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.
{"title":"In silico identification of deleterious NT5C2 and PRPS1 mutations driving thiopurine resistance in relapsed acute lymphoblastic leukemia","authors":"Ramita Sharma , Jeeshitha Kudithipudi , Himanshu Singh , Dhamodharan Prabhu , 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":"2026-01-04","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}
Pub Date : 2026-01-03DOI: 10.1016/j.cancergen.2026.01.002
Qiuting Yang , Bing Li , Yuan Chen , Huiling Yang
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.
{"title":"The role and prospects of the Fudan classification in precision medicine for triple-negative breast cancer","authors":"Qiuting Yang , Bing Li , Yuan Chen , 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":"2026-01-03","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}
Pub Date : 2025-12-24DOI: 10.1016/j.cancergen.2025.12.004
Rofida M. Abd El-Fatah , Heba K. Badawy , Heba F. Pasha , Noha M. Mesbah , Dina M. Abo-Elmatty , Asmaa R. Abdel-Hamed
Breast cancer remains the leading cause of cancer-related deaths among women, underscoring the need for more sensitive and specific biomarkers. Traditional markers such as CA15-3 lack sufficient diagnostic and prognostic accuracy. Quantification of plasma cell-free DNA (cfDNA) offers a minimally invasive liquid-biopsy approach for tumor detection and monitoring. This case–control study assessed a cfDNA panel comprising KLK10, SOX17, WNT5A, and MSH2 in 100 breast cancer patients and 100 matched controls. Plasma cfDNA levels, quantified by qPCR, and CA15-3 levels, measured by ELISA, were evaluated for diagnostic and prognostic value using ROC analyses and a 35-month follow-up for survival endpoints. All cfDNA genes were significantly elevated in patients (p<0.001) and exhibited superior diagnostic accuracy versus CA15-3, with MSH2 showing the highest AUC (95.3%), sensitivity (92%), and specificity (89%). Elevated cfDNA correlated strongly with metastasis and adverse pathological features, outperforming CA15-3 in predicting metastasis (AUC = 0.962–0.987). High cfDNA concentrations associated with poorer disease-free and overall survival (p<0.001). Detection of a cfDNA panel, rather than a single gene, demonstrates superior utility as a minimally invasive biomarker promising for early detection, risk assessment, and disease monitoring in breast cancer.
{"title":"Plasma cell-free DNA biomarkers as novel diagnostic and prognostic tools in breast cancer","authors":"Rofida M. Abd El-Fatah , Heba K. Badawy , Heba F. Pasha , Noha M. Mesbah , Dina M. Abo-Elmatty , Asmaa R. Abdel-Hamed","doi":"10.1016/j.cancergen.2025.12.004","DOIUrl":"10.1016/j.cancergen.2025.12.004","url":null,"abstract":"<div><div>Breast cancer remains the leading cause of cancer-related deaths among women, underscoring the need for more sensitive and specific biomarkers. Traditional markers such as CA15-3 lack sufficient diagnostic and prognostic accuracy. Quantification of plasma cell-free DNA (cfDNA) offers a minimally invasive liquid-biopsy approach for tumor detection and monitoring. This case–control study assessed a cfDNA panel comprising <em>KLK10, SOX17, WNT5A</em>, and <em>MSH2</em> in 100 breast cancer patients and 100 matched controls. Plasma cfDNA levels, quantified by qPCR, and CA15-3 levels, measured by ELISA, were evaluated for diagnostic and prognostic value using ROC analyses and a 35-month follow-up for survival endpoints. All cfDNA genes were significantly elevated in patients (p<0.001) and exhibited superior diagnostic accuracy versus CA15-3, with <em>MSH2</em> showing the highest AUC (95.3%), sensitivity (92%), and specificity (89%). Elevated cfDNA correlated strongly with metastasis and adverse pathological features, outperforming CA15-3 in predicting metastasis (AUC = 0.962–0.987). High cfDNA concentrations associated with poorer disease-free and overall survival (p<0.001). Detection of a cfDNA panel, rather than a single gene, demonstrates superior utility as a minimally invasive biomarker promising for early detection, risk assessment, and disease monitoring in breast cancer.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"302 ","pages":"Pages 1-7"},"PeriodicalIF":2.1,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908866","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}
We describe a proof-of-concept study of a rapid, single-step CRISPR/Cas13a assay using Leptotrichia wadei (LwCas13a) for the detection of small RNA (miRNA) biomarkers in saliva, and compare its performance to real-time PCR (RT-PCR).
Methods
The single-step Cas13a assay was evaluated against RT-PCR for its detection efficiency, sensitivity, specificity, and its ability to function in a complex biological matrix. A proof-of-concept test was conducted on patient saliva samples to detect a known oral cancer biomarker, hsa-miR-21–3p
Results
The Cas13a assay successfully detected candidate miRNA at picomolar concentrations in both in vitro and saliva samples, demonstrating sensitivity and specificity comparable to RT-PCR. Notably, the assay provided discernible detection of the cancer biomarker directly in patient saliva without the need for RNA extraction or reverse transcription steps.
Conclusion
The proposed single-step CRISPR/Cas13a assay may be developed into a promising platform for developing quick and affordable point-of-care diagnostics for cancer and other diseases, circumventing the need for expensive and time-consuming sample preparation steps.
目的：我们描述了一项使用wdei细毛菌（Leptotrichia wadei, LwCas13a）快速单步CRISPR/Cas13a检测唾液中小RNA （miRNA）生物标志物的概念验证研究，并将其性能与实时PCR （RT-PCR）进行比较。方法将单步Cas13a检测方法与RT-PCR相比较，比较其检测效率、灵敏度、特异性以及在复杂生物基质中的功能。在患者唾液样本中进行了概念验证测试，以检测已知的口腔癌生物标志物hsa- mir -21 - 3prepresultcas13a试验成功地在体外和唾液样本中检测到皮摩尔浓度的候选miRNA，显示出与RT-PCR相当的敏感性和特异性。值得注意的是，该分析提供了直接在患者唾液中可识别的癌症生物标志物检测，而无需RNA提取或逆转录步骤。结论提出的单步CRISPR/Cas13a检测方法有望发展成为一个有前景的平台，用于开发快速且价格合理的癌症和其他疾病的即时诊断，避免了昂贵且耗时的样品制备步骤。
{"title":"Single-Step CRISPR/Cas13a Assay for detection of small RNAs in Saliva : a proof-of-concept study","authors":"Devyani Salodkar , Sheetal Dongarwar , Aparna Nair , Prajkta Ashtaputre , Shreya Reddy , Shrutam Somkuwar , Deovrat Begde","doi":"10.1016/j.cancergen.2025.12.003","DOIUrl":"10.1016/j.cancergen.2025.12.003","url":null,"abstract":"<div><h3>Objective</h3><div>We describe a proof-of-concept study of a rapid, single-step CRISPR/Cas13a assay using <em>Leptotrichia wadei</em> (LwCas13a) for the detection of small RNA (miRNA) biomarkers in saliva, and compare its performance to real-time PCR (RT-PCR).</div></div><div><h3>Methods</h3><div>The single-step Cas13a assay was evaluated against RT-PCR for its detection efficiency, sensitivity, specificity, and its ability to function in a complex biological matrix. A proof-of-concept test was conducted on patient saliva samples to detect a known oral cancer biomarker, hsa-miR-21–3p</div></div><div><h3>Results</h3><div>The Cas13a assay successfully detected candidate miRNA at picomolar concentrations in both in vitro and saliva samples, demonstrating sensitivity and specificity comparable to RT-PCR. Notably, the assay provided discernible detection of the cancer biomarker directly in patient saliva without the need for RNA extraction or reverse transcription steps.</div></div><div><h3>Conclusion</h3><div>The proposed single-step CRISPR/Cas13a assay may be developed into a promising platform for developing quick and affordable point-of-care diagnostics for cancer and other diseases, circumventing the need for expensive and time-consuming sample preparation steps.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"300 ","pages":"Pages 67-71"},"PeriodicalIF":2.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797585","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}
Pub Date : 2025-12-09DOI: 10.1016/j.cancergen.2025.12.002
Yu Bai , Wen-wen Feng , Lan Tang , Yan-qing Sun
{"title":"Exploration of a prognostic model for childhood acute lymphoblastic leukemia","authors":"Yu Bai , Wen-wen Feng , Lan Tang , Yan-qing Sun","doi":"10.1016/j.cancergen.2025.12.002","DOIUrl":"10.1016/j.cancergen.2025.12.002","url":null,"abstract":"","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"300 ","pages":"Pages 58-60"},"PeriodicalIF":2.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795123","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}
Pub Date : 2025-12-02DOI: 10.1016/j.cancergen.2025.12.001
Lu-Qi Cao , Yuhao Xie , Xuanyu Chen , Harsh Patel , Luoxi Yuan , John Wurpel , Kunxiang Gong , Zhe-Sheng Chen
Sunvozertinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to treat non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertion mutations under a phase II clinical trial. In this study, we investigated whether sunvozertinib could antagonize ABCB1, also known as multidrug resistance 1 (MDR1/P-gp). ABCB1 is a gene that encodes an important drug transport protein that pumps various substances, including drugs and toxins, out of cells. Sunvozertinib received a high score in docking analysis, indicating a strong interaction between sunvozertinib and ABCB1. ATPase assay indicated that sunvozertinib stimulated ABCB1 ATPase activity in a concentration-dependent manner. MTT assay shows that sunvozertinib significantly reversed ABCB1-mediated MDR but not ABCC1- and ABCG2-mediated MDR. Mechanistic studies show that sunvozertinib significantly reversed ABCB1-mediated MDR by attenuating the efflux activity of the ABCB1 transporter. Furthermore, treatment with sunvozertinib did not change protein expression or subcellular localization of ABCB1. Altogether, these data demonstrate that sunvozertinib, when combined with other conventional chemotherapeutic agents, can overcome MDR and improve therapeutic effect.
{"title":"Genetic modulation of ABCB1: Sunvozertinib reverses ABCB1-mediated multidrug resistance in cancer cells","authors":"Lu-Qi Cao , Yuhao Xie , Xuanyu Chen , Harsh Patel , Luoxi Yuan , John Wurpel , Kunxiang Gong , Zhe-Sheng Chen","doi":"10.1016/j.cancergen.2025.12.001","DOIUrl":"10.1016/j.cancergen.2025.12.001","url":null,"abstract":"<div><div>Sunvozertinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to treat non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertion mutations under a phase II clinical trial. In this study, we investigated whether sunvozertinib could antagonize ABCB1, also known as multidrug resistance 1 (MDR1/P-gp). ABCB1 is a gene that encodes an important drug transport protein that pumps various substances, including drugs and toxins, out of cells. Sunvozertinib received a high score in docking analysis, indicating a strong interaction between sunvozertinib and ABCB1. ATPase assay indicated that sunvozertinib stimulated ABCB1 ATPase activity in a concentration-dependent manner. MTT assay shows that sunvozertinib significantly reversed ABCB1-mediated MDR but not ABCC1- and ABCG2-mediated MDR. Mechanistic studies show that sunvozertinib significantly reversed ABCB1-mediated MDR by attenuating the efflux activity of the ABCB1 transporter. Furthermore, treatment with sunvozertinib did not change protein expression or subcellular localization of ABCB1. Altogether, these data demonstrate that sunvozertinib, when combined with other conventional chemotherapeutic agents, can overcome MDR and improve therapeutic effect.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"300 ","pages":"Pages 47-57"},"PeriodicalIF":2.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745526","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}
Multiple Endocrine Neoplasia type 1 syndrome is caused by pathogenic variants in the MEN1 gene, and is characterised by tumours in multiple endocrine glands. This case study looks at a family with four affected members over two generations who have been diagnosed with the syndrome after next generation sequencing identified a novel Alu insertion. Previous genetic testing in the index patient had not identified an underlying cause.
{"title":"Multiple endocrine neoplasia type 1 syndrome due to novel Alu insertion","authors":"Aislinn Cragg , Hannah Boon , Treena Cranston , Tristan Richardson , Schaida Schirwani","doi":"10.1016/j.cancergen.2025.11.014","DOIUrl":"10.1016/j.cancergen.2025.11.014","url":null,"abstract":"<div><div>Multiple Endocrine Neoplasia type 1 syndrome is caused by pathogenic variants in the MEN1 gene, and is characterised by tumours in multiple endocrine glands. This case study looks at a family with four affected members over two generations who have been diagnosed with the syndrome after next generation sequencing identified a novel Alu insertion. Previous genetic testing in the index patient had not identified an underlying cause.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"300 ","pages":"Pages 61-66"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797584","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}
Pub Date : 2025-11-29DOI: 10.1016/j.cancergen.2025.11.009
Yuan Wang , Li XinWan , Yutian Zhang , Qi Jia , Chao Li , Xiaonan Cui
{"title":"Corrigendum to “Study on the Anticancer Mechanism of Hydroxygenkwanin in Esophageal Cancer via the ESRRA Signaling Pathway” [Cancer Genetics, 298–299, (2025) Pages 180-192]","authors":"Yuan Wang , Li XinWan , Yutian Zhang , Qi Jia , Chao Li , Xiaonan Cui","doi":"10.1016/j.cancergen.2025.11.009","DOIUrl":"10.1016/j.cancergen.2025.11.009","url":null,"abstract":"","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"300 ","pages":"Page 9"},"PeriodicalIF":2.1,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649886","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}
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.
{"title":"Comparative analysis of a founder BRCA2 double mutation versus single mutation carriers reveals no additional clinical risk","authors":"Gemma Caliendo , Chiara Della Pepa , Marialaura Zitiello , Alessia Mignano , Luana Passariello , Luisa Albanese , Maria Teresa Vietri","doi":"10.1016/j.cancergen.2025.11.013","DOIUrl":"10.1016/j.cancergen.2025.11.013","url":null,"abstract":"<div><h3>Background</h3><div>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).</div></div><div><h3>Materials and methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"300 ","pages":"Pages 28-35"},"PeriodicalIF":2.1,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688616","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}
Pub Date : 2025-11-26DOI: 10.1016/j.cancergen.2025.11.011
Adila Abdulla , Vahid Rouhi , Sanaz Habibi , Hikmet Koseoglu , Emre Ari , Mehmet Guven
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.
{"title":"Altered expression of nucleotide excision repair genes ERCC2 and ERCC5 in prostate cancer tissues","authors":"Adila Abdulla , Vahid Rouhi , Sanaz Habibi , Hikmet Koseoglu , Emre Ari , Mehmet Guven","doi":"10.1016/j.cancergen.2025.11.011","DOIUrl":"10.1016/j.cancergen.2025.11.011","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"300 ","pages":"Pages 25-27"},"PeriodicalIF":2.1,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678876","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号