Cancer Genetics最新文献

{"title":"MAGEA4 promotes gastric cancer progression by inducing chromosomal instability through the STAU1/c-Myc axis.","authors":"Hong Deng, Ziwen Long, Cuiping Ren, Chenlong Song, Changyu Chen, Bingbing Zou, Yuanshuang Jin, Changyi Fang, Chenchen Liu","doi":"10.1016/j.cancergen.2026.08.006","DOIUrl":"https://doi.org/10.1016/j.cancergen.2026.08.006","url":null,"abstract":"<p><p>This study aimed to investigate the clinical significance, biological function, and molecular mechanisms of MAGEA4 in the progression of gastric cancer (GC). Analysis of the TCGA database and 40 pairs of GC tissues and matched normal mucosa samples revealed that MAGEA4 expression was significantly upregulated in GC. Immunohistochemical analysis using two tissue microarrays containing 195 GC samples demonstrated that high MAGEA4 expression is significantly associated with advanced tumor stage, lymph node metastasis and unfavorable patient prognosis. Both in vitro and in vivo experiments confirmed that MAGEA4 significantly promoted the proliferation and metastasis of GC cells. Investigations of the underlying mechanisms revealed that MAGEA4 promotes GC progression by inducing chromosomal instability (CIN). This was evidenced by increased γH2AX (a sensitive DNA damage marker for double-strand breaks), abnormal chromosome numbers, abnormal mitosis, and other CIN features. At the molecular level, MAGEA4 binds E2F1 to enhance STAU1 transcription, subsequently promotes c-Myc translation and drives CIN. Knockdown of STAU1 effectively reversed the CIN and malignant phenotypes induced by MAGEA4 overexpression in GC cells, whereas overexpression of c‑Myc restores these phenotypes resulted from MAGEA4 knockdown. In summary, this research demonstrated the crucial role of MAGEA4 in promoting GC progression by inducing CIN via the E2F1/STAU1/c-Myc axis. Consequently, MAGEA4 represents a highly promising novel therapeutic target for GC.</p>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"308-309 ","pages":"30-44"},"PeriodicalIF":11.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148867464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of germline testing, mutation spectrum and clinico-pathological features in male breast cancer: a 27-year retrospective cohort including 69 patients.","authors":"Nicolas Taris, Nile Duflos De Saint Amand, Carole Hild, Carole Mathelin, Manon Chrétien","doi":"10.1016/j.cancergen.2026.07.004","DOIUrl":"https://doi.org/10.1016/j.cancergen.2026.07.004","url":null,"abstract":"<p><strong>Background: </strong>Male breast cancer (MBC) is rare, and its genetic basis remains poorly characterized. Over the past few decades, genetic screening strategies have evolved from analyses focusing solely on the BRCA1/2 genes to extensive multigene panels. Longitudinal data describing this transition in men remain scarce.</p><p><strong>Methods: </strong>All men diagnosed with breast cancer and referred for germline genetic testing between 1998 and 2025 at our institution were included. Clinical characteristics, test indications, genes analyzed, and pathogenic/probably pathogenic (P/LP) variants were extracted. Three periods covering the transition from Sanger sequencing to next-generation sequencing (NGS) were considered: between 1998 and 2015, 26 patients were tested for BRCA1/2 only. Between 2015 and 2018, 10 patients underwent limited multigene panel testing (6-8 genes). From 2018 onward, 29 patients were tested using a nationally validated 13-gene panel, and in the most recent two years, 4 patients underwent extensive genetic testing covering 17 genes, including non-consensus genes.</p><p><strong>Results: </strong>Sixty-nine men underwent genetic testing. Overall, P/LP variants were identified in 13% (9/69) of patients, in BRCA2 (n=4), PALB2 (n=2), ATM (n=2), and BRCA1 (n=1). The mean age at diagnosis was higher among variant carriers compared with non-carriers (69.9 (±7.4) years vs 65.7 (±12.3)), except for BRCA2 carriers, who were diagnosed at a younger age (63.8 (±5.0)). A family history suggestive of hereditary breast and ovarian cancer was absent in 71% of the overall cohort. One BRCA2-positive family included three cases of male breast cancer.</p><p><strong>Conclusion: </strong>Over 27 years, germline testing in male breast cancer shifted from BRCA-focused strategies to multigene panels, revealing a broader spectrum of susceptibility genes. These findings support systematic genetic testing for all men with breast cancer, regardless of age and family history.</p>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148425653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidation of MMP-9 expression and association of MMP-9 rs3918242–1562 C/T promoter polymorphism in the progression of cervical cancer","authors":"Pavan Kumar Poleboyina,&nbsp;Smita C. Pawar","doi":"10.1016/j.cancergen.2026.01.008","DOIUrl":"10.1016/j.cancergen.2026.01.008","url":null,"abstract":"<div><div>This study explores the expression of the <em>MMP-9</em> gene through transcriptomic analysis and quantitative real-time PCR (qRT-PCR), along with the investigation of the promoter polymorphism rs3918242 (C-1562T) using RFLP, confirmed by Sanger sequencing. A total of 200 samples were analyzed, including 100 cervical squamous cell carcinoma tissues and 100 normal control samples. Results revealed a significant upregulation of <em>MMP-9</em> mRNA expression in cancerous tissues compared to normal counterparts. Furthermore, analysis of the rs3918242 polymorphism showed a higher prevalence of the C allele among controls, while the T allele was more frequently observed in patients. Notably, individuals with the T/T genotype, under a recessive genetic model, exhibited a significantly increased risk of cervical cancer (<em>p</em> &lt; 0.02; OR = 2.98; 95 % CI: 1.12–7.98). Although no strong association was found between the polymorphism and overall cervical cancer risk, elevated <em>MMP-9</em> expression was closely linked to disease progression. Transcription factor binding analysis using TRANSFAC revealed that the C-to-T substitution disrupts an SP1 binding site, potentially contributing to increased gene expression. Additionally, assessments of mRNA and pre-mRNA secondary structures indicated that the rs3918242 polymorphism alters RNA conformation, with the C allele displaying higher structural stability than the T allele. These findings suggest that while the polymorphism may not directly confer susceptibility, it could influence gene regulation mechanisms relevant to the development of cervical cancer.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 79-92"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent monosomy 7 in Philadelphia chromosome-negative cells without disease progression over nearly two decades of follow-up in chronic myeloid leukemia","authors":"Menghao Chen ,&nbsp;Guilin Tang ,&nbsp;Shimin Hu","doi":"10.1016/j.cancergen.2026.01.010","DOIUrl":"10.1016/j.cancergen.2026.01.010","url":null,"abstract":"<div><div>Monosomy 7 (−7) is frequently associated with myelodysplastic neoplasm/syndrome (MDS) and acute myeloid leukemia (AML). In chronic myeloid leukemia (CML), the acquisition of −7 in Philadelphia chromosome–positive (Ph-positive) cells is considered a high-risk feature for progression to blast crisis. However, the clinical significance of −7 in Ph-negative cells remains less unclear. We report a patient with CML who developed a − 7 clone in Ph-negative cells during tyrosine kinase inhibitor (TKI) therapy. The −7 clone emerged after 14 months of TKI treatment, persisted for nearly six years, and subsequently disappeared. The patient continued treatment with sequential TKIs under long-term surveillance. Over nearly 20 years of follow-up, there was no evidence of significant dysplasia or progression to AML. This case suggests that the occurrence of −7 in Ph-negative cells does not reflect TKI-induced genotoxicity and does not necessarily confer an increased risk of MDS or AML.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 73-78"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline APC I1307K and MITF E318K variants in a patient with high-grade serous ovarian carcinoma: A case report","authors":"Samantha C. Covey ,&nbsp;Michelle M. De Jesus Ortiz ,&nbsp;Amelia Jernigan ,&nbsp;Ridin Balakrishnan ,&nbsp;Sun Young Kim ,&nbsp;Lucio Miele","doi":"10.1016/j.cancergen.2026.01.011","DOIUrl":"10.1016/j.cancergen.2026.01.011","url":null,"abstract":"<div><div>We report the case of a 76‑year‑old woman with high‑grade serous ovarian carcinoma (HGSOC) who was found to carry germline variants in <em>APC</em> I1307K and <em>MITF</em> E318K. Although neither variant is an established contributor to ovarian cancer risk, their co‑occurrence raises the possibility of polygenic or modifier effects on tumor susceptibility. The <em>APC</em> I1307K allele is a founder variant linked to increased colorectal cancer risk through the creation of a hypermutable region that predisposes to somatic mutations rather than classical tumor‑suppressor inactivation. In contrast, <em>MITF</em> E318K is a gain‑of‑function variant associated with melanoma and renal cell carcinoma, acting through altered transcriptional regulation that promotes cell proliferation and survival. While these genes do not interact directly, both converge on signaling pathways—WNT/β‑catenin, MAPK/ERK, and PI3K/AKT—that are widely implicated in ovarian carcinogenesis. There is a possibility that HGSOC in this patient is sporadic and unrelated to these two variants. Nevertheless, the case underscores the importance of comprehensive germline testing and highlights potential, yet underexplored, genetic interactions that may influence ovarian cancer risk. To our knowledge, this represents the first reported case of HGSOC in a patient harboring both variants, offering a hypothesis‑generating observation for future investigation.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 107-111"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic polymorphisms of tumor necrosis factor receptor-associated factor 3 and their association with acute lymphoblastic leukemia","authors":"Fadwa M Alkhulaifi ,&nbsp;Hana Hakami ,&nbsp;Jamilah Alshammari ,&nbsp;Safa A Alqarzae ,&nbsp;Aeshah Almuhaini ,&nbsp;Sheka Y Aloyouni ,&nbsp;Suliman Alomar","doi":"10.1016/j.cancergen.2026.01.012","DOIUrl":"10.1016/j.cancergen.2026.01.012","url":null,"abstract":"<div><h3>Background</h3><div>Acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy driven by genetic and immunological dysregulation. Tumor necrosis factor receptor-associated factor 3 (TRAF3) plays an essential role in regulating immune signaling, lymphocyte homeostasis, and NF-κB pathways. Although TRAF3 alterations have been implicated in various immune disorders and hematologic cancers, the contribution of TRAF3 genetic polymorphisms to ALL susceptibility remains insufficiently understood.</div></div><div><h3>Purpose</h3><div>To investigate the association between three TRAF3 single nucleotide polymorphisms (SNPs); rs33980500, rs13210247, and rs1131877, and ALL susceptibility in Saudi patients, and to evaluate TRAF3 mRNA expression levels in ALL compared to healthy individuals.</div></div><div><h3>Methods</h3><div>A case-control study was conducted involving 150 newly diagnosed ALL patients and 115 age- and sex-matched healthy controls. Genotyping of the selected TRAF3 SNPs was performed using TaqMan allelic discrimination assays. TRAF3 mRNA expression in peripheral blood white cells was quantified through RT-qPCR. Statistical analyses included genotype/allele frequency comparisons, odds ratios, Hardy-Weinberg equilibrium testing, linkage disequilibrium assessment, and haplotype construction.</div></div><div><h3>Results</h3><div>None of the analyzed SNPs showed a statistically significant association with ALL across genotype, allele, or haplotype models. Linkage disequilibrium between the SNPs was absent. However, TRAF3 mRNA expression was significantly upregulated in ALL patients, exhibiting a 3.88-fold increase compared with controls (<em>p</em> &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>Although the examined TRAF3 SNPs were not associated with ALL susceptibility in this cohort, the marked elevation of TRAF3 mRNA expression suggests a potential role for TRAF3-related signaling in ALL pathogenesis. TRAF3 expression may represent a promising biomarker warranting further investigation.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 112-115"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide cfDNA Methylation Profiling of Pleural Effusion Reveals an Immuno-epigenetic Signature for Differentiating Malignant from Benign Cases","authors":"Zuyu Sun ,&nbsp;Fudong Xu ,&nbsp;Jiemin Chen ,&nbsp;Nana Zhang ,&nbsp;Fang Luo ,&nbsp;Xiaojie Huang ,&nbsp;Zichen Liu ,&nbsp;Xuya Xing ,&nbsp;Kun Li ,&nbsp;Xuejing Chen ,&nbsp;Lili Zhang ,&nbsp;Nanying Che","doi":"10.1016/j.cancergen.2026.01.007","DOIUrl":"10.1016/j.cancergen.2026.01.007","url":null,"abstract":"<div><h3>Background</h3><div>Distinguishing malignant pleural effusion (MPE) from benign pleural effusion (BPE) remains clinically challenging because conventional cytology has limited sensitivity. We investigated whether cfDNA methylation profiling of pleural effusion supernatant could provide a non‑invasive diagnostic alternative.</div></div><div><h3>Methods</h3><div>Patients with pleural effusion were consecutively and prospectively recruited from Beijing Chest Hospital between November 2022 and March 2024. We conducted genome-wide cfDNA methylation profiling on qualified pleural effusion samples. A mechanistically relevant diagnostic signature was developed using a knowledge-driven approach, integrating probes involving immune pathways and immune cell deconvolution data from the training set. The final signature's performance was subsequently tested in an internal validation cohort and benchmarked against conventional cytology.</div></div><div><h3>Results</h3><div>A total of 101 participants were enrolled, including 45 MPE and 56 BPE according to the composite reference standard. We observed a distinct methylation landscape between MPE and BPE, identifying 3,119 hypermethylated and 232 hypomethylated DMPs in MPE that were enriched in immune‑related pathways (such as T cell activation). Deconvolution indicated significant differences in immune cell–derived cfDNA (including CD8+ T cells, B cells, eosinophils) between groups. A 7‑CpG-model based on LASSO classifier achieved an AUC of 0.980 (95% CI: 0.954–1.000) in the training set and 0.963 (95% CI: 0.896–1.000) in the internal validation set. The classifier substantially improved MPE detection in cytology‑negative or indeterminate cases and identified MPEs missed by conventional methods.</div></div><div><h3>Conclusions</h3><div>A 7‑CpG-model from pleural effusion cfDNA reliably discriminates MPE from BPE and shows promise as a reflex test for resolving cytologic uncertainty.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 62-72"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role and prospects of the Fudan classification in precision medicine for triple-negative breast cancer","authors":"Qiuting Yang ,&nbsp;Bing Li ,&nbsp;Yuan Chen ,&nbsp;Huiling Yang","doi":"10.1016/j.cancergen.2026.01.002","DOIUrl":"10.1016/j.cancergen.2026.01.002","url":null,"abstract":"<div><div>Triple-Negative Breast Cancer (TNBC) remains a major challenge in oncology because of its significant heterogeneity and the lack of established therapeutic targets. Conventional diagnostic and treatment methods often fall short in addressing this complexity, which creates a need for molecular subtyping frameworks to guide precision therapy. Here, we systematically review the evolution of TNBC molecular subtyping, with a focus on the \"Fudan Classification\" as a powerful and integrative system. This classification offers a systematic perspective for deciphering the biological essence of TNBC and for designing treatment strategies. Its four principal subtypes—immunomodulatory (IM), luminal androgen receptor (LAR), basal-like immunosuppressed (BLIS), and mesenchymal (MES)—uncover distinct disease entities driven by unique oncogenic pathways, thereby providing a rationale for aligning specific treatments like targeted agents and immunotherapies with the most likely-to-benefit patient subgroups. In parallel, we examine emerging treatments that go beyond traditional subtyping, including TROP-2-targeting Antibody-Drug Conjugates (ADCs). These ADCs, together with subtyping-guided approaches, are expanding the scope of precision medicine. This article aims to demonstrate that a more robust and comprehensive precision therapy system for TNBC can be built on a dual logic of \"subtype-driven\" and \"target-driven\" strategies, offering insights for future work on overcoming drug resistance and optimizing combination therapies.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 93-106"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying transcriptional signatures of leukocytes in tissue and blood for multicancer diagnosis by using machine learning methods","authors":"QingLan Ma ,&nbsp;JingXin Ren ,&nbsp;Lei Chen ,&nbsp;Wei Guo ,&nbsp;KaiYan Feng ,&nbsp;Yu Zhang ,&nbsp;WenFeng Shen ,&nbsp;Tao Huang ,&nbsp;Yu-Dong Cai","doi":"10.1016/j.cancergen.2026.01.003","DOIUrl":"10.1016/j.cancergen.2026.01.003","url":null,"abstract":"<div><div>Investigating the transcriptional signatures of immune cells in various cancer types is crucial for understanding their roles in the tumor microenvironment and developing effective immunotherapeutic strategies. In this study, we employed machine learning methods to analyze RNA-seq data from patients with four different types of cancers and two immune cell types, including T cell and CD45+CD3− leukocyte cell types. We processed seven datasets, each divided into three groups on the basis of cell source: tumor, normal adjacent tissue, and peripheral blood. The datasets were downscaled by using the Boruta method, and the remaining genes were ranked for criticality in a list through the max-relevance and min-redundancy method. The obtained list of genes was fed into incremental feature selection (IFS), which employed decision tree or random forest to distinguish cells, for the identification of key genes associated with immune cell function in different cancer types and construction of efficient classifiers and classification rules (special patterns for different groups). Our results revealed distinct expression patterns of key genes, such as the downregulation of CST7 in T cells from tumor tissues and differential expression of CD2 in non-tumor sites. Furthermore, we identified LCP1, CD27, and MAL as immunologically relevant genes in T cells across different tissue origins, whereas IFI30, CXCR4, and FOSB played various roles in CD45+CD3− leukocytes. The identified key genes were supported by evidence in the literature, highlighting their involvement in antitumor processes in T cells and other immune cells. Our findings provide valuable insights into the transcriptional signatures of immune cells in different cancer types and lay the foundation for the development of novel diagnostic, prognostic, and therapeutic strategies in cancer immunology.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 13-26"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico identification of deleterious NT5C2 and PRPS1 mutations driving thiopurine resistance in relapsed acute lymphoblastic leukemia","authors":"Ramita Sharma ,&nbsp;Jeeshitha Kudithipudi ,&nbsp;Himanshu Singh ,&nbsp;Dhamodharan Prabhu ,&nbsp;Sugunakar Vuree","doi":"10.1016/j.cancergen.2026.01.001","DOIUrl":"10.1016/j.cancergen.2026.01.001","url":null,"abstract":"<div><div>Relapse in Acute Lymphoblastic Leukemia (ALL) are often driven by multiple factors, including thiopurine drug-resistant mutations in NT5C2 and PRPS1. To determine the functional significance of these mutations, we employed comprehensive computational methods to assess their impact on protein stability, evolutionary conservation, and possible drug sensitivity, as well as molecular docking and simulations with 6-MP and 6-TG to show the impact of these mutations on drug binding. The top-ranked pathogenic variants investigated, NT5C2 rs775844720 (D431V) and PRPS1 rs2147684832 (D224G), exhibited the most pronounced destabilizing effects on proteins. Protein-protein interaction networks indicate that these variations are involved in nucleotide metabolism and pharmacological responses, confirming their role in thiopurine resistance. In summary, NT5C2 and PRPS1 gene variations may act as potential biomarkers for resistance and hence require more experimental validation of VUS to determine their significance.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 8-12"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}