Cancer Genetics[JOURNAL]
Sun
200 papers
Diagnostic and prognostic potential of FBXO8 expression in kidney renal clear cell carcinoma and its regulation of renal adenocarcinoma cells.
Luo Z, Wu X, Xie J … +5 more , Tang H, Chen J, Ye D, Dou S, Chen S
Cancer Genet · 2025 Jan · PMID 39647237 · Publisher ↗
BACKGROUND: The F-box protein 8 Gene (FBXO8) has been shown to suppress invasion and metastasis in various cancer types. Recurrence and drug resistance pose significant challenges in renal cell carcinoma (RCC). Identifyi...
BACKGROUND: The F-box protein 8 Gene (FBXO8) has been shown to suppress invasion and metastasis in various cancer types. Recurrence and drug resistance pose significant challenges in renal cell carcinoma (RCC). Identifying novel biomarkers is crucial for addressing these issues. METHODS: Data on RNA sequencing and patient survival for KIRC was obtained from The Cancer Genome Atlas (TCGA), UALCAN, and Gene Expression Omnibus (GEO) databases. We confirmed FBXO8 gene expression and its impact on survival. Clinical characteristics were classified, and FBXO8 expression differences among various categories were observed. We conducted biofunctional predictions and analyzed the tumor microenvironment (TME), immune cell infiltration, and immune checkpoints in relation to FBXO8 expression. FBXO8 was overexpressed using a plasmid, and we assessed Kidney renal clear cell carcinoma (KIRC) cell proliferation, migration, and apoptosis through CCK8, wound healing tests, and western blot analysis. RESULTS: Our findings revealed decreased FBXO8 expression in KIRC, with patients exhibiting low FBXO8 expression experiencing shorter survival times. The low expression group showed elevated TME immune and estimate scores. Biofunctional analyses indicated that FBXO8 expression was notably linked to drug metabolism cytochrome P450, nutrition disease, receptor-ligand activity, and neuroactive ligand-receptor interaction. Furthermore, we discovered significant correlations between FBXO8 expression and immune cell infiltration, as well as checkpoints such as CD274. Overexpression (OE) of FBXO8 led to a marked reduction in cell proliferation and migration, along with increased apoptosis, as evidenced by apoptosis-related protein expression. CONCLUSION: This study demonstrates that FBXO8 serves as a biomarker for KIRC and plays a role in regulating cell proliferation, migration, and apoptosis.
Screening and identification of gene expression in large cohorts of clinical tissue samples unveils the major involvement of EZH2 and SOX2 in lung cancer.
Niharika, Roy A, Sadhukhan R … +1 more , Patra SK
Cancer Genet · 2025 Jan · PMID 39647236 · Publisher ↗
Lung adenocarcinoma (LUAD), the primary subtype of Non-Small Cell Lung Cancer (NSCLC), accounts for 80 % to 85 % of cases. Due to suboptimal screening method, LUAD is often detected in late stage, leading to aggressive p...
Lung adenocarcinoma (LUAD), the primary subtype of Non-Small Cell Lung Cancer (NSCLC), accounts for 80 % to 85 % of cases. Due to suboptimal screening method, LUAD is often detected in late stage, leading to aggressive progression and poor outcomes. Therefore, early disease prognosis for the LUAD is high priority. In order to identify early detection biomarkers, we conducted a meta-analysis of mRNA expression TCGA and GTEx datasets from LUAD patients. A total of 795 differentially expressed genes (DEGs) were identified by exploring the Network-Analyst tool and utilizing combined effect size methods. DEGs refer to genes whose expression levels are significantly different (either higher or lower) compared to their normal baseline expression levels. KEGG pathway enrichment analysis highlighted the TNF signaling pathway as being prominently associated with these DEGs. Subsequently, using the MCODE and CytoHubba plugins in Cytoscape software, we filtered out the top 10 genes. Among these, SOX2 was the only gene exhibiting higher expression, while the others were downregulated. Consequently, our subsequent research focused on SOX2. Further transcription factor-gene network analysis revealed that enhancer of zeste homolog 2 (EZH2) is a significant partner of SOX2, potentially playing a crucial role in euchromatin-heterochromatin dynamics. Structure of SOX2 protein suggest that it is a non-druggable transcription factor, literature survey suggests the same. SOX2 is considered challenging to target directly, or "non-druggable," because of several intrinsic properties that make it difficult to design effective therapeutic agents against it. The primary function of SOX2 is to bind DNA and regulates gene expression. Unlike enzymes or receptors with defined active sites or binding pockets, transcription factors typically have relatively flat or diffuse surfaces that do not offer obvious "pockets" for small molecules to bind effectively. Hence, we drove our focus to investigate on potential drug(s) targeting EZH2. Molecular docking analyses predicted most probable inhibitors of EZH2. We employed several predictive analysis tools and identified GSK343, as a promising inhibitor of EZH2.
Unraveling the Prognostic Role of t(1:19) in Pediatric Pre-B Acute Lymphoblastic Leukemia: Insights from a Saudi Nationwide Cohort.
Sanduqji IA, Ballourah W, Tashkandi S … +9 more , Essa M, Jastaniah W, Alghimlas I, AlBalwi MA, Sahabi M, Ahmed AM, Elimam N, Monagel DA, Algiraigri A
Cancer Genet · 2025 Jan · PMID 39644796 · Publisher ↗
Recurrent translocation t(1;19) (q23;p13) describes a unique cytogenetic group of childhood B-cell acute lymphoblastic leukemia (ALL). Historically, t(1;19)(q23;p13.3) has been associated with poor outcomes. However, rec...
Recurrent translocation t(1;19) (q23;p13) describes a unique cytogenetic group of childhood B-cell acute lymphoblastic leukemia (ALL). Historically, t(1;19)(q23;p13.3) has been associated with poor outcomes. However, recent data suggests that currently intensified treatments have overcome this dismal prognosis. We conducted this study to understand this type of translocation in our population. From January 1999 until May 2020, 44 children with t(1;19) were identified by cytogenetics analysis during charts review. Cytogenetics (CG) testing results (Karyotype and/or FISH) were retrieved from the medical files on 37/44 patients. Of the 37 patients with Cytogenetics results, a total of 12 patients were found to have t(1;19)(q23;p13.3) as the only detectable genetic change, 13 patients were presented with t(1;19)(q23;p13.3) plus further chromosomal rearrangement (Table 1), 12 patients were presented with a variation involving t(1;19)(q23;p13.3) with or without additional chromosomes rearrangement. Patients were treated on different protocols, yet most were derived from the North American guidelines. Among the included subjects, relapse or refractory disease was identified in 15 cases (34 %), and 12 died due to progressive refractory leukemia. At the five-year mark, the estimated overall survival rate stood at 72 %. No statistical difference existed between patients treated on the high-risk (HR) protocol and those treated on the standard-risk (SR) protocol. It appeared that t(1,19) standard risk ALL had more relapses on the standard risk protocol. Furthermore, Relapses were mostly earlier and poorly salvageable. As such, treatment intensification for standard risk ALL with t(1,19) is warranted.
A novel lynch syndrome kindred with hereditary adrenal cortical carcinoma.
Ahuja K, Goudar R
Cancer Genet · 2024 Nov · PMID 39571462 · Publisher ↗
BACKGROUND: Adrenal cortical carcinoma (ACC) is an extremely rare malignancy, and advanced ACC carries a very poor prognosis. Early detection is critical since early-stage disease can be cured with surgical resection. AC...
BACKGROUND: Adrenal cortical carcinoma (ACC) is an extremely rare malignancy, and advanced ACC carries a very poor prognosis. Early detection is critical since early-stage disease can be cured with surgical resection. ACC can be seen in Lynch syndrome; this case and review of the literature provide insight as to the potential biological origin of this malignancy. Clinicians should be aware of this association and the potential impact on cancer screening in these kindreds. CASE PRESENTATION: We describe a novel kindred with hereditary adrenal cortical carcinoma and the Muir- Torre syndrome, a phenotypic variant of Lynch syndrome that includes sebaceous neoplasms and visceral malignancies. We report a 59-year-old Caucasian man with an MSH2 deletion who was diagnosed with metastatic adrenal cortical carcinoma. The patient's brother also had a history of adrenal cortical carcinoma. The patient's cancer initially responded to immunotherapy with pembrolizumab. Somatic genetic testing performed on a tumor biopsy did not identify the germline MSH2 deletion. CONCLUSIONS: A review of the literature identifies an association between germline MSH2 mutations and ACC, suggesting a potential biological basis for carcinogenesis. This case highlights the importance of ACC screening for patients with Lynch Syndrome and a family history of adrenal cortical carcinoma due to the high mortality from this malignancy. This case also highlights the importance of separate germline and somatic testing for patients with a concerning personal or family history of cancers.
Genetic profiling of metastatic colon adenocarcinoma in Iranian patients: Insights into pathogenic variants and tumor characteristics.
Boroonsara P, Esfehani RJ, Kermani AT … +1 more , Shakour N
Cancer Genet · 2024 Nov · PMID 39566319 · Publisher ↗
INTRODUCTION: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality, and understanding the genetic landscape is crucial for improving targeted therapies. This study aimed to analyze the tu...
INTRODUCTION: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality, and understanding the genetic landscape is crucial for improving targeted therapies. This study aimed to analyze the tumor's genetic profiles of patients with metastatic CRC, focusing on pathogenic or likely pathogenic variants in tumor related genes. MATERIALS AND METHODS: The present cross-sectional study was conducted on 40 Persian patients with metastatic colorectal adenocarcinoma. Formalin-fixed paraffin-embedded tumor samples were analyzed using next generation sequencing technique to detect pathogenic variants. The patients' tumor characteristics, including differentiation grades and tumor sites (colon, rectum, or rectosigmoid), were documented and the relationship between variants and tumor characteristics was evaluated. RESULTS: The study population had a mean age of 55.75 ± 12.88 years, and 60 % were female. The most common tumor site was the colon (52.5 %), followed by rectosigmoid (27.5 %) and cecum (20 %). APC gene variants were prevalent in 72.5 % of patients, with the p.Arg876* variant being the most frequent. TP53 gene variants were present in 65 %, with p.Trp146* and p.Arg273His being the most common. Pathogenic KRAS gene variants were observed in 50 %, significantly associated with rectosigmoid involvement (p = 0.001). The ERBB2 CNVs were found in 25 % of patients and were associated with colon involvement (p = 0.021). CONCLUSION: The study highlights the genetic diversity in Persian patients with metastatic colon adenocarcinoma and demonstrated that APC and TP53 variants were the most prevalent, while KRAS and ERBB2 variants were associated with specific tumor sites. These findings provide a basis for personalized treatment strategies in CRC among Persian population.
Contribution of ERCC2 rs13181 (Lys751Gln) and rs1799793 (Asp312Asn) polymorphisms to the risk of bladder cancer in Bangladesh.
Islam MA, Mubashshira S, Rahman MM … +1 more , Kabir Y
Cancer Genet · 2024 Nov · PMID 39551027 · Publisher ↗
BACKGROUND: Human Excision Repair Cross-Complementation Group 2 (ERCC2) proteins play a vital role in the nucleotide excision repair pathway through ATP-dependent helicase activity. Several studies found that polymorphis...
BACKGROUND: Human Excision Repair Cross-Complementation Group 2 (ERCC2) proteins play a vital role in the nucleotide excision repair pathway through ATP-dependent helicase activity. Several studies found that polymorphisms in the ERCC2 gene are associated with susceptibility to different cancers, although the outcomes were confusing. OBJECTIVE: As a result, in this retrospective study, we investigated the relationship between genetic polymorphisms of the ERCC2 gene at codons 312 (rs1799793) and 751 (rs13181) and bladder cancer susceptibility in Bangladesh, as well as the disease's aggressiveness. METHODS: Genetic polymorphisms of ERCC2 were assayed by the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method with 121 bladder cancer patients and 130 healthy controls. RESULTS: Patients who had the Gln/Gln polymorphism of ERCC2 at codon 751 (OR=3.27; 95% CI=1.19-8.67; p<0.05) and Asp/Asn at codon 312 (OR=2.14; 95% CI=1.03-4.29; p<0.05) were significantly associated with a higher risk of developing bladder cancer. Again, Gln/Gln polymorphisms in bladder cancer (p<0.05) were more likely to be present in individuals with cancer in the family. CONCLUSIONS: This study reveals that susceptibility and bladder cancer aggressiveness are associated with polymorphisms at codon 751 and Asp/Asn at codon 312 of the ERCC2 gene.
Mutations of ARID1B, PIK3C2B, KMT2B, and FAT1 genes influence clinical outcome in newly diagnosed myeloma.
Morawska M, Kiełbus M, Paziewska M … +6 more , Szelest M, Karczmarczyk A, Zaleska J, Własiuk P, Giannopoulos K, Grząśko N
Cancer Genet · 2024 Nov · PMID 39536425 · Publisher ↗
The study aimed to elucidate the mutational profile of patients with newly diagnosed multiple myeloma to understand correlations of alterations with clinical outcomes. A cohort of 20 patients was enrolled, and mutational...
The study aimed to elucidate the mutational profile of patients with newly diagnosed multiple myeloma to understand correlations of alterations with clinical outcomes. A cohort of 20 patients was enrolled, and mutational analysis was conducted using the TruSight Oncology 500 DNA Kit. Identified genetic alterations were related to clinicopathologic features and treatment outcomes. A total of 724 high-quality variants were validated. All patients harbored mutations associated with the RTK-RAS pathway, with over half having alterations in PI3 K, NOTCH, and WNT pathways. Several gene mutations were associated with specific clinical characteristics and prognostic indicators, revealing a complex interplay between genetic alterations and myeloma type, standard prognostic indicators, biochemical parameters, and renal function. Genetic alterations significantly influencing progression-free survival concerned PIK3C2B, ARID1B genes, and concomitant mutations in KMT2B, FAT1, and ARID1B. The findings underscore the potential of gene mutation-based prognostic tools in enhancing clinical decision-making and suggest that further exploration of identified genetic markers could pave the way for improved prognostic stratification and targeted therapeutic interventions in multiple myeloma.
Progesterone decreases viability and up regulates membrane progesterone receptors expression on the human Chronic Myeloid Leukemia cell line.
Bagheri V, Rezaei F, Alipour R … +3 more , Sereshki N, Ahmadipanah V, Rafiee M
Cancer Genet · 2024 Nov · PMID 39522451 · Publisher ↗
Progesterone (P4) has an important effect (activatory or inhibitory) on cell proliferation. Although there is evidence of the impact of progesterone on sex-linked cancers, it can affect other cancer cells expressing P4 r...
Progesterone (P4) has an important effect (activatory or inhibitory) on cell proliferation. Although there is evidence of the impact of progesterone on sex-linked cancers, it can affect other cancer cells expressing P4 receptors (PRs). We evaluated the expression of membrane P4 receptors (mPRs) and the viability in progesterone-treated K562 cells to inspect the possible effects route of progesterone on this (CML) cancer cell line. K562 cells were exposed to various concentrations of progesterone or no exposure for 48 and 72 h. The percentage of viability and cells that expressed mPRα and mPRβ were evaluated by MTT test and flow cytometry respectively. Progesterone significantly increased the expression of mPRα and especially mPRβ on the surface of K562 cells and significantly decreased their viability (p ≤ 0.05). Progesterone can reduce viability in K562 cells. Our findings showed that progesterone affects its receptor expression on K562 cells. Thus it may influence the performance of K562 cells in addition to its direct effects on these cells (via binding to its receptors).
Comparison of two cases of Familial Adenomatous Polyposis with the same APC genotype and different phenotypes.
Spier E, Pandya A, Biase MD
Cancer Genet · 2024 Nov · PMID 39514935 · Publisher ↗
Familial adenomatous polyposis (FAP) is a colorectal cancer (CRC) predisposition syndrome characterized by the presence of numerous colorectal adenomatous polyps, resulting from a single germline, heterozygous, likely pa...
Familial adenomatous polyposis (FAP) is a colorectal cancer (CRC) predisposition syndrome characterized by the presence of numerous colorectal adenomatous polyps, resulting from a single germline, heterozygous, likely pathogenic/pathogenic (LP/P) variant in the APC gene, an important tumor suppressor encoding gene. Classic FAP is considered in individuals with a germline LP/P variant in APC and have ≥100 colorectal adenomatous polyps beginning on average in adolescence, while attenuated FAP typically presents with fewer colorectal adenomatous polyps (10-<100 polyps) in adulthood. Both forms can feature extracolonic manifestations, such as desmoid tumors, thyroid cancer, and osteomas. Reported genotype-phenotype correlations in FAP provide valuable insights for healthcare providers, but variable expressivity persists even among individuals sharing a genotype. In this case study, we report two patients with the same pathogenic APC variant [c.4348C>T, p.Arg1450Ter] and different presentations and clinical findings. Case 1 describes a 21-year-old male with an extensive family history of cancer who was diagnosed with FAP at age 4. Case 2 describes a 22-year-old female with no family history who was diagnosed with FAP after she initially presented with a desmoid tumor. Despite genetic similarities, their clinical courses significantly differed, emphasizing the variable expressivity of FAP. These cases highlight the importance of individual management and surveillance, as genotype alone may not predict clinical outcomes. They also underscore the need for further research into factors that influence FAP expressivity.
Recurrent cytogenetic abnormalities reveal alterations that promote progression and transformation in myelodysplastic syndrome.
García R, Alkayyali T, Gomez LM … +4 more , Wright C, Chen W, Oliver D, Koduru P
Cancer Genet · 2024 Nov · PMID 39499993 · Publisher ↗
OBJECTIVE: To illustrate patterns of cytogenetic abnormalities that promote progression and/or transformation in myelodysplastic syndrome. METHODS: In this study we evaluated three different data sets to identify recurre...
OBJECTIVE: To illustrate patterns of cytogenetic abnormalities that promote progression and/or transformation in myelodysplastic syndrome. METHODS: In this study we evaluated three different data sets to identify recurrent cytogenetic abnormalities (RCAs) to delineate the cytogenetic evolutionary trajectories and their clinical significance. RESULTS: Datasets 1 and 2 were 2402 cross sectional samples from Mitelman database of Chromosome Aberrations and Gene Fusions in Cancer; these were used to discover RCAs and to validate them. Dataset 3 was a cohort of 163 institutional patients with serial samples from 35 % of them. This was used to further validate RCAs identified in the cross-sectional data, and their clinical impact. We identified MDS subtype associated RCAs, and some exclusive RCAs (Xp-, 2q-, 17q-, 21q-) that led to disease progression or transformation to leukemia. Evolutionary pathway analysis had shown temporal acquisition of RCAs. Therefore, presence of two or more RCAs suggests cooperative or complementary role in disease progression or transformation. Patients with one or more of these RCAs had poor prognosis and high risk for transformation. Genes frequently altered in MDS are mapped to some of the RCAs and suggest a close correlation between RCAs and molecular alterations in MDS. Karyotypic complexity, clonal evolution, loss of 17p had poor clinical outcomes. CONCLUSION: This study identified a unique combination of RCAs that are components in distinct cytogenetic trajectories. Some of these were primary changes while others were secondary or tertiary changes. Acquiring specific additional aberrations predicts progression or transformation to leukemia.
Potential use of SCAT1, SCAT2, and SCAT8 as diagnostic and prognosis markers in colorectal cancer.
Mohammadi P, Mohammadi S, Eghbalian A … +3 more , Meyabadi AJ, Alizadeh M, Taefehshokr S
Cancer Genet · 2024 Nov · PMID 39499992 · Publisher ↗
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Despite advancements, the underlying mechanisms controlling CRC's etiology remain unclear, and...
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Despite advancements, the underlying mechanisms controlling CRC's etiology remain unclear, and reliable biomarkers for diagnosis and treatment are still lacking. Long noncoding RNAs (lncRNAs) are increasingly recognized for their role in cancer progression, though many remain unidentified and their functions poorly understood. In this study, we investigated the expression of SCAT1, SCAT2, and SCAT8 lncRNAs in both cancerous and adjacent non-cancerous tissues from CRC patients. Using cDNA synthesized from total RNA extracted from 100 tissue samples, we performed Real-Time PCR to measure the expression levels of these lncRNAs. In addition, their diagnostic potential was evaluated through ROC curve analysis. Our results demonstrate that SCAT1, SCAT2, and SCAT8 are significantly upregulated in CRC tissues, with ROC analysis suggesting SCAT1 as a moderate biomarker and SCAT2 and SCAT8 as promising biomarkers for CRC diagnosis. Moreover, we found strong correlations between SCAT1 and SCAT8, as well as SCAT2 and SCAT8. Collectively, our findings indicate that SCAT1, SCAT2, and SCAT8 may act as oncogenes in CRC, offering potential as novel biomarkers for diagnosis and prognosis.
Identification and characterization of ADAR1 mutations and changes in gene expression in human cancers.
Valentine A, Bosart K, Bush W … +2 more , Bouley RA, Petreaca RC
Cancer Genet · 2024 Nov · PMID 39488870 · Publisher ↗
ADAR1 (Adenosine deaminase action on RNA1) is involved in post-transcriptional RNA editing. ADAR1 mutations have been identified in many cancers but its role in tumor formation is still not well understood. Here we used...
ADAR1 (Adenosine deaminase action on RNA1) is involved in post-transcriptional RNA editing. ADAR1 mutations have been identified in many cancers but its role in tumor formation is still not well understood. Here we used available cancer genomes deposited on CSOMIC and cBioPortal to identify and characterize mutations and changes in ADAR1 expression in cancer cells. We identify several high frequency substitutions including one at R767 which is located in one of the dsRNA interacting domains. In silico protein structure analysis suggest the R767 mutations affect the protein stability and are likely to destabilize interaction with dsRNA. Gene expression analysis shows that in samples with under-expressed ADAR1, there is a statistically significant increase in expression of BLCAP (Bladder Cancer Associated Protein). Although BLCAP was initially identified in bladder cancers, more recent evidence shows that it is a tumor suppressor and BLCAP mutations have been detected in many cancer cells. Epistatic analysis using the cBioPortal mutual exclusivity calculator for the TCGA pan-cancer data shows that co-mutations between ADAR1 and other genes regulated by it are likely in cancer cells except for PTEN, AKT1 and BLCAP. This suggests that when ADAR1 function is impaired, PTEN, AKT1 and BLCAP become essential for survival of cancer cells. We also identified several samples with high mutation burden between ADAR1 and other genes regulated primarily in endometrial cancers. Finally, we show that the deaminase domain is highly conserved in metazoans and mutations within conserved residues do occur in human cancers suggesting that destabilization of the enzyme function is contributing to cancer development.
Elucidating the prognostic and therapeutic significance of TOP2A in various malignancies.
Liu G, Lin W, Zhang K … +7 more , Chen K, Niu G, Zhu Y, Liu Y, Li P, Li Z, An Y
Cancer Genet · 2024 Nov · PMID 39454521 · Publisher ↗
Topoisomerase IIα (TOP2A) is a crucial enzyme that plays a vital role in DNA replication and transcription mechanisms. Dysregulated expression of TOP2A has been associated with various malignancies, including hepatocellu...
Topoisomerase IIα (TOP2A) is a crucial enzyme that plays a vital role in DNA replication and transcription mechanisms. Dysregulated expression of TOP2A has been associated with various malignancies, including hepatocellular carcinoma, prostate cancer, colon cancer, lung cancer and breast cancer. In this review, we summarized the prognostic relevances of TOP2A in various types of cancer. The increased expression of TOP2A has been linked to resistance to therapy and reduced survival rates. Therefore, evaluating TOP2A levels could assist in identifying patients who may derive advantages from molecular targeted therapy. The amplification of TOP2A has been linked to a positive response to chemotherapy regimens that contain anthracycline. Nevertheless, the overexpression of TOP2A also indicates a heightened likelihood of disease recurrence and unfavorable prognosis. The prognostic significance of TOP2A has been extensively studied in various types of cancer. The increased expression of TOP2A is associated with poor clinical outcomes, indicating its potential as a valuable biomarker for assessing risk and stratifying treatment in these malignancies. However, further investigation is needed to elucidate the underlying mechanisms by which TOP2A influences cancer progression and to explore its potential as a therapeutic target.
Influence of polymorphisms on the phenotype of TLR1, TLR4 and TLR9 genes and their association with cervical cancer: Bioinformatics prediction analysis and a case-control study.
Moura EL, Santos IFD, Freitas PP … +11 more , Silva DMD, Santos ACMD, Silva ACPE, Lira Neto AB, Barros RP, Neves JDSD, Barbosa NR, Marques CS, Fraga CAC, Farias KF, Figueiredo EVMS
Cancer Genet · 2024 Nov · PMID 39418818 · Publisher ↗
Susceptibility to cervical cancer has been associated with Toll-like receptors (TLRs), which is an important component of innate immunity. According to previous studies, polymorphisms in TLRs genes can affect immune resp...
Susceptibility to cervical cancer has been associated with Toll-like receptors (TLRs), which is an important component of innate immunity. According to previous studies, polymorphisms in TLRs genes can affect immune response pathways and lead to the development of cervical cancer. The present study aims to evaluate the functionality of polymorphisms in TLR1, TLR4 and TLR9 genes and their associations with cervical cancer. To identify the functionality of polymorphisms, we used the following tools: MUpro, ChimeraX, SNP2TFBS and GTEx. A case-control study including 57 cases (11 High-grade Intraepithelial Lesion - HSIL and 46 cervical cancer) and 67 clinically healthy controls was conducted in the Brazilian population. Polymorphisms genotyping was performed by real-time PCR, using TaqMan probes, using the allelic discrimination method. Bioinformatics prediction showed that the TLR1 rs4833095 [NM_003263.4 (TLR1):c.743T>C (p.Asn248Ser)] and TLR4 rs4986790 [NM_138554.5 (TLR4):c.896A>G (p.Asp299Gly)] polymorphisms alter the structure and stability of their respective proteins. TLR9 rs187084 [NM_017442.3(TLR9):c.-1486A>G] polymorphism seems to affect the THAP1 binding site and modify gene expression. In the case-control study, the c.743TC heterozygous genotype of the rs4833095 SNP in the TLR1 gene was associated with an increased risk for HSIL/cervical cancer. No association of TLR4 rs4986790 and TLR9 rs187084 SNPs with HSIL/cervical cancer was found in the studied population. Allelic combination CAG (rs4833095/ rs4986790/ rs187084) increased the risk of cervical cancer. In conclusion, the present study identified that polymorphisms in TLRs genes can affect the phenotype of their respective genes and contribute to the development of HSIL or cervical cancer.
Dysregulation of metallothionein MT1 sub-types in TCF3::PBX1 pre-B-cell acute lymphoblastic leukemia.
Agnihotri A, Kamble VS, Khare SP
Cancer Genet · 2024 Nov · PMID 39306917 · Publisher ↗
The translocation between chromosomes 1 and 19 t(1;19) produces the TCF3::PBX1 fusion protein, which leads to childhood pre-B-cell acute lymphoblastic leukemia (ALL). The molecular mechanism of oncogenesis, however, rema...
The translocation between chromosomes 1 and 19 t(1;19) produces the TCF3::PBX1 fusion protein, which leads to childhood pre-B-cell acute lymphoblastic leukemia (ALL). The molecular mechanism of oncogenesis, however, remains obscure. This study aims to identify the genes specifically dysregulated in TCF3::PBX1 translocation. The publicly available expression microarray datasets on ALL were used for weighted gene co-expression network analysis (WGCNA) to identify modules associated with TCF3::PBX1. The available knockdown and ChIP-Seq datasets were used to assess the direct targets of TCF3::PBX1. The WGCNA revealed a module enriched in genes involved in the metal ion stress to be positively correlated with TCF3::PBX1, with metallothionein isoform MT1 subtypes MT1E, MT1F, MT1G, MT1H, and MT1X as the hub genes. Of the 145 positively correlated genes, 19 were downregulated upon TCF3::PBX1 knockdown. Eleven of these 19 genes including MT1G, showed TCF3::PBX1 occupancy at the promoter. The Metallothionein 1 family has been implicated in various cancers; however, their role in t(1;19) pre-B-cell ALL has not been previously demonstrated. Our analysis effectively accounts for the cellular and population-level heterogeneity and identifies a novel mechanism for the TCF3::PBX1 action.
Data-mining-based biomarker evaluation and experimental validation of SHTN1 for bladder cancer.
Wang Y, Wang J, Zeng T … +1 more , Qi J
Cancer Genet · 2024 Nov · PMID 39260052 · Publisher ↗
BACKGROUND: Gene therapy in bladder cancer (BLCA) remains an area ripe for exploration. Recent studies have highlighted the crucial role of SHTN1 in the initiation and progression of various cancers and SHTN1 may have in...
BACKGROUND: Gene therapy in bladder cancer (BLCA) remains an area ripe for exploration. Recent studies have highlighted the crucial role of SHTN1 in the initiation and progression of various cancers and SHTN1 may have interacted with the FGFR gene. However, its specific function in BLCA remains unclear. MATERIALS AND METHODS: We investigated the association between SHTN1 expression and prognosis, immune infiltration, and the tumor microenvironment (TME) across multiple malignancies using 433 BLCA samples from The Cancer Genome Atlas (TCGA). Differential gene expression analysis, functional annotation via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed for SHTN1-related genes by using R packages. Immune response and TME scores, along with drug sensitivity profiles of SHTN1, were analyzed using R packages. Immunohistochemistry (IHC) and western blotting were conducted to assess SHTN1 expression in surgical specimens from BLCA patients.CCK8 assay and cells wound healing assay were performed.The bioinformatics was analyzed by R software. Significant differences were evaluated using unpaired t test. RESULTS: SHTN1 expression levels were significantly elevated in BLCA associated with poor prognosis (p < 0.01). Receiver operating characteristic (ROC) curves and nomograms demonstrated the diagnostic and prognostic efficacy of SHTN1 in BLCA. Notably, SHTN1 expression was higher in high-grade BLCA compared to lower-grade (p = 5.6e-10), a finding corroborated by IHC and western blotting. Pathway enrichment analysis revealed significant involvement of the Neuroactive ligand-receptor interaction and Chemical carcinogenesis - DNA adducts signaling pathways among SHTN1 differentially expressed genes. In terms of immune infiltration, T cells CD8, T cells follicular helper, and dendritic cells were predominant in the SHTN1 low-expression group, whereas macrophages M0 and M2, and mast cells were predominant in the high-expression group. Multivariate Cox regression analysis identified SHTN1 as an independent prognostic factor for overall survival (HR = 2.93; 95 % CI = 1.40-6.13; p = 0.004).CCK8 and wound healing experiments showed that SHTN1 knockdown reduced the cell proliferation and migration. Western blot showed that the EMT pathway was clearly associated with SHTN1. CONCLUSIONS: Our findings suggest that SHTN1 holds promise as a prognostic and diagnostic biomarker for BLCA. Moreover, it is closely associated with elevated immune infiltration and distinct characteristics of the tumor microenvironment in BLCA.
Novel ABL1 mutation in a Moroccan CML patient with Imatinib resistance.
El Bouchikhi I, Azami Idrissi H, Lazraq A … +6 more , El Makhzen B, Ahakoud M, Berrady R, Ouldim K, Bouguenouch L, El-Azami-El-Idrissi M
Cancer Genet · 2024 Nov · PMID 39244947 · Publisher ↗
Tyrosine Kinase Inhibitors (TKI), such as Imatinib, are known for their effectiveness in achieving complete remission from Chronic Myeloid Leukemia (CML), a malignancy caused by a reciprocal translocation between the ter...
Tyrosine Kinase Inhibitors (TKI), such as Imatinib, are known for their effectiveness in achieving complete remission from Chronic Myeloid Leukemia (CML), a malignancy caused by a reciprocal translocation between the terminal fragments of the long arms of chromosomes 9 and 22 that leads to the famous chimeric BCR::ABL1 gene. Mutations in this fusion gene may induce resistance to TKI treatment, which requires prescribing a second-, or third-generation TKI medication. We report here a case of a Moroccan CML patient with secondary resistance to the frontline TKI treatment (Imatinib), in which, BCR::ABL1 cDNA sequencing reveals the novel mutation p.K375M at the ABL1 Kinase Domain. In-silico prediction tools confirm the pathogenicity of the p.K375M substitution. Homology analysis indicated that the residue is highly conserved and located in a stable region. This potentially pathogenic mutation is likely to disrupt the BCR::ABL1-Imatinib binding, leading to the observed resistance. To overcome the treatment resistance, Imatinib should be substituted with a second-generation TKI medication, such as Dasatinib, Bosutinib, or Nilotinib. The present study further widens the spectrum of TKI resistance mutations and emphasizes particularly the crucial role of molecular investigation in personalizing treatment for CML patients, ensuring efficient follow-up and appropriate healthcare.
Updates on liquid biopsies in neuroblastoma for treatment response, relapse and recurrence assessment.
Jahangiri L
Cancer Genet · 2024 Nov · PMID 39241395 · Publisher ↗
Neuroblastoma is a paediatric malignancy of the sympathoadrenal or Schwann cells derived from the neural crest. Risk stratification in neuroblastoma is informed by MYCN amplification, age, stage, ploidy, and segmental ch...
Neuroblastoma is a paediatric malignancy of the sympathoadrenal or Schwann cells derived from the neural crest. Risk stratification in neuroblastoma is informed by MYCN amplification, age, stage, ploidy, and segmental chromosomal alterations. High-risk cases bear dismal overall survival. A panel of pathology and imaging modalities are utilised for diagnosis, while treatment strategies depend on the risk group. Despite this, relapse can occur in 50% of high-risk neuroblastoma patients in remission post-treatment. Liquid biopsies typically comprise the sampling of the peripheral blood and are attractive since they are less invasive than surgical tumour tissue biopsies. Liquid biopsies retrieve circulating tumour DNA and circulating tumour RNA released by tumours in addition to circulating tumour cells. These biological materials can be utilised to analyse tumour genetic alterations. Monitoring tumour-derived molecular information can assist diagnostics, targeted therapy selection, and treatment while reflecting minimal residual disease, relapse, and recurrence. This study aims to review the latest research on liquid biopsies for disease diagnosis, assessing treatment efficacy, minimal residual disease, relapse, and recurrence in neuroblastoma. A deeper understanding of the application of liquid biopsies could inform future prospective clinical trials, and in time, facilitate their routine implementation in clinical practice.
BMS345541 is predicted as a repurposed drug for the treatment of TMZ-resistant Glioblastoma using target gene expression and virtual drug screening.
Nayak R, Mallick B
Cancer Genet · 2024 Nov · PMID 39213700 · Publisher ↗
Glioblastoma (GBM) is one of the most aggressive and fatal cancers, for which Temozolomide (TMZ) chemo drug is commonly used for its treatment. However, patients gradually develop resistance to this drug, leading to tumo...
Glioblastoma (GBM) is one of the most aggressive and fatal cancers, for which Temozolomide (TMZ) chemo drug is commonly used for its treatment. However, patients gradually develop resistance to this drug, leading to tumor relapse. In our previous study, we have identified lncRNAs that regulate chemoresistance through the competing endogenous RNA (ceRNA) mechanism. In this study, we tried to find FDA-approved drugs against the target proteins of these ceRNA networks through drug repurposing using differential gene expression profiles, which could be used to nullify the effect of lncRNAs and promote the sensitivity of TMZ in GBM. We performed molecular docking and simulation studies of predicted repurposed drugs and their targets. Among the predicted repurposed drugs, we found BMS345541 has a higher binding affinity towards its target protein - FOXG1, making it a more stable complex with FOXG1-DNA. The ADMET analysis of this drug BMS345541 shows a higher half-life and lower cytotoxicity level than other predicted repurposed drugs. Hence, we conjecture that this could be a better drug for increasing the sensitivity of TMZ for treating GBM patients.
Germline variant profiling of CHEK2 sequencing variants in breast cancer patients.
McCarthy-Leo C, Baughan S, Dlugas H … +8 more , Abraham P, Gibbons J, Baldwin C, Chung S, Feldman GL, Dyson G, Finley RL, Tainsky MA
Cancer Genet · 2024 Nov · PMID 39208550 · Publisher ↗
The cell cycle checkpoint kinase 2 (CHEK2) is a tumor suppressor gene coding for a protein kinase with a role in the cell cycle and DNA repair pathways. Variants within CHEK2 are associated with an increased risk of deve...
The cell cycle checkpoint kinase 2 (CHEK2) is a tumor suppressor gene coding for a protein kinase with a role in the cell cycle and DNA repair pathways. Variants within CHEK2 are associated with an increased risk of developing breast, colorectal, prostate and several other types of cancer. Comprehensive genetic risk assessment leads to early detection of hereditary cancer and provides an opportunity for better survival. Multigene panel screening can identify the presence of pathogenic variants in hereditary cancer predisposition genes (HCPG), including CHEK2. Multigene panels, however, also result in large quantities of genetic data some of which cannot be interpreted and are classified as variants of uncertain significance (VUS). A VUS provides no information for use in medical management and leads to ambiguity in genetic counseling. In the absence of variant segregation data, in vitro functional analyses can be used to clarify variant annotations, aiding in accurate clinical management of patient risk and treatment plans. In this study, we performed whole exome sequencing (WES) to investigate the prevalence of germline variants in 210 breast cancer (BC) patients and conspicuously among the many variants in HCPGs that we found, we identified 16 individuals with non-synonymous or frameshift CHEK2 variants, sometimes along with additional variants within other BC susceptibility genes. Using this data, we investigated the prevalence of these CHEK2 variants in African American (AA) and Caucasian (CA) populations identifying the presence of two novel frameshift variants, c.1350delA (p.Val451Serfs*18) and c.1528delC (p.Gln510Argfs*3) and a novel missense variant, c262C>T (p.Pro88Ser). Along with the current clinical classifications, we assembled available experimental data and computational predictions of function for these CHEK2 variants, as well as explored the role these variants may play in polygenic risk assessment.
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