by Climate Change in China from 1901 to 2022

Studying long-term precipitation trends is crucial for sustainable development, as the proper utilization of water resources is essential for maintaining a sustainable water supply. The objective and novelty of this paper was to reveal the gradual mutation process of precipitation in China over a century. This study utilized monthly precipitation data from 1901 to 2022 (at a century scale) to analyze and explore the spatiotemporal variability in precipitation across different time scales and regions with a trend analysis, an abrupt change analysis, and gravity center models. The findings indicate that (1) from 1901 to 2022, the precipitation in China generally decreased from the southeast coastal areas toward the northwest inland regions. (2) There were significant differences in the migration of precipitation gravity centers among the different study regions, with the least dispersion being observed in the Liao River basin, while the Hai River basin, various river basins in the northwest, and the Pearl River basin exhibited certain regularities in gravity center movement, and other regions showed periodic variations. (3) Over the period from 1901 to 2022, there was a trend of transitioning from lower to higher precipitation levels. (4) According to continuous long-term abrupt change tests, the timing of precipitation shifts varied across different basins. Precipitation, as a crucial component of natural resources, directly impacts various aspects of socio-economic life. Research findings provide decision support for regional flood control and disaster reduction and offer scientific decisions for ecological security.

Cell cycle arrest combined with CDK1 inhibition suppresses genome-wide mutations by activating alternative DNA repair genes during genome editing

Cells regularly repair numerous mutations. However, the effect of CRISPR/Cas9-induced dsDNA breaks on the repair processes of naturally occurring genome-wide mutations is unclear. In this study, we used TSCE5 cells with the heterozygous thymidine kinase genotype (TK+/-) to examine these effects. We strategically inserted the target sites for guide RNA (gRNA)/Cas9 and I-SceI into the functional allele and designed the experiment such that deletions of > 81bp or base substitutions within exon five disrupted the TK gene, resulting in a TK-/- genotype. TSCE5 cells in the resting state exhibited 16 genome-wide mutations that affected cellular functions. After gRNA/Cas9 editing, these cells produced 859 mutations, including 67 high-impact variants that severely affected cellular functions under standard culture conditions. Mutation profile analysis indicated a significant accumulation of C to A substitutions, underscoring the widespread induction of characteristic mutations by gRNA/Cas9. In contrast, gRNA/Cas9-edited cells under conditions of S∼G2/M arrest and cyclin-dependent kinase 1 inhibition showed only five mutations. Transcriptomic analysis revealed the downregulation of DNA replication genes and upregulation of alternative DNA repair genes, such as zinc finger protein 384 (ZNF384) and dual specificity phosphatase, under S∼G2/M conditions. Additionally, activation of nucleotide and base excision repair gene, including O-6-methylguanine-DNA methyltransferase and xeroderma pigmentosum complementation group C, was observed. This study highlights the profound impact of CRISPR/Cas9 editing on genome-wide mutation processes and underscores the emergence of novel DNA repair pathways. Finally, our findings provide significant insights into the maintenance of genome integrity during genome editing.

Prognostic genome and transcriptome signatures in colorectal cancers

Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFβ pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.

DNA Repair and Mutagenesis of ADP-Ribosylated DNA by Pierisin.

Pierisin is a DNA-targeting ADP-ribosyltransferase found in cabbage white butterfly (Pieris rapae). Pierisin transfers an ADP-ribosyl moiety to the 2-amino group of the guanine residue in DNA, yielding N2-(ADP-ribos-1-yl)-2'-deoxyguanosine (N2-ADPR-dG). Generally, such chemically modified DNA is recognized as DNA damage and elicits cellular responses, including DNA repair pathways. In Escherichia coli and human cells, it has been experimentally demonstrated that N2-ADPR-dG is a substrate of the nucleotide excision repair system. Although DNA repair machineries can remove most lesions, some unrepaired damages frequently lead to mutagenesis through DNA replication. Replication past the damaged DNA template is called translesion DNA synthesis (TLS). In vitro primer extension experiments have shown that eukaryotic DNA polymerase κ is involved in TLS across N2-ADPR-dG. In many cases, TLS is error-prone and thus a mutagenic process. Indeed, the induction of G:C to T:A and G:C to C:G mutations by N2-ADPR-dG in the hypoxanthine phosphoribosyltransferase gene mutation assay with Chinese hamster cells and supF shuttle vector plasmids assay using human fibroblasts has been reported. This review provides a detailed overview of DNA repair, TLS and mutagenesis of N2-ADPR-dG induced by cabbage butterfly pierisin-1.

Co-occurrence of ST412 Klebsiella pneumoniae isolates with hypermucoviscous and non-mucoviscous phenotypes in a short-term hospitalized patient.

K. pneumoniae with a hypermucoviscosity (HMV) phenotype is a community-acquired pathogen that is associated with increased invasiveness and pathogenicity, and underlying diseases are the most common comorbid risk factors inducing metastatic complications. HMV was earlier attributed to the overproduction of capsular polysaccharide, and more data point to the possibility of several causes contributing to this bacterial phenotype. Here, we describe a unique event in which the same clonal population showed both HMV and non-HMV characteristics. Studies have demonstrated that this process is influenced by mutational processes and genes related to transport and central metabolism. These findings provide fresh insight into the mechanisms behind co-occurrence of HMV and non-HMV phenotypes in monoclonal populations as well as potentially being critical in developing strategies to control the further spread of HMV K. pneumoniae.

Mitochondrial DNA mosaicism in normal human somatic cells

Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10−8 per base pair) and a turnover frequency of 10–20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.

Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer

Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.

Genetic polymorphism in waxweed (Red Book of the Russian Federation) in North-West Russia

BACKGROUND: Waxweed (Myrica gale L.) is a protected plant species found in the Russian Federation only in the Leningrad Region and Karelia. It is almost not studied from the genetic point of view. This species is presumably hexaploid; it propagates mainly vegetatively, and the role of sexual reproduction in the life cycle of waxweed is unclear. All waxweed populations in the Russian Federation are small and belong to the edge ones (occupy the easternmost positions in the range). AIM: The aim of the study is to investigate genomic DNA polymorphism in waxweed populations in the Russian Federation, and to evaluate the role of sexual reproduction in propagation and dispersal of this species. MATERIALS AND METHODS: AFLP-analysis of waxweed genomic DNA in 6 natural populations (5 populations in the Leningrad Region, 1 in Karelia). Using 3 pairs of primers, we studied waxweed genomic polymorphism for 22 DNA fragments. RESULTS: Each of the studied waxweed populations is genetically polymorphic. Among 182 analyzed plants we distinguished 27 different AFLP-genotypes, two of which were common in all populations studied. Most of others AFLP genotypes (20) were represented just by a single plant or a couple of plants. Some of these rare AFLP genotypes are likely the results of mutation and/or recombination processes affecting the common AFLP genotypes. CONCLUSIONS: The role of sexual reproduction in waxweed propagation, although minor, is noticeable.

Evolution and strain diversity advance exploration of Candida albicans biology.

Fungi were some of the earliest organismal systems used to explore mutational processes and its phenotypic consequences on members of a species. Yeasts that cause significant human disease were quickly incorporated into these investigations to define the genetic and phenotypic drivers of virulence. Among Candida species, Candida albicans has emerged as a model for studying genomic processes of evolution because of its clinical relevance, relatively small genome, and ability to tolerate complex chromosomal changes. Here, we describe major recent findings that used evolution of strains from defined genetic backgrounds to delineate mutational and adaptative processes and include how nascent exploration into naturally occurring variation is contributing to these conceptual frameworks. Ultimately, efforts to discern adaptive mechanisms used by C. albicans will continue to divulge new biology and can better inform treatment regimens for the increasing prevalence of fungal disease.

Research Progress on Immune Evasion of Mycoplasma hyopneumoniae.

As the main pathogen associated with enzootic pneumonia (EP), Mycoplasma hyopneumoniae (Mhp) is globally prevalent and inflicts huge financial losses on the worldwide swine industry each year. However, the pathogenicity of Mhp has not been fully explained to date. Mhp invasion usually leads to long-term chronic infection and persistent lung colonization, suggesting that Mhp has developed effective immune evasion strategies. In this review, we offer more detailed information than was previously available about its immune evasion mechanisms through a systematic summary of the extant findings. Genetic mutation and post-translational protein processing confer Mhp the ability to alter its surface antigens. With the help of adhesins, Mhp can achieve cell invasion. And Mhp can modulate the host immune system through the induction of inflammation, incomplete autophagy, apoptosis, and the suppression of immune cell or immune effector activity. Furthermore, we offer the latest views on how we may treat Mhp infections and develop novel vaccines.

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer.

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime , we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily 'active' mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

Inhibition of Uracil DNA Glycosylase Alters Frequency and Spectrum of Action-at-a-Distance Mutations Induced by 8-Oxo-7,8-dihydroguanine.

The generation of DNA damage causes mutations and consequently cancer. Reactive oxygen species are important sources of DNA damage and some mutation signatures found in human cancers. 8-Oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine) is one of the most abundant oxidized bases and induces a G→T transversion mutation at the modified site. The damaged G base also causes untargeted base substitution mutations at the G bases of 5'-GpA-3' dinucleotides (action-at-a-distance mutations) in human cells, and the cytosine deaminase apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3) is involved in the mutation process. The deaminated cytosine, i.e., uracil, bases are expected to be removed by uracil DNA glycosylase. Most of the substitution mutations at the G bases of 5'-GpA-3' might be caused by abasic sites formed by the glycosylase. In this study, we expressed the uracil DNA glycosylase inhibitor from Bacillus subtilis bacteriophage PBS2 in human U2OS cells and examined the effects on the GO-induced action-at-a-distance mutations. The inhibition of uracil DNA glycosylase increased the mutation frequency, and in particular, the frequency of G→A transitions. These results indicated that uracil DNA glycosylase, in addition to APOBEC3, is involved in the untargeted mutation process induced by GO.

Study on Stability Analysis Method of Loess Slope Based on Catastrophe Theory – A Case Study of Loess Slope in Yili, Xinjiang

Based on the mutation theory, the paper studies the stability of loess slope, and discusses the loess slope in Yili region in Xinjiang. From the perspective of mechanics, the paper focuses on the influence of mutation phenomenon on the stability of loess slope, and deeply analyzes the mechanical mechanism in the mutation process. As an effective tool to study the phenomenon of discontinuous change, mutation theory has important applications in the stability analysis of loess slopes. By applying the mutation theory, the mutation characteristics of the loess slope in the Xinjiang Yili area were analyzed. In terms of mechanical mechanism, the stress distribution, deformation characteristics and the instability mode are discussed in detail. Through theoretical analysis and numerical simulation, it is found that when the slope stress reaches a certain critical value, mutation will occur, leading in a sharp decline of slope stability. Specific data show that in a typical loess slope in Yili area, when the stress reaches about 0.6 MPa, the slope changes, and the displacement instantly increases to more than twice the original, indicating that the slope has been in a state of instability. In the case study of loess slope in Yili, Xinjiang, the slope stability is comprehensively evaluated by combining field investigation to monitoring data and indoor test. By identifying and analyzing the mutation characteristics of the slope, it is found that there are widespread subsidence and disintegration problems in this area, which play a key role in the mutation process. The specific data show that the subsidence coefficient of the loess slope in Yili area is generally above 0.05, and the disintegration rate is more than 0.5% per hour. These factors jointly aggravate the mutation risk of the slope. Based on the above data analysis, the paper puts forward targeted disaster prevention and mitigation measures, including strengthening slope drainage, using appropriate reinforcement technology, etc. These measures aim to reduce the risk of mutation and improve the stability of the loess slope.

A Pareto-optimality based black widow spider algorithm for energy efficient flexible job shop scheduling problem considering new job insertion

The utilization of flexible job shops is on the rise, driven by the decreasing life cycle of consumer products. In dynamic flexible job shops, the occurrence of disruptive events like machine breakdown, tool wear, and new job arrivals is common, emphasizing the critical need for efficient scheduling to achieve productivity and cost-effectiveness. Additionally with the growing concerns about energy consumption and global warming, the imperative to contemplate workshops with lower energy usage is becoming increasingly significant. Therefore, in this study a multi-objective dynamic flexible job shop scheduling problem (MODFJSP) with insertion of new jobs for optimization objectives: makespan, total energy consumption and schedule instability is addressed. A novel multi-objective black widow spider algorithm (MOBWSA), inspired by the mating behavior of black widow spiders, is proposed. The MOBWSA ensures an optimal balance between minimizing makespan and energy consumption through its superior evolutionary processes of procreation, mutation and cannibalism. Furthermore, a strategic on/off strategy is implemented to enhance energy efficiency. The disruptions in schedule at rescheduling stage are addressed through the proposed sigmoidal weighted instability function. To handle the multi-objective nature of the problem this work incorporates Pareto-optimality approach in combination with novel hybrid crowding distance metric. The optimization is further aided by exploitation of search space through an ensemble of local search operators. Testing and evaluation of the MOBWSA with 30 benchmark problems is conducted, and its performance for multiple metrics is compared with recently published state-of-the-art algorithms. The results establish the effectiveness and efficiency of the proposed algorithm.

Low-input PacBio sequencing generates high-quality individual fly genomes and characterizes mutational processes

Long-read sequencing, exemplified by PacBio, revolutionizes genomics, overcoming challenges like repetitive sequences. However, the high DNA requirement ( > 1 µg) is prohibitive for small organisms. We develop a low-input (100 ng), low-cost, and amplification-free library-generation method for PacBio sequencing (LILAP) using Tn5-based tagmentation and DNA circularization within one tube. We test LILAP with two Drosophila melanogaster individuals, and generate near-complete genomes, surpassing preexisting single-fly genomes. By analyzing variations in these two genomes, we characterize mutational processes: complex transpositions (transposon insertions together with extra duplications and/or deletions) prefer regions characterized by non-B DNA structures, and gene conversion of transposons occurs on both DNA and RNA levels. Concurrently, we generate two complete assemblies for the endosymbiotic bacterium Wolbachia in these flies and similarly detect transposon conversion. Thus, LILAP promises a broad PacBio sequencing adoption for not only mutational studies of flies and their symbionts but also explorations of other small organisms or precious samples.

Kataegis associated mutational processes linked to adverse prostate cancer presentation in African men.

Kataegis, the focal hypermutation of single base substitutions (SBS) in tumour genomes, has received little attention with respect to prostate cancer (PCa) associated molecular and clinical features. Most notably, data is lacking with regards to this tumour evolutionary phenomenon and PCa racial disparities, with African men disproportionately impacted. Here through comparison between African (n = 109) and non-African (n = 79) whole genome sequenced treatment naïve primary tumours, using a single analytical workflow we assessed for shared and unique features of kataegis. Linking kataegis to aggressive presentation, structural variant burden and copy number loss, we attributed APOBEC3 activity through higher rates of SBS2 to high-risk African tumours. While kataegis positive African patients presented with elevated prostate specific antigen levels, their tumours showed evolutionary unique trajectories marked by increased subclonal and structural variant-independent kataegis. The potential to exacerbate tumour heterogeneity emphases the significance of continued exploration of biological behaviours and environmental exposures for African patients.

Aberrant Expression of Sprouty2 In Human Colon Cancer

Purpose: The study investigates the role of Sprouty2 (SPRY2) in colorectal cancer (CRC) cell function. It found that SPRY2 inhibits the RAS/MAPK/ERK pathway and promotes cancer invasion in KRAS-WT CRC. However, it did not significantly alter p-ERK levels, cell proliferation, or invasion in KRAS-mutant CRCs. High SPRY2 expression was associated with shorter cancer-specific survival in both KRAS-WT and KRAS-mutant CRC patients. The study suggests that SPRY2 may promote invasion and progression in both types of CRC. Methods: The gene expression data were retrieved from Gene Expression Omnibus (GEO). Fold change, p.value t-test and David Functional analysis, hierarchical clustering was performed. Results: In this study, we identified altered genes involved in SPRY2 mutation in the colon and the relevant pathways to understand whether the SPRY2 mutation changes cancer progression. 4 genes of 5 genes were downregulated following the mutation in colon cancer cells. We identified a network between these genes and pathways they belong to. Pathway analysis showed that these genes are mostly associated with cancer cell proliferation. Conclusion: MAL2, ESRP1, CDH3, CXCL14 and CDH1 genes were found to be associated with in SPRY2 mutation in colon cancer pathogenesis. Almost all these genes are effective in the proliferation of cancer cells, especially during the SPRY2 mutation process. Therefore, it is hypothesized that downregulation or upregulation of these genes may affect colon cancer pathogenesis by reducing cell proliferation. And it is predicted that SPRY2 mutation may be an important factor for colon cancer.