Types Of Mutations Research Articles

RCA-Supported Multipedal DNA Walker Integrated with TSDR for Simultaneous Detection of Single Nucleotide Polymorphisms in Circulating Tumor DNA.

Peripheral blood circulating tumor DNA (ctDNA) is a crucial liquid biopsy biomarker that correlates overall systemic tumor burden with malignant progression. However, identifying multiple single nucleotide polymorphisms (SNPs) in ctDNA presents significant challenges. In this study, we developed a rolling circle amplification (RCA)-supported multipedal DNA walker integrated with toehold-mediated strand displacement (TSDR) to facilitate the detection of ctDNA SNPs. Initially, separate identification of ctDNAs is performed using TSDR procedures, along with the release of the triggers for RCA. Once the RCA processes are initiated, long single-stranded oligonucleotide products containing repeated DNAzyme sequences are generated. Finally, these RCA products function as multipedal legs that traverse a track in a quasi-mechanical manner, producing detectable fluorescence signals. The multipedal DNA walking mechanism exhibits a high walking efficiency and signal amplification capability, as the multipedal legs can interact with multiple signal probes simultaneously. Concurrent detection of the wild type (WT) and mutation type (MT) of multiple ctDNAs is achieved, and the detection limits are at the attomolar (aM) level, with a linear range of 10 aM to 5.0 μM. Furthermore, the proposed method demonstrates remarkable specificity for mismatched sequences and single-base mutant genes, due to the TSDR-assisted detection process. Additionally, the analysis of ctDNA SNPs in clinical serum samples reveals significant differences in ctDNA expression between the blood of cancer patients and that of healthy individuals. Therefore, the proposed method can be employed for the detection of clinical ctDNA SNPs and demonstrates significant potential for early diagnosis, treatment monitoring, and prognosis.

Abstract A042: Advancing early detection and targeted therapy: A comprehensive review of cholangiocarcinoma biomarkers

Abstract Background: Cholangiocarcinoma (CCA) is a highly malignant tumor derived from the bile duct epithelium with increasing incidence worldwide. It divides into three subtypes: intrahepatic (iCCA), perihilar (pCCA), and extrahepatic (eCCA). Imaging techniques such as abdominal ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) can assist in diagnosing CCA. Gemcitabine combined with cisplatin is the first-line treatment for CCA. However, CCA often carries a poor prognosis due to advanced stage at time of diagnosis. Isocitrate dehydrogenase (IDH)1 mutations are the most common targetable alteration in CCA, occurring in 13% of iCCA cases. Recently, the FDA approved ivosidenib for the treatment of IDH1-mutated CCA. Our study aims to highlight the effect of IDH-1 alteration and its response to ivosedinib as compared to the presence of other genomic alterations. Methods: We used cBioPortal for Cancer Genomics server to retrospectively analyze and gather genomic data related to CCA from 2018 to 2024. Our search included five studies, from which we identified 699 cases of iCCA. The prevalence of genetic mutations such as IDH1, IDH2, FGFR2, ARID1A, BRAF, KRAS, and TP53 was obtained. Survival outcomes were extracted with a 95% confidence interval (CI) in patients who received ivosedinib therapy. We ensured to include overlapping groups to detect survival outcome superiority or inferiority based on the co-existence of genomic alterations. The Kaplan-Meier curves were conducted for an illustrated presentation of median overall survival (mOS) outcomes. Results: Among the studied cohort, IDH1 mutations were the most frequent, present in 16 cases. Combinations of mutations were also observed, with ARID1A (n=1), BAP1 (n=4), BRAF (n=1), FGFR2 (n=2), KRAS (n=2), TP53 (n=2), and PIK3CA (n=1) alongside IDH1. Survival outcomes varied based on mutation combinations. TP53 and IDH1 co-mutations (n=2) were associated with a mOS of 14.26 months. Co-mutations of ARID1A and IDH1 (n=4) were associated with a mOS of 21.85 months (95% CI: 12.55 - NA). Patients with IDH1 mutations alone (n=16) had a mOS of 46.75 months (95% CI: 20.87 - NA). While BAP1 and IDH1 co-mutations (n=4) demonstrated a mOS of 63.60 months (95% CI: 11.34 - NA). Conclusion: Our study showed that patients with IDH1 mutations, whether isolated or associated with other mutations such as BAP1, in patients who received ivosidenib as part of the treatment regimen, had superior mOS compared with other mutation types. More studies are needed to further elaborate on the effect of genomic alterations, both individually and in combination, on tumor response to therapy. Citation Format: Bayan Khasawneh, Waseem Abdelrahim, Abdullah Esmail, Ebtesam Al-Najjar, Ala Abudayyeh. Advancing early detection and targeted therapy: A comprehensive review of cholangiocarcinoma biomarkers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A042.

Predicting Kidney Outcomes in Autosomal Dominant Polycystic Kidney Disease: a Comprehensive Biomarker Analysis.

Risk stratification tools for Autosomal Dominant Polycystic Kidney Disease (ADPKD) predict kidney outcomes on a group level but lack precision in individuals. We assessed the value of adding 13 prognostic biomarkers to established risk factors (sex, age, estimated glomerular filtration rate (eGFR), systolic blood pressure, Mayo Imaging Class (MIC), and mutation type) for predicting disease progression. We included 596 patients from the DIPAK (Developing Intervention strategies to halt Progression of Autosomal Dominant Polycystic Kidney Disease) cohorts with ≥2 eGFR measurements and ≥1 year follow-up. During a mean±SD follow-up of 5.0±2.3 years, the mean±SD eGFR slope was -3.46±2.5 mL/min/1.73m2/year. Rapid disease progression (eGFR loss ≥3 mL/min/1.73m2/year) occurred in 303 patients (50.8%), and 279 patients (46.8%) reached the combined endpoint of kidney failure or 30% eGFR decline. Urinary albumin/creatinine, urinary monocyte chemotactic protein-1 (MCP-1)/creatinine, and serum copeptin consistently and independently predicted eGFR slope (all P <0.001), rapid disease progression (AUC increasing from 0.79 [95% CI: 0.76, 0.85] for a baseline model to 0.83 [95% CI: 0.81, 0.88] when MCP-1/creatinine and copeptin were included, P=0.006) and reaching the combined kidney endpoint (C-index improving from 0.806 [95% CI: 0.78, 0.84] for a baseline model to 0.82 [95% CI: 0.79, 0.85] for a model also containing albumin/creatinine and copeptin, P <0.001). These results were confirmed in an independent external validation cohort (N=144), and were robust in early disease stages and in patients with moderately increased kidney volumes (MIC 1C). Our findings suggest that incorporating these biomarkers into ADPKD risk stratification tools will improve risk prediction, even in subgroups where prognostication is most challenging and relevant.

Abstract A002: Immunotherapy responses in liver cancer: How TERT and TP53 mutations affect outcomes

Abstract Background: Genomic profiling has revolutionized therapeutic approaches and clinical management for liver cancer. However, the pathogenetic mechanisms, molecular drivers of recurrence, and predictive biomarkers remain only partially understood. An analysis of the United States Hepatocellular Carcinoma (HCC) cohort from The Cancer Genome Atlas showed that common mutations are mainly located in the TERT promoter region, TP53, and CTNNB1 genes. Recent studies on smaller Chinese have also identified TP53, TERT, and CTNNB1 as the most frequently mutated genes among Chinese HCC patients. Our study further explores the correlation between specific genomic mutations (TERT, TP53), and immunotherapy response in HCC cases. Methods: The cBioPorta was used for genomic profiling in multiple cohort studies of hepatobiliary cancer cases. Only HCC cases with TERT and TP53 mutation, and patients who had received immunotherapy, were included. Cases involving cholangiocarcinoma (CCA), HCC with CCA, other genetic mutations, or patients treated with chemotherapy were excluded from this study. Kaplan-Meier survival curves were created to assess the median overall survival (OS) based on immunotherapy response, and we calculated pooled 95% confidence intervals (CIs) to determine the reliability and precision of our result. The log-rank P-value was used to assess differences in OS between mutated genes. Results: The total cases were 1915 of hepatobiliary cancer after excluding 873 cases remaining with HCC among them, 400 patients (45.8%) had mutations in TERT, and 403 patients (46.2%) had mutations in TP53. The finalized number was 65 (64.4%) with TERT and 43 (42.4%) with TP53 who received immunotherapy. The median OS differed substantially across mutation types: 42 months for TERT mutations, 37 months for TP53 mutations, and 58 months for cases with both mutations (p=0.5). Conclusion: Our study observed improved OS in patients with both TERT and TP53 mutations. Although patients with only TERT mutations had better OS compared to those with TP53 mutations alone. Further research is required to clarify the specific associations between TERT mutations and treatment outcomes. Citation Format: Ebtesam Al-Najjar, Bayan Khasawneh, Waseem Abdelrahim, Abdullah Esmail, Ala Abudayyeh. Immunotherapy responses in liver cancer: How TERT and TP53 mutations affect outcomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A002.

Tumor protein 53 gene polymorphism, demographic attributes and associated risk factors among liver cancer patients in Calabar, Nigeria

Mutations in the TP53 gene had been attributed to the development of liver cancer. Hepatocellular carcinoma (HCC) and liver tumour are liver diseases having high mortality rates in several populations. There is no information on the TP53 gene polymorphism among liver diseases patients in Calabar, Nigeria. This study investigated the genetic polymorphism of TP53 among HCC and liver tumour in Calabar. This research was carried out in the University of Calabar Teaching Hospital, Calabar. Blood samples were collected from 35 clinically diagnosed hepatocellular carcinoma and 10 tumour patients and 10 healthy controls. DNA was extracted from all blood samples and Polymerase Chain Reaction (PCR) was performed using specific primers. The PCR amplicons were digested using Hae III restriction enzyme and the genotypic and allelic frequencies was determined. Demographic data among participants showed that males were 68.9% (31), females (31.1%; 14), sex ratio (2.2: 0.5), mean age was 41.51 ± 2.13 years with an odds ratio of 1.25. The distribution of participants according to marital status were 33(73.3%), 10(22.2%), and 2(4.4%) for married, single, and widowed respectively. The participants were from different extractions with varied representations of Yakurr (22.2%, 10), Efik (20%, 9), Boki (13.3%, 6), Ogoja (13.3%, 6), Annang (8.8%, 4), Ibibio (2.2%, 1) and Igbo (2.2%, 1) and respectively. Approximately, 64.7% (30) of the chronic liver diseases were from the Central and Northern part of Cross River State. The risk factors were HCV infection, HBsAg+, alcoholism, smoking, consumption of groundnuts that may have been contaminated with aflatoxin and family history of the disease. PCR product yielded 254 bp and digested PCR product showed homozygous TT mutation (27), heterozygous GT mutation (17) and homozygous GG wild type (1) in cases. The overall TP53 gene mutation frequency was 46.32% (44). The frequency of G allele, T allele, GG, GT and TT were 0.21, 0.79, 0.04, 0.33 and 0.62 respectively among cases, while GG (wild type) was only detected among controls in the study population. The genotypic and allelic frequencies conform to Hardy-Weinberg equilibrium meaning that the forces of evolution were not acting on the locus. There were significant differences in the genotypic proportions of the TP53 gene polymorphism among patients and controls. This study on the TP53 gene polymorphism will serve as baseline information on the molecular etiology of hepatocellular carcinoma and liver tumour in Cross River State.

Detection of a novel large fragment deletion in the alpha-globin gene cluster using the CNVplex technology

ObjectiveTo describe the characterization of a novel deletion causing α-thalassemia.MethodsThe proband was a 4-year-old boy who presented with abnormal hematological parameters identified during routine blood investigation conducted for a cold. Three common α-globin gene deletions, three mutations, and 17 mutations in the β-globin gene were detected using PCR-flow fluorescence hybridization. Next-generation sequencing (NGS) and CNVplex technologies were employed to identify potential rare pathogenic mutation types. The CNVplex technology leverages variations in the lengths of linkage sequences of differential sequences at the same locus to produce linkage products of varying lengths, thereby enabling the detection of multiple loci within the same system. The newly identified deletions were further validated using customized third-generation sequencing (TGS) and Sanger sequencing.ConclusionIn this study, hematological analysis indicated a potential diagnosis of thalassemia in the proband, characterized by typical microcytic hypodermic features. A novel 134-kb deletion in the α-globin gene cluster was identified in this proband using the CNVplex technology. This deletion encompasses the genes HBZ, HBM, HBA2, HBA1, and HBQ1. Furthermore, we confirmed the gene deletion through customized TGS testing and Sanger sequencing, allowing us to determine the size of the deletion. The results suggest that this represents a new deletion of 146 kb that has not been previously reported, and we hypothesize that this deletion is likely the primary cause of the α-thalassemia trait observed in the proband.

Activation of endogenous full-length utrophin by MyoAAV-UA as a therapeutic approach for Duchenne muscular dystrophy

Activation of endogenous full-length utrophin, a dystrophin homolog, presents an attractive therapeutic strategy for Duchenne muscular dystrophy (DMD), regardless of mutation types and loci. However, current dCas9-based activators are too large for efficient adeno-associated virus delivery, and the feasibility and durability of such treatments remain unclear. Here, we develop a muscle-targeted utrophin activation system using the compact dCasMINI-VPR system, termed MyoAAV-UA. Systemic administration of MyoAAV-UA in male mdx mice leads to substantial upregulation of utrophin at the sarcolemma, resulting in significant improvements in skeletal muscle function and a slowing of heart function deterioration. These benefits remain observable at six months post-treatment. In male nonhuman primates, systemic administration of MyoAAV-UA increases utrophin expression by twofold in skeletal muscle, with no significant side effects observed. Furthermore, MyoAAV-UA upregulates utrophin and utrophin-glycoprotein complexes in induced pluripotent stem cell-derived myotubes from DMD patients. In conclusion, these findings demonstrate the potential of MyoAAV-UA as a therapeutic approach for DMD.

An empirical study on the impact of genetics and gender and its consequences in hypertrophic cardiomyopathy

Background: Gender-associated variations in phenotypic expression and their consequences are established in numerous cardiac circumstances. However, their impact is questionable in the case of HCM. Objective: To investigate the demographic and clinical profiles of the HCM patients. Also, to compare the echocardiographic features according to the HCM subtypes in the study populace. Methodology: The present study was conducted at the DMCH, Ludhiana, from March 2019 to May 2021, using a prospective observational and non-blinded design. The data regarding demographic and clinical profile are gathered for the specified duration. The clinical features are confirmed through the Echocardiography. The gathered data are analyzed through chi-square to determine the differences among the groups with the aid of the SPSS tool. Results and discussion: The demographic profiles and clinical assessment of 103 patients are analyzed. The subjective assessment reveals that HCM is predominantly in males in a ratio of 2.1:1. Dyspnea is a chief complaint of both genders (77.67%). Apical type is prevalent in male HCM patients. MYBPC3 and MYH7 are the general mutations found in the genetic tests. SCD is found in patients possessing this type of genetic mutation. The non-obstructive type is more common than the obstructive type. Conclusions: HCM is a chronic disease and causes morbidity as well as mortality globally. HCM patients are vulnerable to SCD and stroke. These risk factors rely on the diagnosis associated with age, gender, obstruction, obesity, and coronary diseases. Hence, the present research on the demographic characteristics of HCM patients promotes awareness regarding the complications among the Indian populace.

Characteristic PIK3CA gene mutation in breast cancer

Objective: To investigate the mutation spectrum of the PIK3CA gene in breast cancer, providing a new basis for the precise treatment of breast cancer with PIK3CA inhibitors. Methods: A retrospective analysis was conducted on 144 breast cancer patients who underwent biopsy before neoadjuvant therapy archived from 2015 to 2020 at the Fourth Hospital of Hebei Medical University. Next-generation sequencing (NGS) was utilized to detect the mutations of 520 genes closely related to the development of solid tumors and targeted therapies. The study compared the differences between reported mutation types and focused on analyzing the mutation status of the PIK3CA gene. The clinical and pathological characteristics, including age of onset, molecular subtypes, and Ki-67, were also analyzed. The correlation between PIK3CA mutations and clinicopathological characteristics was examined using Pearson×s chi-square test and Mann Whitney test. Logistic regression was employed to analyze factors influencing PIK3CA mutations. Kaplan-Meier survival analysis and Cox regression models were constructed using R programming. Results: Among the 144 breast cancer samples, 61 (42.3%, 61/144) exhibited PIK3CA gene mutations, of which 23 cases (53.5%, 23/43) were HER2-positive breast cancer, 28 cases (44.4%, 28/63) were luminal breast cancer, and 10 cases (27.8%, 10/36) were triple-negative breast cancer. Of the detected mutations, three hotspot mutations (H1047R, E545K, and E542K) accounted for 72.1% of the total PIK3CA mutations, with H1047R (52.4%), E545K (16.4%), and E542K (3.3%) most commonly detected. The remaining rare mutations accounted for 26.3%. Co-mutations involving PIK3CA and other genes were also observed in the cohort, occurring with TOP2A and FOXA1, while being mutually exclusive with GATA3 and BRCA2. PIK3CA mutations were significantly associated with HER2 status and were not significantly correlated with the patient's age, menopausal status, HR status, Ki-67 index, molecular typing, TNM stage or pCR status. Likewise, no significant correlation was found between different PIK3CA mutation status and overall survival. Conclusions: This cohort study shows the overall mutation rate of PIK3CA in breast cancer and the mutation frequencies across different molecular subtypes. The findings reveal a significant correlation between PIK3CA mutations and HER2 status, which provides a new basis for the precise treatment of breast cancer with PIK3CA inhibitors.

Comprehensive analysis of TMEM9 in human tumors

BackgroundTMEM9, a transmembrane protein, has emerged as a significant player in tumor progression, yet its comprehensive role across various cancers remains unclear. This study investigates the expression patterns, genetic alterations, immune associations, and prognostic implications of TMEM9 across multiple cancer types using large-scale bioinformatics approaches.MethodsTMEM9 expression was analyzed in normal and tumor tissues using data from the TCGA and GTEx databases, with protein expression verified via CPTAC datasets. The prognostic impact of TMEM9 was assessed using overall survival (OS) and disease-free survival (DFS) analyses across various cancers. Genetic alterations, including mutation types and copy number alterations, were explored using the cBioPortal platform. We also examined DNA methylation, RNA modifications, and immune infiltration correlations using bioinformatics tools, including TIMER2 and UALCAN. TMEM9’s relationship with tumor mutational burden (TMB) and microsatellite instability (MSI) was analyzed, and gene enrichment analyses were performed using the STRING database and GO/KEGG pathway analyses.ResultsTMEM9 was significantly overexpressed in several cancers, including ACC, BLCA, BRCA, CHOL, COAD, GBM, and others. Elevated TMEM9 expression correlated with worse OS and DFS in ACC, CESC, KICH, UVM, and additional tumor types. Genetic alterations, predominantly amplifications, were frequent in BRCA, LIHC, and UCEC. DNA methylation analysis revealed hypermethylation in tumors like HNSC and KIRC, while RNA modification analyses showed TMEM9 associations with m6A and m1A-related genes. TMEM9 expression was strongly correlated with immune infiltration, particularly cancer-associated fibroblasts in tumors like THYM and HNSC. Positive associations between TMEM9 and TMB/MSI were observed in several cancers, suggesting genomic instability. Enrichment analyses identified TMEM9 involvement in pathways related to the endoplasmic reticulum, Wnt signaling, and protein processing.ConclusionTMEM9 plays a crucial role in cancer progression, influencing gene expression, immune modulation, and genomic instability. These findings highlight TMEM9 as a potential prognostic biomarker and therapeutic target across multiple cancer types.

Functional Role of Protein Phosphatase-6 (PPP6c): Regulation of Expression and Modulation of Activity.

This review produces information about the role of protein phosphatase-6 (PPP6C) in various biological processes such as cell proliferation, cell cycle regulation, apoptosis, autophagy, cell migration and differentiation, and DNA damage repair. The issues of the participation of PPP6C in the formation of tumor progression and the role of PPP6C in the epigenetic regulation of the tumor process are covered. The article presents in detail the classification of mutations depending on the biological effects they have. It has been shown that various types of mutations in the PPP6C gene can change the composition of the heterotrimeric complex, favoring some regulatory subunits over others, which promotes selective dephosphorylation of substrates to maintain cell viability and change their biological behavior. In particular, their proliferative activity is disrupted, leading to mitosis arrest at various cell cycle stages. An increase in the activity of Aurora A or a decrease in the activity of DNA-dependent protein kinase is considered the main molecular mechanism of tumor development associated with the inactivation of the pp6c protein. The article also discusses the topic of pharmacological modulation of PPP6C activity. PP6 is a protein involved in many biological processes. In this regard, it is especially important to clarify the role of each PP6 holoenzyme and the molecular mechanisms that regulate the formation of the PP6 complex. Changes in the activity of this phosphatase can disrupt cell functioning.

An evaluation of the performance of the PAP-PCR method in detecting UGT1A1 gene polymorphisms.

Gilbert's syndrome (GS) is a hereditary disorder caused by mutations in the UGT1A1 gene, leading to unconjugated hyperbilirubinemia. Accurate detection of UGT1A1 gene polymorphisms is crucial for diagnosis and management of GS. This study evaluated the clinical application of pyrophosphorolysis-activated polymerization PCR (PAP-PCR) method in dection of UGT1A1 gene polymorphisms. Whole-blood samples from 53 patients with GS were genotyped using PAP-PCR for UGT1A1 variations, including UGT1A1*60 (c.-3279T > G), UGT1A1*28 ([TA]6 > [TA]7), UGT1A1*6 (c.211G > A, G71R), UGT1A1*27 (c.686C > A, P229Q), UGT1A1*63 (c.1091C > T, P364L), and UGT1A1*7 (c.1456T > G, Y486D). For each locus, all cases were verified using the direct sequencing to assess PAP-PCR precision. One mutation type per locus was selected to investigate reproducibility and detection limits. The UGT1A1 gene polymorphism detected using PAP-PCR showed that, among the 53 patients, 83.02% presented missense mutations at UGT1A1*60 (c.-3279T > G), 54.72% had heterozygous or homozygous insertions in the TATA box in the promoter, 52.38% had the UGT1A1*6 variant (c.211G > A, G71R). The results obtained using the PAP-PCR and direct sequencing methods were almost consistent among all patients with UGT1A1 gene variants. However, there were different results in the promoter region variants among 2 patients in which PAP-PCR showed [TA]7 homozygosity, whereas direct sequencing revealed [TA]7/[TA]6 heterozygosity. This inconsistent result had been confirmed to be caused by differences in DNA polymerase activity. PAP-PCR could effectively detect UGT1A1 gene polymorphisms associated with Gilbert's syndrome. And it had exhibited superior accuracy in the analysis of TA repeat sequences compared to direct sequencing method. Additionally, due to its reduced program complexity, easy execution, and simple standardization, PAP-PCR may be a highly favorable option for clinical diagnosis.

Limb-Girdle Muscular Dystrophies (LGMD): Clinical features, diagnosis and genetic variability through next generation sequencing.

Limb-Girdle Muscular Dystrophies (LGMD): Clinical features, diagnosis and genetic variability through next generation sequencing.

Integrated Somatic Mutation Network Diffusion Model for Stratification of Breast Cancer into Different Metabolic Mutation Subtypes

Background: Mutations in metabolism-related genes in somatic cells potentially lead to disruption of metabolic pathways, which results in patients exhibiting different molecular and pathological features. Objective: In this study, we focused on somatic mutation data to investigate the significance of metabolic mutation typing in guiding the prognosis and treatment of breast cancer patients. Methods: The somatic mutation profile of breast cancer patients was analyzed and smoothed by utilizing a network diffusion model within the protein-protein interaction network to construct a comprehensive somatic mutation network diffusion profile. Subsequently, a deep clustering approach was employed to explore metabolic mutation typing in breast cancer based on integrated metabolic pathway information and the somatic mutation network diffusion profile. In addition, we employed deep neural networks and machine learning prediction models to assess the feasibility of predicting drug responses through somatic mutation network diffusion profiles. Results: Significant differences in prognosis and metabolic heterogeneity were observed among the different metabolic mutation subtypes, characterized by distinct alterations in metabolic pathways and genetic mutations, and these mutational features offered potential targets for subtype-specific therapies. Furthermore, there was a strong consistency between the results of the drug response prediction model constructed on the somatic mutation network diffusion profile and the actual observed drug responses. Conclusion: Metabolic mutation typing of cancer assists in guiding patient prognosis and treatment.

RET-AREAL: A multi-center, real-world data analysis on the efficacy of pralsetinib in acquired RET fusion after resistance to EGFR/ALK-TKIs.

RET-AREAL: A multi-center, real-world data analysis on the efficacy of pralsetinib in acquired RET fusion after resistance to EGFR/ALK-TKIs.

Spread through air spaces may predict early progression after salvage surgery for EGFR-mutant advanced lung adenocarcinoma treated with targeted therapy

ObjectiveSalvage resection for residual lung cancer harboring epidermal growth factor receptor (EGFR) mutations following EGFR-tyrosine kinase inhibitor (TKI) treatment is gaining traction for its survival benefits. However, the impact of pathological factors on survival remains unclear.MethodsBetween 2013 and 2023, we retrospectively reviewed 34 patients with advanced lung adenocarcinoma who received EGFR-TKI therapy. After a median TKI treatment duration of 9.1 months, all patients demonstrated either partial response (n = 27) or stable disease (n = 7) before salvage surgery. Demographic, pathological outcomes, progression-free survival (PFS), and overall survival (OS) were analyzed.ResultsAmong the 34 patients, six (17.6%) achieved a pathological complete response (pCR) and nine (26.5%) had a major pathological response (MPR). Additionally, 11 patients (32.4%) exhibited spread through air spaces (STAS), and lymphovascular invasion (LVI) was observed in nine patients (26.5%). The 3-year PFS and OS rates were 55.8% and 60.5%, respectively. No significant differences in PFS or OS were observed regarding mutation type, TKI generation, pCR, MPR, or LVI. However, Kaplan-Meier analysis revealed that STAS was associated with shorter PFS compared to non-STAS cases (p = 0.01). In multivariate analysis, STAS was identified as an independent prognostic factor for PFS (hazard ratio: 2.83, 95% CI: 1.35–28.54, p = 0.02). No significant prognosticators were found for OS in univariate or multivariate analyses.ConclusionWhile salvage surgery following TKI treatment is feasible and prolongs survival by removing residual primary tumor with potential TKI resistance, STAS may contribute to a higher risk of early progression. This finding warrants further investigation and tailored treatment strategies.

Similar Ehlers–Danlos Syndrome Profiles Produced by Variants in Multiple Collagen Genes

Background: Despite increased attention to double-jointedness or joint hypermobility as seen in connective tissue dysplasias like Ehlers–Danlos syndrome, improved clinical DNA correlations are needed to reduce decadal delays in diagnosis. Methods: To this end, patterns of history (among 80) and physical (among 40) findings are compared for 121 Ehlers–Danlos syndrome patients with recurring variants in collagen type I, II, III, V, VI, VII, IX, XI, and XII genes and novel ones in type XV, XVII, XVIII, and XXVII. Results: A recognizable tissue laxity–dysautonomia profile that transcended collagen biochemical class, triple helix component, mutation type, or presence of accessory DNA variants was defined with a few exceptions. Patients with novel variations experienced severe symptoms at younger ages (6–10 versus 14–18 years) and those with collagen type III variations had more than one significant difference in finding frequencies (spinal disk issues 75% versus 49%; bloating-reflux 100% versus 69%; migraines or menorrhagia 92% versus 53%). Conclusions: These results suggest that collagen DNA variants of diverse gene and molecular type can demonstrate EDS disposition and hasten its diagnosis when distress and disease become manifest.

Genetic variability of tobacco plants regenerated from cell lines resistant to heavy metal ions

One of the main elements of cytological observations carried out at all stages of creating new forms of plants is the determination of ploidy, both of the crossing components and of the resulting hybrids, varieties, and variants. The traditional method of determining ploidy by counting chromosomes on pressurized or permanent preparations under a microscope is laborious, and other methods of determining ploidy by the size of oysters, pollen or the number of chloroplasts in epidermal stomatal cells are not very accurate, especially if the ploidy of the samples does not differ significantly. The most reliable method for determining plant ploidy is the cytophotometric method of ploidy determination based on changes in the amount of DNA in the cell. The essence of flow cytometry (FCM) is that the fluorochrome light pulse recorded by a flow cytometer is proportional to the amount of DNA of each individual cell nucleus, in turn, the amount of DNA of the interphase nucleus reflects the ploidy of the latter. Data on the analysis of fertility in experimental plants are presented. The genomes of tobacco (Nicotiana tabacum L.) regenerants obtained from cell lines resistant to barium, cadmium, and vanadium ions were studied by cytometric analysis. It was found that the regenerant obtained from the cadmium (Cd2+) resistant line is a triploid. The regenerants obtained from cell lines resistant to barium (Ba2+) and vanadium ions are mixoploids. Control tobacco plants have a diploid genome. Regenerants retain the phenotypic characteristics of resistant cell lines. In our opinion, these characteristics are probably related to the phenomenon of polyploidy. However, other types of mutations in the studied tobacco plant variants are not excluded.

DSCC1 Identified as Promising Tumor Biomarker and Potential Therapeutic Target Through Comprehensive Multi-omics Analysis and Experimental Validation.

As a component of the alternative replication factor C (RFC) complex, DSCC1 plays a significant role in cancer progression due to its aberrant expression. However, the potential function of DSCC1 in a pan-cancer context remains unclear. In this study, we conducted a comprehensive analysis of DSCC1's role in tumors by integrating multi-omics bioinformatics tools. First, we utilized various databases to compare the expression of DSCC1 between tumor and normal tissues, revealing a strong association between its dysregulated expression and clinical diagnosis, prognosis, and staging. Additionally, we investigated different mutation types of DSCC1 and their contributions to cancer progression, finding that DSCC1 expression is regulated by epigenetics and RNA modifications. Furthermore, we explored the correlation between DSCC1 and immune-infiltrating cells, as well as immunotherapeutic biomarkers, suggesting that its expression influences the tumor immune microenvironment. By employing single-cell and spatial transcriptome data through platforms such as SingleCellBase, CancerSEA, and CROST, we further uncovered the heterogeneity of DSCC1 across various cancer types. Finally, we validated the significant upregulation of DSCC1 mRNA in multiple tumor cell lines using q-RTPCR, and demonstrated through CCK8 assays that silencing DSCC1 expression effectively suppressed cell proliferation. Our findings establish a foundational understanding of DSCC1's potential as a biomarker for cancer diagnosis, prognosis, and immunotherapy.

Association between P53 Gene Mutations and Colorectal Cancer in the Iranian Population: A Systematic Review

Background: Colorectal cancer (CRC) is the fourth most common cancer and one of the most significant cancers affecting the Iranian population. This systematic review aimed to investigate the association between mutations in the P53 gene and CRC. Methods: We conducted a search of six databases, including; Scopus, PubMed, Web of Science, Cochrane Library, SID, and Magiran up to Aug 10, 2024. Concepts in the search strategy were Iran, P53, and "Colorectal cancer". Original articles written in English or Persian that investigated the association between P53 gene mutations and CRC in the Iranian population were included. Results: Out of 313 articles, 17 articles were included in the study. Six case-control studies investigated the association between the codon 72 polymorphism of the P53 gene and colorectal cancer. Three studies found a significant difference in genotype frequencies of this polymorphism between CRC patients and healthy individuals. Exon 6 was shown to be one of the most common mutated exons in colorectal cancer. Mutations in exon 7 were associated with poor prognosis. The most common type of mutation was G to A mutation from exons 5 to 8 CpG sites. Conclusion: The present study suggests a potential association between the presence of the Arg allele at codon 72 within the P53 gene and a heightened susceptibility for developing and metastasizing CRC within the Iranian population. Furthermore, exons 5 to 8 of the P53 gene suggests that mutations localized at these sites may portend a poor prognosis.