Caliendo G, Della Pepa C, Zitiello M
… +4 more, Mignano A, Passariello L, Albanese L, Vietri MT
Cancer Genet
· 2026 Jan · PMID 41349144
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BACKGROUND: Double mutations (DMs) in cis within the same BRCA gene are extremely rare, and their clinical significance remains uncertain, as it is unclear whether they confer an additive risk compared with single pathog...BACKGROUND: Double mutations (DMs) in cis within the same BRCA gene are extremely rare, and their clinical significance remains uncertain, as it is unclear whether they confer an additive risk compared with single pathogenic variants (PVs). MATERIALS AND METHODS: We retrospectively analyzed a cohort of 1722 patients referred for suspected Hereditary Breast and Ovarian Cancer (HBOC). Among them, 9 unrelated probands were found to carry the same BRCA2 DM: c.631G>A (p.Val211Ile) in exon 7 and c.7008-2A>T (IVS13-2A>T) at the acceptor splice site of intron 13. Both variants were confirmed to co-segregate in cis. A control group of 19 probands with a single BRCA2 PV located between exons 7 and 14 was selected for comparison. RESULTS: All DM families originated from the same geographic area in Southern Italy, suggesting a founder effect. The mean age at breast cancer onset was 50.7 years in the DM group and 51.4 years in the control group. Tumor spectrum and distribution among probands and relatives were comparable between groups, and BRCA2-related breast cancers were predominantly hormone receptor-positive in both cohorts. No statistically significant differences were observed regarding cancer types, stage, or receptor profile. CONCLUSIONS: These findings suggest that the BRCA2 double mutation c.631G>A/c.7008-2A>T may have a founder effect, and the coexistence of the two variants does not appear to confer an additive cancer risk or a more severe clinical phenotype compared with carriers of a single BRCA2 pathogenic mutation.
Abdulla A, Rouhi V, Habibi S
… +3 more, Koseoglu H, Ari E, Guven M
Cancer Genet
· 2026 Jan · PMID 41344137
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Disruptions in the genome's maintenance capacity pose a problem for every organism, potentially leading to carcinogenesis. Therefore, it is extremely important to determine the relationship between factors affecting geno...Disruptions in the genome's maintenance capacity pose a problem for every organism, potentially leading to carcinogenesis. Therefore, it is extremely important to determine the relationship between factors affecting genome stability and disease pathogenesis. Nucleotide Excision Repair (NER) is a key mechanism maintaining genomic stability, repairing major DNA lesions caused by environmental factors like UV light, chemical agents, and cigarette smoke. In our study, we investigated the role of two NER-related genes, XPD/ERCC2 and XPG/ERCC5, in the pathogenesis of prostate cancer and their relationship with patients' clinical and pathological findings. Gene expression of ERCC2 and ERCC5 was analyzed using the RT-PCR method on pathologically verified matched tumor and normal biopsy samples collected from 50 prostate cancer patients. ERCC5 expression was significantly upregulated by 5.94-fold in tumor tissues (p = 0.005), whereas ERCC2 exhibited a non-significant 2.25-fold increase (p = 0.12). There was no significant correlation between ERCC2 and ERCC5 expression levels. Furthermore, the expression of both genes remained unaffected by key clinical variables, including smoking, diabetes, hypertension, nodule presence, PSA level, Gleason, and PIRADS scores. The high expression of the ERCC5 gene in prostate cancer suggests that the NER pathway plays a significant role in this disease, and that ERCC5 may be considered a potential biomarker.
Onyia AF, Lawal A, Ogo C
… +9 more, Nkom ES, Lasebikan NN, Ayegbusi OT, De Campos OC, Rotimi OA, Oyelade JO, Aliyu UM, Iweala EEJ, Rotimi SO
Cancer Genet
· 2026 Jan · PMID 41338003
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PURPOSE: Disparities in the care and management of breast cancer (BC) contribute to poor outcomes and limited access to precision oncology in Nigerian patients. Existing studies on Nigerian patients have largely been con...PURPOSE: Disparities in the care and management of breast cancer (BC) contribute to poor outcomes and limited access to precision oncology in Nigerian patients. Existing studies on Nigerian patients have largely been conducted abroad, restricting their direct application to local healthcare. This study addresses this gap through a locally led investigation of germline and somatic mutations using tumor-normal paired sequencing. METHODS: Forty-two female BC patients were recruited from teaching hospitals between January and April 2024. DNA was extracted from blood and matched fresh-frozen tumor tissue. Targeted sequencing of 50 cancer-related genes was performed with the Illumina AmpliSeq Cancer Hotspot Panel and MiSeq platform. Germline and somatic variants were identified through matched normal filtering, with oncogenic significance assessed using the ESCAT/ESMO Tier classification. Visualization was performed in R (v4.4.2) using the maftools package. RESULTS: A germline TP53 pathogenic variant, TP53 c.694dupA (p.Ile232Asnfs) was identified in a 35-year-old triple-negative BC patient with recurrent metastatic disease, representing its first report as a germline alteration. Additionally, eighteen oncogenic/likely oncogenic somatic variants were detected, nine of which were actionable (Tier I-III). EGFR amplification was found in 7 % of patients, alongside copy number losses in genes including CDKN2A and KIT. CONCLUSION: This study demonstrates the feasibility of localized tumor-normal sequencing in Nigerian BC patients, revealing actionable variants with clinical relevance. These findings highlight the need to integrate genomic profiling into routine cancer care and establish molecular tumor boards to advance precision oncology in Nigeria.
Khoo A, Pudjihartono M, O'Sullivan JM
… +1 more, Schierding W
Cancer Genet
· 2026 Jan · PMID 41317429
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Understanding how genomic variants contribute to lung cancer (LC) risk is key to better understanding the molecular mechanisms underlying that risk. While genome-wide association studies (GWAS) have identified numerous L...Understanding how genomic variants contribute to lung cancer (LC) risk is key to better understanding the molecular mechanisms underlying that risk. While genome-wide association studies (GWAS) have identified numerous LC risk loci, most single nucleotide polymorphisms (SNPs) reside in non-coding regions, making the interpretation of their function challenging. We accounted for lung-specific chromatin interactions and allele-specific gene expression levels in lung tissue to identify novel interactions between LC GWAS SNPs and distal genes. Pathway enrichment analysis implicated eight target genes (CYP2A6, ADCY2, CHRNA3, CHRNA5, LATS1, RAD52, RIF1, TP53BP1) in functional networks involving caffeine metabolism, DNA ionizing radiation (IR)-double strand breaks and cellular response, and nicotine effect on dopaminergic neurons. Novel findings include a role for rs2853677 in ADCY2 dysregulation (previous attribution to TERT) and rs9322193 in targeting tumour suppressor gene LATS1 (previous attribution to RPS18P9/KATNA1). By linking germline variants to more biologically relevant gene targets and somatic processes, our results align more closely with established epidemiological and environmental risk factors for lung cancer, including a potential genetic explanation for the environmental interaction of caffeine and smoking in LC risk. This highlights the value of integrating 3D genome architecture and tissue-specific expression to refine our understanding of cancer susceptibility.
Sina M, Majidzadeh-A K, Zarinfam S
… +4 more, Ferraro RM, Mazzoldi EL, Mousavi SZ, Giliani SC
Cancer Genet
· 2025 Nov · PMID 41308444
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Lynch syndrome is an inherited autosomal-dominant cancer-predisposition condition that results from germline defects in the DNA mismatch-repair (MMR) pathway or inactivation of the EPCAM gene. Variants involving EPCAM ar...Lynch syndrome is an inherited autosomal-dominant cancer-predisposition condition that results from germline defects in the DNA mismatch-repair (MMR) pathway or inactivation of the EPCAM gene. Variants involving EPCAM are detected in roughly 1-3 % of Lynch syndrome cases, whereas combined EPCAM-MSH2 deletions remain very uncommon. We investigated two Iranian families from the same village, each with multiple members affected by colorectal cancer (CRC), to identify the underlying genetic causes. In Family A, colon tumor immunohistochemistry showed loss of MSH2 and MSH6 expression in formalin-fixed paraffin-embedded tissue. Despite negative Sanger sequencing results for MSH2, whole-exome sequencing (WES) followed by copy number variant (CNV) analysis using CNVkit and ExomeDepth identified a large CNV across EPCAM and MSH2. Breakpoints were confirmed by MLPA and SYBR Green qPCR. A second family from the same village showed multi-generational CRC; Family B was therefore tested by MLPA/qPCR for the same CNV. We identified a heterozygous ∼76.7 kb deletion spanning EPCAM exons 1-9 and MSH2 exons 1-8. In Family A, 15/23 tested relatives were carriers; six carriers had CRC at 35-53 years, and no extracolonic tumors were observed. The CRC affected proband of Family B harbored the identical deletion. Cascade testing achieved remarkable uptake, with >20 relatives tested in family A-over tenfold higher than typical reports-facilitated by direct clinician contact and streamlined logistics such as convenient blood collection. This is the first documented EPCAM-MSH2 deletion reported from the Middle East and North Africa region (MENA).
Cancer Genet
· 2025 Nov · PMID 41274095
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Hepatocellular carcinoma (HCC) is a major health threat worldwide. This study found that WDR54 is overexpressed in liver cancer tissues and is inversely correlated with patient prognosis. Through comprehensive cell biolo...Hepatocellular carcinoma (HCC) is a major health threat worldwide. This study found that WDR54 is overexpressed in liver cancer tissues and is inversely correlated with patient prognosis. Through comprehensive cell biology experiments, we demonstrated that WDR54 plays a pivotal role in promoting the malignant proliferation and metastasis of HCC. Further molecular biology investigations, including transcriptome sequencing, revealed that WDR54 exerts its biological effects by modulating the NF-κB signaling pathway. Specifically, WDR54 interacts with RBBP5 to enhance the transcription of p65, thereby promoting HCC proliferation and metastasis. Additionally, the potential impact of WDR54 on tumor cell metabolism and tumor heterogeneity is explored. The findings of this study deepen our understanding of the molecular pathology of liver cancer and lay a foundation for future clinical applications.
Chkeir M, Gnangnon F, Dangbemey P
… +20 more, Fassinou G, Lacorre S, Chaumet M, Ivanga M, Fassinou RM, Takin R, Ogoula SN, Agbanlinsou A, Forestier L, Duprat N, Durand K, Chaunavel A, Preux PM, Darré T, Ngoungou EB, Gnonlonfoun DD, Azonbakin S, Laleye A, Blanquet V, Parenté A
Cancer Genet
· 2025 Nov · PMID 41270494
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Sub-Saharan African women often develop breast cancer at a younger age, with a high prevalence of aggressive subtypes such as triple-negative breast cancer and elevated mortality. Genetic factors may underlie these patte...Sub-Saharan African women often develop breast cancer at a younger age, with a high prevalence of aggressive subtypes such as triple-negative breast cancer and elevated mortality. Genetic factors may underlie these patterns, but African populations remain underrepresented in genomic research. As an initial step toward addressing this gap, we evaluated DNA extracted from formalin-fixed paraffin-embedded (FFPE) breast cancer blocks collected in anatomic pathology laboratories in Gabon, Togo, and Benin. Although DNA could be successfully extracted, its functional quality was significantly impaired. Quantitative PCR revealed progressive degradation, with poor amplification efficiency for larger fragments, and next-generation sequencing (NGS) libraries exhibited degraded electropherogram profiles, low coverage, and elevated duplication rates. These limitations likely stem from socio-economic constraints, including delayed processing and prolonged formalin fixation, which promote nucleic acid fragmentation and crosslinking. To overcome these barriers, we established a preservation protocol adapted to the resource and infrastructural limitations of the region: storage of biopsies in physiological saline at -20 °C. This method requires only basic equipment widely available in local hospitals, yet yielded DNA of high integrity, enabled efficient library construction, and produced significantly superior NGS performance compared with FFPE-derived DNA. This cost-effective and scalable approach provides a feasible solution for genomic research in resource-limited settings. Future efforts should focus on complementary strategies for RNA preservation and tumor enrichment to enable comprehensive molecular profiling and advance precision oncology in West Africa.
Fang Z, Li J, Xiong Y
… +7 more, Luo P, Lu Q, Wu M, Huang K, Zhang L, Zhu X, Wu L
Cancer Genet
· 2025 Nov · PMID 41265012
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Gliomas are characterized by an immunosuppressive tumor microenvironment (TME), which significantly limits the efficacy of current immunotherapies. To address this challenge, we explored the role of FBXL16, a gene with d...Gliomas are characterized by an immunosuppressive tumor microenvironment (TME), which significantly limits the efficacy of current immunotherapies. To address this challenge, we explored the role of FBXL16, a gene with distinct expression patterns in nervous system tumors identified through analysis of public databases. Our study utilized clinical sample analysis, survival correlation, in vitro functional assays, and in vivo mouse models to investigate FBXL16's impact on glioma progression. Gene set enrichment analysis (GSEA), immunosuppression profiling, and co-culture assays with flow cytometry validation were employed to elucidate its immunological role, particularly in regulating M2-type tumor-associated macrophage (M2-TAM) recruitment. Our investigation revealed a substantial decrease in FBXL16 expression within glioma tissues, which exhibited and positively correlation with patient survival rates. Overexpression of FBXL16 in glioma cells suppressed proliferation, migration, and invasion, and extended survival in glioma-bearing mice. Mechanistically, FBXL16 regulated the secretion of key immunoregulatory cytokines such as TGF-β, IL-6, IFN-α, and VEGF, thereby disrupting macrophage recruitment to the TME. These findings suggest that FBXL16 attenuates glioma progression by inhibiting cytokine release and limiting TAM recruitment, thus interrupting the immunosuppressive feedback loop within the TME. Our study highlights FBXL16 as a promising immunomodulatory target for glioma therapy, offering new insights into overcoming immunosuppression in gliomas.
Cancer Genet
· 2025 Nov · PMID 41237675
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Adjuvant transcatheter arterial chemoembolization (TACE) has traditionally been performed as an effective treatment for hepatocellular carcinoma (HCC). The present study aims to explore key genes associated with TACE tre...Adjuvant transcatheter arterial chemoembolization (TACE) has traditionally been performed as an effective treatment for hepatocellular carcinoma (HCC). The present study aims to explore key genes associated with TACE treatment for HCC. We used weighted gene co-expression network analysis (WGCNA) to identify the core gene related to the efficacy of TACE for HCC. The raw data of GSE104580 were downloaded from the Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were analyzed. WGCNA was used to identify the key modules related to the efficacy of TACE for HCC, and the protein-protein interaction (PPI) network was used to screen the core genes. Villin1 (VIL1) was identified as a core gene for predicting TACE response. VIL1 was highly expressed in HCC compared to normal tissues, and high expression of VIL1 was strongly correlated with the poor prognosis of HCC patients. Finally, we used one cohort from our center to validate that high expression of VIL1 was closely related to low TACE efficacy in HCC patients. Our study identified the Villin1 gene that may play an important role in the efficacy of TACE for HCC and may become a potential predictive biomarker for evaluating the efficacy of TACE in HCC patients.
Chong ML, Ng SME, Chai H
… +5 more, Diadamo A, Flagg A, Owen NM, Li P, Wen J
Cancer Genet
· 2025 Nov · PMID 41232304
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B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous hematologic malignancy caused by diverse genetic alterations. While cytogenetic methods such as karyotyping and FISH are routinely used in diagnostics, crypt...B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous hematologic malignancy caused by diverse genetic alterations. While cytogenetic methods such as karyotyping and FISH are routinely used in diagnostics, cryptic and novel oncogenic gene fusions often go undetected. We report a 15-year-old male diagnosed with high-risk B-ALL, presenting with anemia, leukocytosis, and significant lymphoblast burden. Initial karyotyping identified an abnormal clone with a t(7;20)(q34;q13.3) and FISH detected a partial deletion of the ABL1 gene. Chromosome microarray analysis revealed a deletion at 9p21.3 encompassing CDKN2A/CDKN2B and several contiguous copy number aberrations at 9q34.12q34.2. Further long-read genomic sequencing uncovered cryptic NUP214::ABL1 and ABL1::TSC1 fusions, as well as a novel VAPB::TRBV30 rearrangement from the t(7;20). RNA sequencing confirmed the transcripts for both ABL1 fusions and a noncoding rearrangement involving the TCRB locus. Notably, the presence of NUP214::ABL1 identified a clinically actionable target, supporting the use of tyrosine kinase inhibitors (TKIs) such as imatinib. This case underscores the critical role of integrated sequencing approaches in identifying cryptic genetic alterations in B-ALL for precise classification of oncogenic drivers and for targeted therapeutic strategies to improve patient outcomes.
Cancer Genet
· 2025 Nov · PMID 41232303
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BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant disease caused by heterozygous germline pathogenic variant in TP53 gene and frequently predisposes to a broad spectrum of cancers including early-onset canc...BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant disease caused by heterozygous germline pathogenic variant in TP53 gene and frequently predisposes to a broad spectrum of cancers including early-onset cancers. To date, clinical and genetic features of LFS are largely unknown in Algerian population. In this study, we performed germline variants screening in TP53 gene in an Algerian LFS family and we have reclassified the TP53 germline missense variant c.314G>T/ (p.Gly105Val). PATIENTS AND METHODS: We selected an LFS family with strong history of cancer along three generations that meets updated Chompret clinical criteria. Four family members were affected with various tumors. The proband in this family, a 4-year-old girl has been diagnosed with rhabdomyosarcoma at age 3 years old and she developed a secondary cancer in the right lung after radiotherapy. Her mother developed an early-onset breast cancer at age 30 years old, her maternal grandmother and her maternal aunt have also been diagnosed with breast cancer at age 33 and 27 years, respectively. We screened TP53 exons 3-11 using PCR-Sanger sequencing in 4 members of this LFS family: the proband, her mother and her father (trio) and her kid brother aged of 2 years old, respectively. RESULTS: The analysis identified the rare germline missense variant TP53 c.314G>T/ (p.Gly105Val) in heterozygous status in three members of the LFS family: the proband, her mother and her kid brother, respectively. The father has been tested negative for the variant. As the TP53 missense germline variant c.314G>T co-segregates within cancer in our LFS family along two generations, we can classify it for the first time as Class 4 variant with the status "Likely Pathogenic" according to ACMG nomenclature. CONCLUSIONS: Our study highlights the importance of the identification, the interpretation and the reclassification of TP53 missense variants detected in carriers in order to improve prognosis, treatment strategies, and LFS patients monitoring and identifying high risk family members.
Dai C, Ye N, Wang L
… +7 more, Zhou J, Xu S, Jiang Y, Pu J, Zhang L, Jia X, Xu P
Cancer Genet
· 2025 Nov · PMID 41202710
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Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer in women. Long noncoding RNAs (lncRNAs) are critically involved in malignant progression by modulating proliferation, apoptosis, invasion, metastasis, a...Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer in women. Long noncoding RNAs (lncRNAs) are critically involved in malignant progression by modulating proliferation, apoptosis, invasion, metastasis, and chemotherapy resistance. The long noncoding RNA small nucleolar RNA host gene 29 (SNHG29) is involved in multiple malignancies, although its role in EOC has not been elucidated. In our study, SNHG29 expression was significantly downregulated in EOC tissues and was negatively related to lymphatic invasion in EOC patients according to data from the TCGA database. Kaplan-Meier survival analysis revealed that among patients with early stage EOC, compared with patients with low SNHG29 expression levels, patients with high expression levels had markedly longer progression-free survival (PFS) and overall survival (OS) times. Further studies suggested that SNHG29 knockdown enhanced the invasive and migrative potential of EOC cells, whereas SNHG29 overexpression attenuated the invasive and migrative potential capacity. In animal experiments, SNHG29 knockdown significantly promoted lung metastasis in tail vein injection models. Mechanistically, the downregulation of SNHG29 expression inhibited its competitive endogenous RNA activity, resulting in increased miR-20b-3p availability and subsequent degradation of the downstream target gene GNAI3, as determined by RNA immunoprecipitation (RIP) and luciferase reporter gene assays. miR-20b-3p inhibition significantly reduces the invasive and metastatic capabilities of EOC cells resulting from a reduction in SNHG29 expression. Our study revealed that SNHG29 may be a promising prognostic factor and therapeutic target for EOC.
Schieffer KM, Bajaj R, Koo SC
… +9 more, Lavoie J, Lopez-Terrada D, Lu X, Luo M, Phung T, Smolarek TA, Sutcliffe M, Hodge JC, Cancer Genomics Consortium Sarcoma Working Group
Cancer Genet
· 2025 Nov · PMID 41197375
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The genomic landscape of pediatric sarcomas is constantly expanding, and the utilization of integrated cytogenetic and molecular evaluation of these tumors for diagnosis, prognostication, and therapeutic implications con...The genomic landscape of pediatric sarcomas is constantly expanding, and the utilization of integrated cytogenetic and molecular evaluation of these tumors for diagnosis, prognostication, and therapeutic implications continues to evolve. As a result, there are diverse approaches to the clinical practice of genomic testing in pediatric sarcomas. The Cancer Genomics Consortium Sarcoma Working Group conducted a survey to understand the current state of diagnostic genetic testing for pediatric sarcomas and assess the challenges faced in the field. Among 46 respondents across the United States and Canada, most utilized conventional karyotyping (61 %) and/or fluorescence in situ hybridization (87 %). Molecular methodologies, such as chromosomal microarray (30 %), targeted RT-PCR (22 %), gene fusion sequencing panels (35 %), pan-cancer sequencing panels (37 %), exome sequencing (11 %), and genome sequencing (7 %) were less frequently implemented clinically. When asked about challenges in the field of pediatric sarcoma, a scarcity of standard practice testing guidelines was noted most commonly, especially in the setting of limited tissue availability. Systematic evidence reviews and guidelines are needed for pediatric sarcomas with a consideration for multidisciplinary and international collaboration of individuals representing both high- and low-resource settings. As a resource in the interim, three case-based testing workflow scenarios are presented based on working group member experience to illustrate how differing technologies could be applied during evaluation considering diagnostic, prognostic and/or therapeutic needs. Finally, emerging technologies that are being applied to the diagnostic genetic evaluation of pediatric sarcomas are described, which upon implementation, may serve to streamline the work-up and further optimize patient care.
Cancer Genet
· 2025 Nov · PMID 41187487
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Inflammatory conditions in which immunoglobulin G4 secreting plasma cells infiltrate the affected tissue and form a systemic immune-mediated fibroinflammatory lesion is recognized as IgG4+ related disease. Patients with...Inflammatory conditions in which immunoglobulin G4 secreting plasma cells infiltrate the affected tissue and form a systemic immune-mediated fibroinflammatory lesion is recognized as IgG4+ related disease. Patients with this disease are at an increased risk for developing neoplasm. Lymphadenopathy is common in patients with IgG4+ related disease; and may clinically resemble lymphoma. Here we describe a patient presented with an IgG4+ related lymphadenopathy (disease) and harbored a clonal cytogenetic abnormality; to our knowledge this is the first report.
Li H, Jin C, Zhou F
… +8 more, Bao M, Tan C, Luo Z, Li N, Jin Y, Han L, Xiao G, Yan J
Cancer Genet
· 2025 Nov · PMID 41183464
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BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and a leading cause of cancer-related mortality. Tumor progression and metastasis, particularly to the lymph nodes, are critical fac...BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and a leading cause of cancer-related mortality. Tumor progression and metastasis, particularly to the lymph nodes, are critical factors contributing to poor patient outcomes. Identifying molecular markers that predict disease progression and patient survival is essential for improving CRC prognosis and therapeutic strategies. OBJECTIVE: This study aims to investigate the clinical significance of PHLDA2 expression in CRC and its potential as a prognostic marker. METHODS: PHLDA2 expression levels in CRC tissues were analyzed using Oncomine database and validated through immunohistochemistry. Mean optical density (MOD) scores were used to quantify PHLDA2 protein expression, and mRNA levels were analyzed in tissue samples. Kaplan-Meier survival analysis was performed to determine the effect of PHLDA2 expression on overall survival (OS). The impact of PHLDA2 on CRC cell behavior was examined by knocking out PHLDA2 in HCT 116 and DLD-1 cell lines, followed by assessments of cell proliferation, migration, invasion, and colony formation in vitro. Additionally, the effects of PHLDA2 knockout were evaluated in xenograft models. RESULTS: PHLDA2 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues. Elevated PHLDA2 levels were associated with lymph node metastasis, with a high expression in 69.23% of rectal cancer patients with metastasis compared to 33.33% in those without metastasis (p = 0.0363). Patients with higher PHLDA2 expression (2+/3+) had significantly worse OS than those with low or no expression (p < 0.05). Functional assays revealed that PHLDA2 knockout significantly reduced proliferation, migration, invasion, and colony formation in HCT 116 and DLD-1 cells. In vivo, PHLDA2 knockout markedly decreased tumor growth in xenograft models. CONCLUSIONS: Increased PHLDA2 expression is associated with more advanced CRC, particularly in cases with lymph node metastasis, and is linked to poorer survival outcomes. These findings suggest that PHLDA2 may be a valuable prognostic marker in CRC.
Cancer Genet
· 2025 Nov · PMID 41166795
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Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy with limited therapeutic options and poor clinical outcomes. To identify molecular biomarkers with diagnostic and prognostic relevance,...Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy with limited therapeutic options and poor clinical outcomes. To identify molecular biomarkers with diagnostic and prognostic relevance, an integrative ceRNA network analysis was performed using transcriptomic profiles from TCGA-ACC and GTEx adrenal tissues. miR-466, the highest-centrality miRNA in the ceRNA network, was used as the focal regulatory component in this framework. Experimentally validated targets were obtained from miRTarBase and miRDB, refined by TargetScan binding-site specificity and correlation-based filtering, and evaluated for tumor-specific expression. Among these candidates, CKS2 and ACAT2 emerged as consistently and significantly upregulated across therapy subgroups, with expression patterns confirmed across patient-level clinical heterogeneity. Both genes demonstrated markedly elevated expression in ACC relative to normal adrenal tissue and exhibited reinforced transcriptional co-regulation in tumors, suggesting a coordinated regulatory shift. Kaplan-Meier survival analyses indicated that high expression of either gene was associated with reduced overall survival, while a multivariate CoxPH model integrating both markers stratified patients into distinct high- and low-risk groups. Additionally, ROC classification demonstrated strong diagnostic performance for distinguishing tumor from normal tissue (AUC = 0.90 for CKS2, 0.88 for ACAT2, and 0.90 for the combined logistic regression model). Functional annotation revealed that CKS2 regulates cyclin-dependent cell cycle transitions, while ACAT2 participates in lipid and fatty-acid metabolic pathways. Together, these roles support a synergistic oncogenic axis in which proliferative acceleration is metabolically sustained, reinforcing tumor growth. These findings nominate CKS2 and ACAT2 as robust biomarkers and mechanistic drivers with translational relevance in ACC.
Wu M, Qian W, Xu M
… +4 more, Zhang J, Gao F, Chen L, Huang S
Cancer Genet
· 2025 Nov · PMID 41166794
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As a key regulatory enzyme in mitochondria, YME1L is crucial for regulation of mitochondrial dynamic balance and metabolic plasticity in tumors. Yet its role in non-small cell lung cancer (NACLC) and underlying mechanism...As a key regulatory enzyme in mitochondria, YME1L is crucial for regulation of mitochondrial dynamic balance and metabolic plasticity in tumors. Yet its role in non-small cell lung cancer (NACLC) and underlying mechanism are still unclear. In this study, we found YME1L was highly expressed at both protein and RNA levels in NSCLC tissues, which was consistent with the result of database analysis. The bioinformatics analysis also showed that YME1L expression negatively correlated with survival rate. The significance of YME1L was investigated through gain- and loss-of-function studies in vivo and vitro. As expected, the protease activity was consistent with the expression of YME1L. Knockdown of YME1L significantly inhibited mitochondrial activity, proliferation and migration of NACLC cell lines, and suppressed the growth of xenografted tumors in nude mice. While over-expression of YME1L promoted the development of tumors. Further study revealed that YME1L increased the proportion of S-phase and reduced the number of G0/G1 ratio in NSCLC cells, suggesting the strong proliferation activity. Mechanically, knockdown of YME1L decreased the expression of Gαi1 and the phosphorylation of Akt, and on the contrary, YME1L over-expression increased the Gαi1 expression and Akt activation, which in turn stimulated cell proliferation, migration and survival, and promoted the progression of NSCLC. In this study, we revealed that YME1L played a novel oncogenic role in promoting NSCLC tumorigenesis and progression via the mitochondria-Gαi1-AKT axis, providing a new target for the treatment of lung cancer.
Dhiflaoui A, Daldoul A, Chouchene S
… +4 more, Chenbeh W, Boukhris S, Almawi WY, Abdennebi HB
Cancer Genet
· 2025 Nov · PMID 41161132
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BACKGROUND: While miR-100 is a tumor suppressor in several malignancies, its role in pediatric acute lymphoblastic leukemia (ALL) remains poorly understood. This study investigated the relationship between two miR-100 si...BACKGROUND: While miR-100 is a tumor suppressor in several malignancies, its role in pediatric acute lymphoblastic leukemia (ALL) remains poorly understood. This study investigated the relationship between two miR-100 single-nucleotide polymorphisms (SNPs), rs543412 and rs183430, and ALL susceptibility in North African Tunisian children. METHODS: We conducted a case-control study involving 128 pediatric ALL patients and 157 healthy controls. Genotyping of rs543412 and rs183430 was performed using TaqMan SNP assays. Logistic regression analysis was used to assess associations between genotypes, haplotypes, and ALL risk, with multiple corrections applied. RESULTS: The rs543412 T allele was more frequent in ALL cases than controls (41 % vs. 32 %, p = 0.046), and increased ALL risk was seen with C/T (OR=2.20, 95 %CI=1.03-4.70) and T/T (OR=2.48, 95 %CI=1.16- 5.28) genotypes. However, this association did not survive multiple testing correction. The rs183430 G allele showed stronger association with ALL (57 % vs. 41 %, p < 0.001), and with G/G homozygosity conferring a markedly elevated risk (OR=2.94, 95 %CI:1.56-5.54). Two-locus haplotype analysis revealed that C∼G (aOR=1.77, 95 %CI=1.09-2.88) and T∼G (aOR=2.59, 95 %CI=1.51-4.44) haplotypes significantly increased ALL risk. However, no significant associations were observed between these polymorphisms and the clinicopathological features. CONCLUSIONS: This exploratory study identifies rs183430 as significantly associated with pediatric ALL susceptibility in North African children. These preliminary results suggest that miR-100 SNPs could serve as potential ALL biomarkers, although validation in independent cohorts is needed before clinical use.