Comprehensive Mutational Analysis Research Articles

Comprehensive analysis of Novel mutations in CCM1/KRIT1 and CCM2/MGC4607 and their clinical implications in Cerebral Cavernous malformations

BackgroundCerebral Cavernous Malformations (CCM) is a genetic disease characterized by vascular abnormalities in the brain and spinal cord, affecting 0.4-0.5 % of the population. We identified two novel pathogenic mutations, CCM1/KRIT1 c.811delT (p.Trp271GlyfsTer5) and CCM2/MGC4607 c.613_614insGG p.Glu205GlyfsTer31), which disrupt crucial protein domains and potentially alter disease progression. ObjectiveThe study aims to comprehensively analyze a Brazilian cohort of CCM patients, integrating genetic, clinical, and structural aspects. Specifically, we sought to identify novel mutations within the CCM complex, and explore their potential impact on disease progression. MethodsWe conducted a detailed examination of neuroradiological and clinical features in both symptomatic and asymptomatic CCM patients, performing genetic analyses through sequencing of the CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes In silico structural predictions were carried out using PolyPhen-2, SIFT, and Human Genomics Community tools. Protein-protein interactions and docking analyses were explored using the STRING database. ResultsGenetic analysis identifies 6 pathogenic mutations, 4 likely pathogenic, 1 variants of uncertain significance, and 7 unclassified mutations, including the novel mutations in CCM1 c.811delT and CCM2 c.613_614insGG. In silico structural analysis revealed significant alterations in protein structure, supporting their pathogenicity. Protein-protein interaction analysis indicated nuanced impacts on cellular processes. Clinically, we observed a broad spectrum of symptoms, including seizures and focal neurological deficits. However, no statistically significant differences were found in lesion burden, age of first symptom onset, or sex between the identified CCM1/KRIT1 and CCM2/MGC4607 mutations among all patients studied. ConclusionThis study enhances the understanding of CCM by linking clinical variability, genetic mutations, and structural effects. The identification of these novel mutations opens new avenues for research and potential therapeutic strategies.

Somatic mutational landscape across Indian breast cancer cases by whole exome sequencing

Breast cancer (BC) has emerged as the most common malignancy among females. The genomic profile of BC is diverse in nature and complex due to heterogeneity among various geographically different ethnic groups. The primary objective of this study was to carry out a comprehensive mutational analysis of Indian BC cases by performing whole exome sequencing. The cohort included patients with a median age of 48 years. TTN, TP53, MUC16, SYNE1, and OBSCN were the frequently altered genes found in our cohort. The PIK3CA and KLC3 genes are driver genes implicated in various cellular functions and cargo transportation through microtubules, respectively. Except for CCDC168 and PIK3CA, several gene pairings were found to be significantly linked with co-occurrence. Irrespective of their hormonal receptor status, RTK/RAS was observed with frequently altered signaling pathways. Further analysis of the mutational signature revealed that SBS13, SBS6, and SBS29 were mainly observed in our cohort. This study supplements the discovery of diagnostic biomarkers and provides new therapeutic options for the improved management of BC.

Investigating the WNT and TGF-beta pathways alterations and tumor mutation burden in young-onset colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the United States. Recent epidemiological evidence demonstrates an increasing incidence of young-onset CRC cases, defined as CRC cases in individuals 50 years old or younger. Studies have established that alterations in both the WNT and TGF-Beta signaling pathways have contributed to CRC development. While this is well understood, the comprehensive analysis of WNT and TGF-Beta pathway alterations in young-onset CRC cases has yet to be investigated. Here, we conducted a comprehensive bioinformatics analysis of mutations associated with each of the WNT and TGF-Beta signaling pathways according to age (≤ 50 years old versus > 50 years old) utilizing published genomic data from the cBioPortal. Chi-square results demonstrated no significant difference in WNT alterations between young-onset CRC and those > 50 years old. However, across all age groups, WNT alterations were frequently found in rectal cancers. We also found that WNT alterations were associated with better outcomes. The mutations associated with TGF-beta were observed at a higher rate in older CRC patients when compared to those ≤ 50 years old. Additionally, these mutations were found more frequently in colon primaries.

Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency

PurposeTranscription factor 3 (TCF3) encodes 2 transcription factors generated by alternative splicing, E12 and E47, which contribute to early lymphocyte differentiation. In humans, autosomal dominant (AD) E47 transcription factor deficiency is an inborn error of immunity characterized by B-cell deficiency and agammaglobulinemia. Only the recurrent de novo p.E555K pathogenic variant has been associated with this disease and acts via a dominant-negative (DN) mechanism. In this study, we describe the first Asian patient with agammaglobulinemia caused by the TCF3 p.E555K variant and provide insights into the structure and function of this variant.MethodsTCF3 variant was identified by inborn errors of immunity-related gene panel sequencing. The variant E555K was characterized by alanine scanning of the E47 basic region and comprehensive mutational analysis focused on position 555.ResultsThe patient was a 25-year-old male with B-cell deficiency, agammaglobulinemia, and mild facial dysmorphic features. We confirmed the diagnosis of AD E47 transcription factor deficiency by identifying a heterozygous missense variant, c.1663 G>A; p.E555K, in TCF3. Alanine scanning of the E47 basic region revealed the structural importance of position 555. Comprehensive mutational analysis focused on position 555 showed that only the glutamate-to-lysine substitution had a strong DN effect. 3D modeling demonstrated that this variant not only abolished hydrogen bonds involved in protein‒DNA interactions, but also inverted the charge on the surface of the E47 protein.ConclusionsOur study reveals the causative mutation hotspot in the TCF3 DN variant and highlights the weak negative selection associated with the TCF3 gene.

Next-generation sequencing technology in cancer

Next-generation sequencing (NGS) technology has revolutionized cancer research and treatment by enabling comprehensive analysis of genetic mutations, alterations, and expression profiles. It allows for the identification of cancer-driving mutations, helping in the development of targeted therapies. NGS provides detailed insights into tumor heterogeneity, resistance mechanisms, and clonal evolution. Its high-throughput capacity facilitates large-scale studies, improving our understanding of cancer genomics. By enabling personalized treatment plans based on individual genetic profiles, NGS holds promise for more effective and tailored cancer therapies. Early reviews on cancer genomics often lacked comprehensive coverage of emerging technologies. They missed in-depth analysis of NGS advancements, their impact on cancer research, and clinical applications. The review addresses this gap by reviving a thorough examination of NGS methods, their role in identifying genetic mutations, and their potential in personalized cancer treatment, thus providing essential insights into the evolving landscape of cancer genomics. The article covers the advancements in technology and bioinformatic approaches for NGS data analysis. It delves into NGS applications in research and diagnostics, particularly for solid cancer diagnosis. The review highlights specific cancer types, including hereditary breast cancer, melanoma, prostate cancer, thyroid cancer, lung cancer, and colorectal cancer. It explores NGS contribution in understanding the genetic basis of these cancers and its potential for enhancing personalized diagnosis and treatment strategies. This review rectifies early lacunas by providing a comprehensive and updated examination of NGS technology, addressing gaps in previous analyses and emphasizes bioinformatic approaches for NGS data analysis, crucial for interpreting vast genomic data accurately. The review meets the current need for a thorough understanding of NGS’s role in personalized cancer treatment and research.

TP53 mutations in myeloid neoplasms: implications for accurate laboratory detection, diagnosis, and treatment.

Genetic alterations that affect the function of p53 tumor suppressor have been extensively investigated in myeloid neoplasms, revealing their significant impact on disease progression, treatment response, and patient outcomes. The identification and characterization of TP53 mutations play pivotal roles in subclassifying myeloid neoplasms and guiding treatment decisions. Starting with the presentation of a typical case, this review highlights the complicated nature of genetic alterations involving TP53 and provides a comprehensive analysis of TP53 mutations and other alterations in myeloid neoplasms. Currently available methods used in clinical laboratories to identify TP53 mutations are discussed, focusing on the importance of establishing a robust testing protocol within clinical laboratories to ensure the delivery of accurate and reliable results. The treatment implications of TP53 mutations in myeloid neoplasms and clinical trial options are reviewed. Ultimately, we hope that this review provides valuable insights into the patterns of TP53 alterations in myeloid neoplasms and offers guidance to establish practical laboratory testing protocols to support the best practices of precision oncology.

Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients.

RAS, BRAF, and mismatch repair (MMR)/microsatellite instability (MSI) are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer (CRC). However, their characteristics and influencing factors in Chinese patients have not been thoroughly described. To analyze the clinicopathological features of KRAS, NRAS, BRAF, and PIK3CA mutations and the DNA MMR status in CRC. We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital. MMR proteins were tested using immunohistochemical analysis, and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction. Microsatellite status was determined using an MSI detection kit. Statistical analyses were conducted using SPSS software and logistic regression. The KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 44.6%, 3.4%, 3.7%, and 3.9% of CRC patients, respectively. KRAS mutations were more likely to occur in patients with moderate-to-high differentiation. BRAF mutations were more likely to occur in patients with right-sided CRC, poorly differentiated, or no perineural invasion. Deficient MMR (dMMR) was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas. KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 29.6%, 1.1%, 8.1%, and 22.3% of patients with dMMR, respectively. The dMMR was more likely to occur in patients with a family history of CRC, aged < 50 years, right-sided CRC, poorly differentiated histology, no perineural invasion, and with carcinoma in situ, stage I, or stage II tumors. This study analyzed the molecular profiles of KRAS, NRAS, BRAF, PIK3CA, and MMR/MSI in CRC, identifying key influencing factors, with implications for clinical management of CRC.

Multi-target measurable residual disease assessed by error-corrected sequencing in patients with acute myeloid leukemia: An ALFA study

The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A, TET2, and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p < 0.0001), lower RFS (HR = 3.36, p < 0.0001) and OS (HR = 3.81, p = 0.00023) whereas persistence of only one mutation was not. In 100 analyzable patients, WT1-MRD, but not NGS-MRD, was an independent factor for RFS and OS. In the subset of 67 NPM1 mutated patients, both NPM1 mutation detection (p = 0.0059) and NGS-MRD (p = 0.035) status were associated with CIR. We conclude that detectable NGS-MRD including DTA mutations correlates with unfavorable prognosis in AML. Its integration with alternative MRD strategies in AML management warrants further investigations.

CFTR mutations and phenotypic correlations in people with cystic fibrosis: a retrospective study from a single centre in south India

Emerging data reveal higher-than-expected prevalence of cystic fibrosis (CF) among non-European populations worldwide including in the Indian subcontinent. Systematic analyses of the CFTR mutation profile, and genotype-phenotype correlations among people with CF from south, east, or northeast India have not been reported before. We wanted to identify CFTR mutations in people with CF, and highlight novel variants, selective phenotypic correlations, and regional variances within India. A retrospective study was conducted at Christian Medical College, Vellore, India (single tertiary referral hospital) from September 2010 to August 2022, involving 120 people with CF from (i) four south Indian states (Tamil Nadu, Andhra Pradesh, Kerala, Karnataka), (ii) in and nearby regions of West Bengal, India and (iii) Bangladesh. Comprehensive CFTR mutation analyses were done by Next-Generation Sequencing, and variants were categorized per American College of Medical Genetics guidelines and compared with validated Locus-specific databases. Demographic characteristics, mutation profile, novel mutations, selective phenotype correlations, and regional variances were assessed. In 120 people with CF, 55 CFTR variants were identified, including six novel variants. F508del was the predominant mutation, yet with a lower allele frequency than reported among European populations (27% versus 70%). Phenotypic correlations suggested high mutational pathogenicity causing severe multi-organ morbidity, and death in 27%. Milder variants associated with pancreatic sufficiency were also evident in 23% of people with CF. Statistically significant regional variances were noted in genotype frequency, and clinical phenotype among people with CF from the two regions. Hotspot exons and introns that could potentially help create targeted mutation panels were identified. The identification of 55 different CFTR variants among 120 people with CF describes the diversity of mutations noted in India, while also revealing the challenges that providers may encounter in timely diagnosis and treatment of CF. However, these single-centre data have specific limitations and cannot be generalised to all people with CF from India or to those of non-European origin. Our data on regional CFTR mutations contribute to the emerging national registry on CF epidemiology in India, help formulate diagnostic and newborn screening algorithms, help optimise clinical care, and highlight urgency to improve access to life-changing modulator therapy. Cystic Fibrosis Foundation, USA (towards the CF-India Demonstration Project) and Christian Medical College, Vellore, India.

Studies on the PII-PipX-NtcA Regulatory Axis of Cyanobacteria Provide Novel Insights into the Advantages and Limitations of Two-Hybrid Systems for Protein Interactions.

Yeast two-hybrid approaches, which are based on fusion proteins that must co-localise to the nucleus to reconstitute the transcriptional activity of GAL4, have greatly contributed to our understanding of the nitrogen interaction network of cyanobacteria, the main hubs of which are the trimeric PII and the monomeric PipX regulators. The bacterial two-hybrid system, based on the reconstitution in the E. coli cytoplasm of the adenylate cyclase of Bordetella pertussis, should provide a relatively faster and presumably more physiological assay for cyanobacterial proteins than the yeast system. Here, we used the bacterial two-hybrid system to gain additional insights into the cyanobacterial PipX interaction network while simultaneously assessing the advantages and limitations of the two most popular two-hybrid systems. A comprehensive mutational analysis of PipX and bacterial two-hybrid assays were performed to compare the outcomes between yeast and bacterial systems. We detected interactions that were previously recorded in the yeast two-hybrid system as negative, as well as a "false positive", the self-interaction of PipX, which is rather an indirect interaction that is dependent on PII homologues from the E. coli host, a result confirmed by Western blot analysis with relevant PipX variants. This is, to our knowledge, the first report of the molecular basis of a false positive in the bacterial two-hybrid system.

Cyanobacterial α-carboxysome carbonic anhydrase is allosterically regulated by the Rubisco substrate RuBP.

Cyanobacterial CO2 concentrating mechanisms (CCMs) sequester a globally consequential proportion of carbon into the biosphere. Proteinaceous microcompartments, called carboxysomes, play a critical role in CCM function, housing two enzymes to enhance CO2 fixation: carbonic anhydrase (CA) and Rubisco. Despite its importance, our current understanding of the carboxysomal CAs found in α-cyanobacteria, CsoSCA, remains limited, particularly regarding the regulation of its activity. Here, we present a structural and biochemical study of CsoSCA from the cyanobacterium Cyanobium sp. PCC7001. Our results show that the Cyanobium CsoSCA is allosterically activated by the Rubisco substrate ribulose-1,5-bisphosphate and forms a hexameric trimer of dimers. Comprehensive phylogenetic and mutational analyses are consistent with this regulation appearing exclusively in cyanobacterial α-carboxysome CAs. These findings clarify the biologically relevant oligomeric state of α-carboxysomal CAs and advance our understanding of the regulation of photosynthesis in this globally dominant lineage.

Functional analysis and validation of oncodrive gene AP3S1 in ovarian cancer through filtering of mutation data from whole-exome sequencing

BackgroundHigh-grade serous ovarian carcinoma (HGSOC) is the most aggressive and prevalent subtype of ovarian cancer and accounts for a significant portion of ovarian cancer-related deaths worldwide. Despite advancements in cancer treatment, the overall survival rate for HGSOC patients remains low, thus highlighting the urgent need for a deeper understanding of the molecular mechanisms driving tumorigenesis and for identifying potential therapeutic targets. Whole-exome sequencing (WES) has emerged as a powerful tool for identifying somatic mutations and alterations across the entire exome, thus providing valuable insights into the genetic drivers and molecular pathways underlying cancer development and progression.MethodsVia the analysis of whole-exome sequencing results of tumor samples from 90 ovarian cancer patients, we compared the mutational landscape of ovarian cancer patients with that of TCGA patients to identify similarities and differences. The sequencing data were subjected to bioinformatics analysis to explore tumor driver genes and their functional roles. Furthermore, we conducted basic medical experiments to validate the results obtained from the bioinformatics analysis.ResultsWhole-exome sequencing revealed the mutational profile of HGSOC, including BRCA1, BRCA2 and TP53 mutations. AP3S1 emerged as the most weighted tumor driver gene. Further analysis of AP3S1 mutations and expression demonstrated their associations with patient survival and the tumor immune response. AP3S1 knockdown experiments in ovarian cancer cells demonstrated its regulatory role in tumor cell migration and invasion through the TGF-β/SMAD pathway.ConclusionThis comprehensive analysis of somatic mutations in HGSOC provides insight into potential therapeutic targets and molecular pathways for targeted interventions. AP3S1 was identified as being a key player in tumor immunity and prognosis, thus providing new perspectives for personalized treatment strategies. The findings of this study contribute to the understanding of HGSOC pathogenesis and provide a foundation for improved outcomes in patients with this aggressive disease.

Mutational and transcriptional landscape of pediatric B-cell precursor lymphoblastic lymphoma

AbstractPediatric B-cell precursor (BCP) lymphoblastic malignancies are neoplasms with manifestation either in the bone marrow or blood (BCP acute lymphoblastic leukemia [BCP-ALL]) or are less common in extramedullary tissue (BCP lymphoblastic lymphoma [BCP-LBL]). Although both presentations are similar in morphology and immunophenotype, molecular studies have been virtually restricted to BCP-ALL so far. The lack of molecular studies on BCP-LBL is due to its rarity and restriction on small, mostly formalin-fixed paraffin-embedded (FFPE) tissues. Here, to our knowledge, we present the first comprehensive mutational and transcriptional analysis of what we consider the largest BCP-LBL cohort described to date (n = 97). Whole-exome sequencing indicated a mutational spectrum of BCP-LBL, strikingly similar to that found in BCP-ALL. However, epigenetic modifiers were more frequently mutated in BCP-LBL, whereas BCP-ALL was more frequently affected by mutation in genes involved in B-cell development. Integrating copy number alterations, somatic mutations, and gene expression by RNA sequencing revealed that virtually all molecular subtypes originally defined in BCP-ALL are present in BCP-LBL, with only 7% of lymphomas that were not assigned to a subtype. Similar to BCP-ALL, the most frequent subtypes of BCP-LBL were high hyperdiploidy and ETV6::RUNX1. Tyrosine kinase/cytokine receptor rearrangements were detected in 7% of BCP-LBL. These results indicate that genetic subtypes can be identified in BCP-LBL using next-generation sequencing, even in FFPE tissue, and may be relevant to guide treatment.

Abstract 1220: Deep mutational scanning of EGFR reveals potential domain-specific TKI sensitivities in lung cancer and glioblastoma

Abstract The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We performed saturation mutagenesis of EGFR and assessed function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach revealed enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, lacking approved targeted therapies, were sensitive to dacomitinib. Strikingly, at least two glioblastoma patients with G598V dimerization domain mutations showed responses to dacomitinib treatment together with subsequent off-target resistance in one case. In summary, this comprehensive screen reveals novel functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations. Citation Format: Tikvah Hayes, Elisa Aquilanti, Erica Kim, Nicole Persky, Lisa Brenan, Amy Goodale, Ted Sharpe, Doug Alan, Robert Shue, Lior Golomb, Brianna Silverman, Yvonne Li, Lindsay Westlake, Federica Piccioni, Andrew Cherniack, Xiaoping Yang Yang, David Root, J. Kevin Hicks, Andrew Chi, Jorg Dietrich, Daniel Cahill, Cory Johannessen, Tracy Batchelor, Matthew Meyerson. Deep mutational scanning of EGFR reveals potential domain-specific TKI sensitivities in lung cancer and glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1220.

Abstract 1470: Advancing cancer research: A novel PanCancer digital PCR tool for simultaneous detection of multiple hallmark mutations in BRAF and EGFR

Abstract The paradigm shift towards precision medicine in oncology emphasizes the importance of identifying specific genetic mutations driving cancer. Some hallmark mutations in cancer-associated genes, such as BRAF and EGFR, are important in analyzing many cancer types. With the emergence of digital PCR (dPCR) technology, high-sensitivity and quantitative mutation analysis can be performed, lending valuable support to cancer research. In this work, we introduce a new and innovative dPCR method, the dPCR PanCancer assays (RUO), designed for concurrently detecting multiple hallmark mutations in BRAF and EGFR. This work includes two novel PanCancer assays for BRAF and EGFR, each tailored to target a spectrum of mutations associated with these genes, facilitating a comprehensive mutation analysis. The dPCR assay for BRAF targets multiple V600 hallmark mutations, and the dPCR assay for EGFR targets various important deletions on exon 19. This also includes a reference gene as a control for PCR efficiency in the duplex reaction. Here, we present our initial data from various sample types, including blood, plasma and FFPE samples. Through a meticulously optimized dPCR setup, we achieved exceptional sensitivity and specificity, enabling the detection of multiple mutations in a single channel at allelic frequencies below 1%. Both dPCR PanCancer Kits (RUO) have potential use in research for pre-screening samples (e.g., prior to next-generation sequencing) or monitoring cancer cells. They simultaneously assess the mutations, reducing time and costs and saving sample material. Additionally, our technology is adaptable to other cancer-associated genes, where similar assays can potentially be developed. Overall, we have demonstrated that our dPCR PanCancer Kits (RUO) provide a robust, fast and efficient technology to identify critical mutations, ultimately enhancing our understanding of BRAF and EGFR-driven cancers. The dPCR PanCancer Kit is for research use only. Not for the diagnosis, prevention, or treatment of a disease. Citation Format: Claudia Kappmeier, Sherina Edward, Corinna Hochstein, Ellen Inga Bruske, Francesca Di Pasquale, Ronny Kellner. Advancing cancer research: A novel PanCancer digital PCR tool for simultaneous detection of multiple hallmark mutations in BRAF and EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1470.

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.

Comprehensive analysis of spike protein mutations in coronavirus subvariants reveals newly emerging change in mode of entry and establishment of infection in hosts

Comprehensive analysis of spike protein mutations in coronavirus subvariants reveals newly emerging change in mode of entry and establishment of infection in hosts

Comprehensive Analysis of HIV-1 Integrase Resistance-Related Mutations in African Countries.

The growing emergence of non-nucleoside reverse transcriptase inhibitor (NNRTI) HIV drug resistance in sub-Saharan Africa (SSA) led to the World Health Organization (WHO) recommending, in 2018, a transition to dolutegravir (DTG) as a first-line antiretroviral therapy (ART) in SSA. The broad HIV-1 genetic diversity in SSA could shape DTG effectiveness and the pattern of drug resistance mutations (DRMs) in this region. This study evaluated HIV-1 integrase (IN) DRMs and conserved regions among published groups M, N, O, and P HIV-1 sequences spanning forty years of the HIV epidemic during the transition of DTG-based ART. Overall, we found low levels of integrase strand transfer inhibitor (INSTI)-DRMs (<1%) across HIV groups between the years 1983 and 2023; however, it was unexpected to detect DRMs at statistically significantly higher frequencies in pre-INSTI (1983-2007) than in the INSTI (2008-2023) era. The variability of accessory INSTI-DRMs depended on the HIV subtypes, with implications for susceptibility to DTG. Our findings provide new perspectives on the molecular epidemiology and drug resistance profiles of INSTIs in SSA, emphasizing the need for ongoing surveillance and customized treatment approaches to address the continent's varied HIV subtypes and changing resistance patterns.

Comprehensive full genome analysis of norovirus strains from eastern India, 2017–2021

BackgroundWorldwide, noroviruses are the leading cause of acute gastroenteritis (AGE) in people of all age groups. In India, norovirus rates between 1.4 to 44.4% have been reported. Only a very few complete norovirus genome sequences from India have been reported.ObjectiveTo perform full genome sequencing of noroviruses circulating in India during 2017–2021, identify circulating genotypes, assess evolution including detection of recombination events.MethodologyForty-five archived norovirus-positive samples collected between October 2017 to July 2021 from patients with AGE from two hospitals in Kolkata, India were processed for full genome sequencing. Phylogenetic analysis, recombination breakpoint analysis and comprehensive mutation analysis were also performed.ResultsFull genome analysis of norovirus sequences revealed that strains belonging to genogroup (G)I were genotyped as GI.3[P13]. Among the different norovirus capsid-polymerase combinations, GII.3[P16], GII.4 Sydney[P16], GII.4 Sydney[P31], GII.13[P16], GII.16[P16] and GII.17 were identified. Phylogenetic analysis confirmed phylogenetic relatedness with previously reported norovirus strains and all viruses were analyzed by Simplot. GII[P16] viruses with multiple residue mutations within the non-structural region were detected among circulating GII.4 and GII.3 strains. Comprehensive mutation analysis and selection pressure analysis of GII[P16] viruses showed positive as well as negative selection sites. A GII.17 strain (NICED-BCH-11889) had an untypeable polymerase type, closely related to GII[P38].ConclusionThis study highlights the circulation of diverse norovirus strains in eastern India. These findings are important for understanding norovirus epidemiology in India and may have implications for future vaccine development.

Comprehensive somatic mutational analysis in glioblastoma: Implications for precision medicine approaches.

Glioblastoma multiforme (GBM), a malignant neoplasm originating from glial cells, remains challenging to treat despite the current standard treatment approach that involves maximal safe surgical resection, radiotherapy, and adjuvant temozolomide chemotherapy. This underscores the critical need to identify new molecular targets for improved therapeutic interventions. The current study aimed to explore the somatic mutations and potential therapeutic targets in GBM using somatic mutational information from four distinct GBM datasets including CGGA, TCGA, CPTAC and MAYO-PDX. The analysis included the evaluation of whole exome sequencing (WES) of GBM datasets, tumor mutation burden assessment, survival analysis, drug sensitivity prediction, and examination of domain-specific amino acid changes. The results identified the top ten commonly altered genes in the aforementioned GBM datasets and patients with mutations in OBSCN and AHNAK2 alone or in combination had a more favorable overall survival (OS). Also, the study identified potential drug sensitivity patterns in GBM patients with mutations in OBSCN and AHNAK2, and evaluated the impact of amino acid changes in specific protein domains on the survival of GBM patients. These findings provide important insights into the genetic alterations and somatic interactions in GBM, which could have implications for the development of new therapeutic strategies for this aggressive malignancy.