Pub Date : 2025-06-29DOI: 10.1016/j.cancergen.2025.06.007
Patrick Maher , Tim Jang , Ruben Ruiz Vega , Jennifer Miatech , Gabriela Bastidas Mora , W.J.R. Quan , Reeba Prince , Joanna Chaffin , Lijun Yang , Petr Starostik , Rachel D. Burnside
Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions (MLN-TK) is a newly added entity in the World Health Organization (WHO) 5th Edition, and within this category, ETV6::ABL1 gene fusions are the most commonly reported in the literature. While patients may respond favorably to tyrosine kinase inhibitor (TKI) therapy, prognosis is generally less favorable than for BCR::ABL1-positive chronic myelogenous leukemia (CML), also treated with tyrosine kinase inhibitor therapy (TKIs). We report two patients diagnosed with MLN-TK, both of whom were positive for ETV6::ABL1 gene fusions, albeit by different mechanisms but with the same breakpoints. Importantly, one of our subjects also demonstrated BCR::ABL1 fusion subclonally to the ETV6::ABL1 fusion positive clone. This study emphasizes the importance of resolving false negative and/or discrepant fluorescence in situ hybridization (FISH) results using alternative methods, such as RNA fusion analysis, to aid in the diagnosis of MLN-TK.
{"title":"Two MLN-TK patients with ETV::ABL1 fusions mediated by different mechanisms with false negative FISH results resolved with RNA fusion analysis","authors":"Patrick Maher , Tim Jang , Ruben Ruiz Vega , Jennifer Miatech , Gabriela Bastidas Mora , W.J.R. Quan , Reeba Prince , Joanna Chaffin , Lijun Yang , Petr Starostik , Rachel D. Burnside","doi":"10.1016/j.cancergen.2025.06.007","DOIUrl":"10.1016/j.cancergen.2025.06.007","url":null,"abstract":"<div><div>Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions (MLN-TK) is a newly added entity in the World Health Organization (WHO) 5<sup>th</sup> Edition, and within this category, <em>ETV6::ABL1</em> gene fusions are the most commonly reported in the literature. While patients may respond favorably to tyrosine kinase inhibitor (TKI) therapy, prognosis is generally less favorable than for <em>BCR::ABL1</em>-positive chronic myelogenous leukemia (CML), also treated with tyrosine kinase inhibitor therapy (TKIs). We report two patients diagnosed with MLN-TK, both of whom were positive for <em>ETV6::ABL1</em> gene fusions, albeit by different mechanisms but with the same breakpoints. Importantly, one of our subjects also demonstrated <em>BCR::ABL1</em> fusion subclonally to the <em>ETV6::ABL1</em> fusion positive clone. This study emphasizes the importance of resolving false negative and/or discrepant fluorescence in situ hybridization (FISH) results using alternative methods, such as RNA fusion analysis, to aid in the diagnosis of MLN-TK.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 100-105"},"PeriodicalIF":1.4,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564004","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 : 2025-06-28DOI: 10.1016/j.cancergen.2025.06.009
Gomathy Baskar
Breast cancer is the most prevalent cancer among women globally. Triple-negative breast cancer (TNBC) is an exceptionally aggressive and challenging kind of breast cancer to manage. Triple-negative breast cancer (TNBC) lacks oestrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). As a result, there are no effective targeted therapies for it, and it doesn't respond well to standard treatment. Platinum-based treatments and neoadjuvant chemotherapy have shown promise, but the outlook is still not good. Ferroptosis, a type of regulated cell death that depends on iron, is a new way to treat diseases. Ferroptosis inducers like erastin may help make TNBC cells more sensitive to treatment, but they are still hard to deliver because they are toxic and don't dissolve well. Nanotechnology and drug delivery systems, especially exosome-based carriers, are promising ways to get around these problems. Exosomes are a new way to deliver drugs that cause ferroptosis because they are biocompatible and can target specific cells. This is a very interesting area for developing new treatments for TNBC.
{"title":"GPX4 in triple-negative breast cancer: A key regulator of ferroptosis and therapeutic target","authors":"Gomathy Baskar","doi":"10.1016/j.cancergen.2025.06.009","DOIUrl":"10.1016/j.cancergen.2025.06.009","url":null,"abstract":"<div><div>Breast cancer is the most prevalent cancer among women globally. Triple-negative breast cancer (TNBC) is an exceptionally aggressive and challenging kind of breast cancer to manage. Triple-negative breast cancer (TNBC) lacks oestrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). As a result, there are no effective targeted therapies for it, and it doesn't respond well to standard treatment. Platinum-based treatments and neoadjuvant chemotherapy have shown promise, but the outlook is still not good. Ferroptosis, a type of regulated cell death that depends on iron, is a new way to treat diseases. Ferroptosis inducers like erastin may help make TNBC cells more sensitive to treatment, but they are still hard to deliver because they are toxic and don't dissolve well. Nanotechnology and drug delivery systems, especially exosome-based carriers, are promising ways to get around these problems. Exosomes are a new way to deliver drugs that cause ferroptosis because they are biocompatible and can target specific cells. This is a very interesting area for developing new treatments for TNBC.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 76-83"},"PeriodicalIF":1.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523587","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 : 2025-06-26DOI: 10.1016/j.cancergen.2025.06.008
Yuankun Liu , Qisheng He , Lingjie Zhu , Mengmeng Zhong , Hao Zhuang , Ning Zhao , Yijin Cai , Chao Cheng , Junfei Shao
Tripartite motif-containing protein 29 (TRIM29) is a regulator of tumor progression across multiple cancer types. However, its functional significance in glioblastoma (GBM) remains poorly defined. In this study, we investigated the biological roles of TRIM29 in GBM and elucidated its underlying molecular mechanisms. Clinically, TRIM29 expression was significantly upregulated in glioma tissues compared to adjacent normal brain tissues, and elevated TRIM29 levels correlated with unfavorable prognosis in GBM patients. Functionally, both in vitro (GBM cell lines) and in vivo (a mouse xenograft model) experiments demonstrated that TRIM29 overexpression robustly enhanced GBM cell proliferation, migration, and invasive capacity. Mechanistically, TRIM29 directly interacted with neurofilament light polypeptide (NEFL), triggering K48-linked polyubiquitination and subsequent proteasomal degradation of NEFL[1]. This ubiquitination-dependent NEFL downregulation led to constitutive activation of the PI3K/AKT signaling pathway. Our findings uncover a novel TRIM29-NEFL-PI3K/AKT axis that drives glioblastoma malignancy, highlighting the therapeutic potential of targeting this pathway for GBM treatment.
Tripartite motif-containing protein 29 （TRIM29）是多种癌症进展的调节因子。然而，其在胶质母细胞瘤（GBM）中的功能意义仍不明确。在这项研究中，我们研究了TRIM29在GBM中的生物学作用，并阐明了其潜在的分子机制。临床上，与邻近正常脑组织相比，胶质瘤组织中TRIM29的表达明显上调，TRIM29水平升高与GBM患者预后不良相关。在功能上，体外（GBM细胞系）和体内（小鼠异种移植模型）实验均表明，TRIM29过表达可显著增强GBM细胞的增殖、迁移和侵袭能力。在机制上，TRIM29直接与神经丝轻多肽（NEFL）相互作用，触发k48连锁的多泛素化和随后的NEFL[1]蛋白酶体降解。这种泛素化依赖性NEFL下调导致PI3K/AKT信号通路的组成性激活。我们的研究结果揭示了一种新的驱动胶质母细胞瘤恶性肿瘤的TRIM29-NEFL-PI3K/AKT轴，突出了靶向该途径治疗GBM的治疗潜力。
{"title":"TRIM29 promotes glioblastoma progression via ubiquitinating NEFL and activating the PI3K/AKT signaling pathway","authors":"Yuankun Liu , Qisheng He , Lingjie Zhu , Mengmeng Zhong , Hao Zhuang , Ning Zhao , Yijin Cai , Chao Cheng , Junfei Shao","doi":"10.1016/j.cancergen.2025.06.008","DOIUrl":"10.1016/j.cancergen.2025.06.008","url":null,"abstract":"<div><div>Tripartite motif-containing protein 29 (TRIM29) is a regulator of tumor progression across multiple cancer types. However, its functional significance in glioblastoma (GBM) remains poorly defined. In this study, we investigated the biological roles of TRIM29 in GBM and elucidated its underlying molecular mechanisms. Clinically, TRIM29 expression was significantly upregulated in glioma tissues compared to adjacent normal brain tissues, and elevated TRIM29 levels correlated with unfavorable prognosis in GBM patients. Functionally, both in vitro (GBM cell lines) and in vivo (a mouse xenograft model) experiments demonstrated that TRIM29 overexpression robustly enhanced GBM cell proliferation, migration, and invasive capacity. Mechanistically, TRIM29 directly interacted with neurofilament light polypeptide (NEFL), triggering K48-linked polyubiquitination and subsequent proteasomal degradation of NEFL[1]. This ubiquitination-dependent NEFL downregulation led to constitutive activation of the PI3K/AKT signaling pathway. Our findings uncover a novel TRIM29-NEFL-PI3K/AKT axis that drives glioblastoma malignancy, highlighting the therapeutic potential of targeting this pathway for GBM treatment.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 88-99"},"PeriodicalIF":1.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564003","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 : 2025-06-18DOI: 10.1016/j.cancergen.2025.06.004
Jisha John , Ashwini Bapat , Siddharth Gahlaut , Naveen Luke , Rahul Kumar , Yashaswi Thakur , Christina Mathew , Aishwarya Konnur , Namrata Namewar , Ruhi Reddy , Sanket Nagarkar , Smeeta Nare , George Thomas , Laleh Busheri , Asha Reddy , Devaki Kelkar , Santosh Dixit , Chetan Deshmukh , Ashraf ul Mannan , Radhakrishnan Sabarinathan , Chaitanyanand B Koppiker
Background
Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25 %) in India remains a challenge in clinical management. Association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. These studies are, however, predominantly representative of western population. Therefore, we investigated germline profiles of multi-institutional cohort of TNBC patients in India
Methods
Multigene NGS (next-generation sequencing) panel testing of Triple Negative Breast Cancer patients was conducted. All patients were offered pre-test and post-test counseling.
Results
In our study cohort of 192 TNBC patients, median age at diagnosis was 47 years (23–78). Germline pathogenic mutations were identified in 28.6 % cases. Of the 58 pathogenic mutations identified, BRCA1 accounted for 72.4 % and BRCA2 for 13.8 %. Eight pathogenic mutations were identified in non-BRCA genes associated with DNA damage response pathway. Ten novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. Comparison of allele-frequency with the global databases like TCGA (The Cancer Genome Atlas), gnomAD and Genome Asia 100 K indicated that the novel mutations were unique.
Conclusions
Our study confirms the major proportion of mutations in BRCA1/2 genes in TNBCs in India. Interestingly, a higher proportion of VUS were found in the non-BRCA genes compared to BRCA1/2 emphasizing the need for functional studies of the non-BRCA genes. Large scale studies are warranted to elucidate the landscape of germline mutations relevant to the Indian population and their probable clinical implications.
背景乳腺癌是印度女性中最常见的癌症，三阴性乳腺癌（TNBC）的发病率很高。在印度，TNBC的高患病率（25%）仍然是临床管理的一个挑战。tnbc中生殖系BRCA1/2突变的关联已被确定为遗传性乳腺癌风险的易感因素。然而，这些研究主要代表的是西方人口。因此，我们研究了印度三阴性乳腺癌患者的多机构队列的生殖系谱。所有患者均接受检测前和检测后咨询。结果192例TNBC患者中位诊断年龄为47岁（23-78岁）。28.6%的病例存在种系致病性突变。在鉴定出的58个致病突变中，BRCA1占72.4%，BRCA2占13.8%。在与DNA损伤反应途径相关的非brca基因中鉴定出8个致病突变。在BRCA1、BRCA2和PALB2 3个基因中发现10个新突变。与TCGA （the Cancer Genome Atlas）、gnomAD和Genome Asia 100k等全球数据库的等位基因频率比较表明，新突变具有独特性。结论我们的研究证实，BRCA1/2基因突变在印度tnbc中占主要比例。有趣的是，与BRCA1/2相比，在非brca基因中发现了更高比例的VUS，这强调了对非brca基因进行功能研究的必要性。有必要进行大规模的研究，以阐明与印度人口有关的种系突变及其可能的临床意义。
{"title":"Assessing germline mutational profile and its clinicopathological associations in Triple Negative Breast Cancer","authors":"Jisha John , Ashwini Bapat , Siddharth Gahlaut , Naveen Luke , Rahul Kumar , Yashaswi Thakur , Christina Mathew , Aishwarya Konnur , Namrata Namewar , Ruhi Reddy , Sanket Nagarkar , Smeeta Nare , George Thomas , Laleh Busheri , Asha Reddy , Devaki Kelkar , Santosh Dixit , Chetan Deshmukh , Ashraf ul Mannan , Radhakrishnan Sabarinathan , Chaitanyanand B Koppiker","doi":"10.1016/j.cancergen.2025.06.004","DOIUrl":"10.1016/j.cancergen.2025.06.004","url":null,"abstract":"<div><h3>Background</h3><div>Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25 %) in India remains a challenge in clinical management. Association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. These studies are, however, predominantly representative of western population. Therefore, we investigated germline profiles of multi-institutional cohort of TNBC patients in India</div></div><div><h3>Methods</h3><div>Multigene NGS (next-generation sequencing) panel testing of Triple Negative Breast Cancer patients was conducted. All patients were offered pre-test and post-test counseling.</div></div><div><h3>Results</h3><div>In our study cohort of 192 TNBC patients, median age at diagnosis was 47 years (23–78). Germline pathogenic mutations were identified in 28.6 % cases. Of the 58 pathogenic mutations identified, <em>BRCA1</em> accounted for 72.4 % and <em>BRCA2</em> for 13.8 %. Eight pathogenic mutations were identified in non-BRCA genes associated with DNA damage response pathway. Ten novel mutations were identified in 3 genes namely <em>BRCA1, BRCA2</em> and <em>PALB2</em>. Comparison of allele-frequency with the global databases like TCGA (The Cancer Genome Atlas), gnomAD and Genome Asia 100 K indicated that the novel mutations were unique.</div></div><div><h3>Conclusions</h3><div>Our study confirms the major proportion of mutations in <em>BRCA1/2</em> genes in TNBCs in India. Interestingly, a higher proportion of VUS were found in the non-BRCA genes compared to BRCA1/2 emphasizing the need for functional studies of the non-BRCA genes. Large scale studies are warranted to elucidate the landscape of germline mutations relevant to the Indian population and their probable clinical implications.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 65-75"},"PeriodicalIF":1.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490551","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 aimed to investigate the role played by special AT-rich sequence binding protein 2 (SATB2) in the immune system of pancreatic cancer (PC).
Methods
Expression of SATB2 was detected in online databases, PC cell lines, and PC tumor tissues. The correlation between SATB2 expression and immune cell infiltrations was examined. Cytotoxic activity of T lymphocytes to different PC cell lines was examined using CCK8. The constructed SATB2 overexpression and knockdown vectors were transformed into PC cell lines to detect T lymphocyte activity, cancer cell migration and proliferation levels. Finally, RNA-seq assay was performed on the overexpression and knockdown cell lines to screen for differentially expressed genes and performed qRT-PCR assay.
Results
Expression level of SATB2 in tumor tissues was significantly higher than that in normal tissues. SATB2 was associated with levels of multiple immune cells infiltration. SATB2 overexpression can inhibit the cytotoxicity of T lymphocytes in PC patients, promote the migration of PC cells, and increase the proportion of S-phase PC cells. There were 1,997 genes differentially expressed in PC cells after SATB2 overexpression and knockout, and these genes were participated in some immune processes, such as B cell chemotaxis and T cell differentiation.
Conclusion
SATB2 was highly expressed in PC and correlated with various levels of immune cell infiltration. SATB2 also inhibited the cytotoxicity of T cells and promoted PC cell migration. Altogether, SATB2 is recognized as a potential target for improving PC immunotherapy.
目的探讨特殊AT-rich sequence binding protein 2 （SATB2）在胰腺癌（PC）免疫系统中的作用。方法在在线数据库、PC细胞系和PC肿瘤组织中检测SATB2的表达。检测SATB2表达与免疫细胞浸润的相关性。用CCK8检测T淋巴细胞对不同PC细胞株的细胞毒活性。将构建的SATB2过表达和敲低载体转化到PC细胞系中，检测T淋巴细胞活性、癌细胞迁移和增殖水平。最后，对过表达和低表达细胞系进行RNA-seq检测，筛选差异表达基因，并进行qRT-PCR检测。结果SATB2在肿瘤组织中的表达水平明显高于正常组织。SATB2与多种免疫细胞浸润水平相关。SATB2过表达可抑制PC患者T淋巴细胞的细胞毒性，促进PC细胞的迁移，增加s期PC细胞的比例。SATB2过表达和敲除后，PC细胞中有1997个基因差异表达，这些基因参与了B细胞趋化和T细胞分化等免疫过程。结论satb2在PC中高表达，并与不同程度的免疫细胞浸润相关。SATB2还能抑制T细胞的细胞毒性，促进PC细胞的迁移。总之，SATB2被认为是改善PC免疫治疗的潜在靶点。
{"title":"SATB2 plays a critical role in pancreatic cancer cell proliferation, migration and T cell cytotoxicity","authors":"Guixing Jiang , Xinyang Zhou , Shehuang Chen , Faming Zhong , Gaoshi Huang , Bicheng Wu , Qiaoyan Mou , Gang Jiang , Tianyu Lin","doi":"10.1016/j.cancergen.2025.06.006","DOIUrl":"10.1016/j.cancergen.2025.06.006","url":null,"abstract":"<div><h3>Objective</h3><div>We aimed to investigate the role played by special AT-rich sequence binding protein 2 (SATB2) in the immune system of pancreatic cancer (PC).</div></div><div><h3>Methods</h3><div>Expression of SATB2 was detected in online databases, PC cell lines, and PC tumor tissues. The correlation between SATB2 expression and immune cell infiltrations was examined. Cytotoxic activity of T lymphocytes to different PC cell lines was examined using CCK8. The constructed SATB2 overexpression and knockdown vectors were transformed into PC cell lines to detect T lymphocyte activity, cancer cell migration and proliferation levels. Finally, RNA-seq assay was performed on the overexpression and knockdown cell lines to screen for differentially expressed genes and performed qRT-PCR assay.</div></div><div><h3>Results</h3><div>Expression level of SATB2 in tumor tissues was significantly higher than that in normal tissues. SATB2 was associated with levels of multiple immune cells infiltration. SATB2 overexpression can inhibit the cytotoxicity of T lymphocytes in PC patients, promote the migration of PC cells, and increase the proportion of S-phase PC cells. There were 1,997 genes differentially expressed in PC cells after SATB2 overexpression and knockout, and these genes were participated in some immune processes, such as B cell chemotaxis and T cell differentiation.</div></div><div><h3>Conclusion</h3><div>SATB2 was highly expressed in PC and correlated with various levels of immune cell infiltration. SATB2 also inhibited the cytotoxicity of T cells and promoted PC cell migration. Altogether, SATB2 is recognized as a potential target for improving PC immunotherapy.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 53-64"},"PeriodicalIF":1.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329945","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 : 2025-06-16DOI: 10.1016/j.cancergen.2025.06.005
Samarth Satish , Matan Bone , Deborah Ritter , Sharon E. Plon
Pathogenic SMARCB1 variants are associated with multiple Mendelian syndromes: Schwannomatosis (SM), Rhabdoid Tumour Predisposition Syndrome (RTPS1), and/or Coffin-Siris Syndrome (CSS). Although some data suggests genotype/phenotype relationships based on mutation type and location, this is not used consistently potentially due to inconsistent or absent phenotypic data. We used ClinVar, the largest public platform of variant classifications, to evaluate variant-specific data from clinical laboratories and cited publications to assess reporting consistency and genotype-phenotype relationships. When available, we extracted the mutation type, HGVS nomenclature, submitters, publications, and disease conditions. We compared the disease assertions made by laboratory submissions with those made in cited publications. Across 59 SMARCB1 pathogenic variants, we identified 91 laboratory submissions (38 single and 20 multiple laboratories) and 40 cited articles. Of 91 submissions, 40 did not provide any disease assertion. Nonsense RTPS1 variants (n = 23) were mostly located in exon 2, with some in exons 1, 4 and 5, and other variant types were limited to frameshifts and large deletions/duplications. SM variants (n = 10) were found throughout SMARCB1 with diverse variant types. CSS variants (n = 6) were single amino-acid deletions, missense and frameshift variants limited to exons 8 and 9. Although ClinVar is a rich source of variant data and extensively used during variant classification, the frequent absence of disease assertions and inconsistent reporting impedes implementation of clear genotype-phenotype relationships for SMARCB1. Given the significant clinical impact of these diagnoses a more standardized way of reporting pathogenic variants for diseases associated with multiple Mendelian disorders is needed.
{"title":"Evaluating the consistency of SMARCB1 variant classification and assertions of genotype-phenotype relationships in ClinVar","authors":"Samarth Satish , Matan Bone , Deborah Ritter , Sharon E. Plon","doi":"10.1016/j.cancergen.2025.06.005","DOIUrl":"10.1016/j.cancergen.2025.06.005","url":null,"abstract":"<div><div>Pathogenic <em>SMARCB1</em> variants are associated with multiple Mendelian syndromes: Schwannomatosis (SM), Rhabdoid Tumour Predisposition Syndrome (RTPS1), and/or Coffin-Siris Syndrome (CSS). Although some data suggests genotype/phenotype relationships based on mutation type and location, this is not used consistently potentially due to inconsistent or absent phenotypic data. We used ClinVar, the largest public platform of variant classifications, to evaluate variant-specific data from clinical laboratories and cited publications to assess reporting consistency and genotype-phenotype relationships. When available, we extracted the mutation type, HGVS nomenclature, submitters, publications, and disease conditions. We compared the disease assertions made by laboratory submissions with those made in cited publications. Across 59 <em>SMARCB1</em> pathogenic variants, we identified 91 laboratory submissions (38 single and 20 multiple laboratories) and 40 cited articles. Of 91 submissions, 40 did not provide any disease assertion. Nonsense RTPS1 variants (<em>n</em> = 23) were mostly located in exon 2, with some in exons 1, 4 and 5, and other variant types were limited to frameshifts and large deletions/duplications. SM variants (<em>n</em> = 10) were found throughout <em>SMARCB1</em> with diverse variant types. CSS variants (<em>n</em> = 6) were single amino-acid deletions, missense and frameshift variants limited to exons 8 and 9. Although ClinVar is a rich source of variant data and extensively used during variant classification, the frequent absence of disease assertions and inconsistent reporting impedes implementation of clear genotype-phenotype relationships for <em>SMARCB1</em>. Given the significant clinical impact of these diagnoses a more standardized way of reporting pathogenic variants for diseases associated with multiple Mendelian disorders is needed.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 84-87"},"PeriodicalIF":1.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549345","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 : 2025-06-11DOI: 10.1016/j.cancergen.2025.06.003
Yue Wang , Xiaorong Zhang , Fan Yang, Jiaqi Shang, Qing Yang
N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic transcriptomes and plays a key role in various biological processes. However, its function in disease, particularly in microRNA regulation, remains unclear. Hepatocellular carcinoma (HCC) is a major global health challenge, with high morbidity and mortality rates. Investigating the role of m6A modification in HCC may provide valuable insights into its molecular mechanisms.
This study found that METTL3, an m6A methyltransferase, is significantly upregulated in HCC and is associated with poor prognosis. Bioinformatics analysis of the GSE37001 dataset showed that silencing METTL3 in HepG2 cells suppressed cell cycle-related pathways. Among several candidate miRNAs potentially regulated by METTL3 in an m6A-dependent manner, miR-93–5p was selected for further study. Experimental results demonstrated that METTL3-mediated m6A modification promotes miR-93–5p expression by facilitating pri-miR-93 processing. Functional assays confirmed that miR-93–5p directly targets CDKN1A and downregulates its expression. Moreover, METTL3 overexpression rescued the effects of METTL3 knockdown on pri-miR-93 m6A levels and miR-93–5p expression. Rescue experiments further showed that METTL3 promotes HCC cell proliferation and cell cycle progression while inhibiting apoptosis via the miR-93–5p/CDKN1A axis.
In summary, METTL3 is highly expressed in HCC and contributes to tumor progression by promoting miR-93–5p expression through m6A modification, thereby suppressing CDKN1A. These findings highlight a potential regulatory mechanism in HCC and suggest that targeting the METTL3/miR-93–5p/CDKN1A axis could be a novel therapeutic strategy.
{"title":"METTL3-mediated m6A modification of pri-miR-93 promotes hepatocellular carcinoma progression via CDKN1A suppression","authors":"Yue Wang , Xiaorong Zhang , Fan Yang, Jiaqi Shang, Qing Yang","doi":"10.1016/j.cancergen.2025.06.003","DOIUrl":"10.1016/j.cancergen.2025.06.003","url":null,"abstract":"<div><div>N6-methyladenosine (m<sup>6</sup>A) is the most common RNA modification in eukaryotic transcriptomes and plays a key role in various biological processes. However, its function in disease, particularly in microRNA regulation, remains unclear. Hepatocellular carcinoma (HCC) is a major global health challenge, with high morbidity and mortality rates. Investigating the role of m<sup>6</sup>A modification in HCC may provide valuable insights into its molecular mechanisms.</div><div>This study found that METTL3, an m<sup>6</sup>A methyltransferase, is significantly upregulated in HCC and is associated with poor prognosis. Bioinformatics analysis of the GSE37001 dataset showed that silencing METTL3 in HepG2 cells suppressed cell cycle-related pathways. Among several candidate miRNAs potentially regulated by METTL3 in an m<sup>6</sup>A-dependent manner, miR-93–5p was selected for further study. Experimental results demonstrated that METTL3-mediated m<sup>6</sup>A modification promotes miR-93–5p expression by facilitating pri-miR-93 processing. Functional assays confirmed that miR-93–5p directly targets CDKN1A and downregulates its expression. Moreover, METTL3 overexpression rescued the effects of METTL3 knockdown on pri-miR-93 m<sup>6</sup>A levels and miR-93–5p expression. Rescue experiments further showed that METTL3 promotes HCC cell proliferation and cell cycle progression while inhibiting apoptosis via the miR-93–5p/CDKN1A axis.</div><div>In summary, METTL3 is highly expressed in HCC and contributes to tumor progression by promoting miR-93–5p expression through m<sup>6</sup>A modification, thereby suppressing CDKN1A. These findings highlight a potential regulatory mechanism in HCC and suggest that targeting the METTL3/miR-93–5p/CDKN1A axis could be a novel therapeutic strategy.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 31-40"},"PeriodicalIF":1.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288923","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 : 2025-06-10DOI: 10.1016/j.cancergen.2025.06.001
Olesya A. Kuznetsova , Maxim V. Ivanov , Alexandra A. Lebedeva , Alexey A. Tryakin , Egor M Veselovsky , Maria S. Cheporova , Fedor V. Moiseenko , Margarita S. Gileva , Alena I. Cherentsova , Anna N. Tiatiushkina , Mikhail Y. Fedyanin
Introduction
Comprehensive molecular profiling (CMP) and molecularly matched therapy (MMT) have uncertain roles in advanced solid tumors. This study evaluates CMP's real-world application in Russia.
Methods
A retrospective, multicenter study analyzed CMP data from 448 patients with advanced non-hematologic malignancies (2018–2024). Genomic alterations (GA) were classified by ESMO Scale for Clinical Actionability of molecular Targets (ESCAT).
Results
ESCAT tiers included I (15.4 %), II (4.9 %), III (31.5 %), IV (19.6 %), and V/X (28.6 %). Therapy data were available for 374 patients. MMT was recommended for 56.9 % but implemented in only 23.2 % (MMT group, n = 87). MMT group showed better objective response rate (61.3 % vs. 37.1 %, p = 0.001), disease control rate (24.0 % vs. 9.2 %, p = 0.003), and progression-free survival ratio (PFS 2/1) ≥ 1.3 (45.0 % vs. 16.2 %, p < 0.01) compared to non-MMT group (n = 287). Median overall survival (OS) was borderline improved (12 vs. 8 months, HR 0.74, p = 0.06). Reasons for non-MMT management were low GA targetability (40 %), drug unavailability (30 %), clinical decline (23 %), and clinician preference (7 %). Patients with ≤3 prior therapies, ECOG performance status 0–1, and molecular tumor board discussion saw significant OS gains with MMT even for ESCAT III-V GA (5 vs. 18 months, HR 0.25, p < 0.01).
Conclusion
MMT following CMP offers clinical benefit for selected patients, even with ESCAT III-V GA, underscoring its potential in personalized oncology.
综合分子谱分析（CMP）和分子匹配治疗（MMT）在晚期实体瘤中的作用尚不确定。本研究评估了CMP在俄罗斯的实际应用。方法一项回顾性、多中心研究分析了448例晚期非血液恶性肿瘤患者（2018-2024）的CMP数据。基因组改变（GA）按照ESMO分子靶点临床可操作性量表（ESCAT）进行分类。结果escat分级包括I（15.4%）、II（4.9%）、III（31.5%）、IV（19.6%）和V/X（28.6%）。374例患者的治疗数据可用。MMT推荐率为56.9%，但实施率仅为23.2% （MMT组，n = 87）。MMT组客观有效率（61.3% vs. 37.1%, p = 0.001）、疾病控制率（24.0% vs. 9.2%, p = 0.003）、无进展生存率(PFS 2/1)≥1.3 (45.0% vs. 16.2%, p <；0.01)，与非mmt组相比（n = 287）。中位总生存期（OS）有边缘性改善（12个月vs 8个月，HR 0.74, p = 0.06）。非mmt治疗的原因是GA靶向性低（40%），药物不可用（30%），临床衰退（23%）和临床医生偏好（7%）。既往治疗≤3次、ECOG表现状态0-1和分子肿瘤委员会讨论的患者，即使对于ESCAT III-V型GA， MMT也能显著提高OS(5个月vs. 18个月，HR 0.25, p <；0.01)。结论：CMP后mmt治疗可为特定患者提供临床益处，即使是ESCAT III-V GA，强调其在个性化肿瘤学方面的潜力。
{"title":"Comprehensive molecular profiling in MOTION study","authors":"Olesya A. Kuznetsova , Maxim V. Ivanov , Alexandra A. Lebedeva , Alexey A. Tryakin , Egor M Veselovsky , Maria S. Cheporova , Fedor V. Moiseenko , Margarita S. Gileva , Alena I. Cherentsova , Anna N. Tiatiushkina , Mikhail Y. Fedyanin","doi":"10.1016/j.cancergen.2025.06.001","DOIUrl":"10.1016/j.cancergen.2025.06.001","url":null,"abstract":"<div><h3>Introduction</h3><div>Comprehensive molecular profiling (CMP) and molecularly matched therapy (MMT) have uncertain roles in advanced solid tumors. This study evaluates CMP's real-world application in Russia.</div></div><div><h3>Methods</h3><div>A retrospective, multicenter study analyzed CMP data from 448 patients with advanced non-hematologic malignancies (2018–2024). Genomic alterations (GA) were classified by ESMO Scale for Clinical Actionability of molecular Targets (ESCAT).</div></div><div><h3>Results</h3><div>ESCAT tiers included I (15.4 %), II (4.9 %), III (31.5 %), IV (19.6 %), and V/X (28.6 %). Therapy data were available for 374 patients. MMT was recommended for 56.9 % but implemented in only 23.2 % (MMT group, <em>n</em> = 87). MMT group showed better objective response rate (61.3 % vs. 37.1 %, <em>p</em> = 0.001), disease control rate (24.0 % vs. 9.2 %, <em>p</em> = 0.003), and progression-free survival ratio (PFS 2/1) ≥ 1.3 (45.0 % vs. 16.2 %, <em>p</em> < 0.01) compared to non-MMT group (<em>n</em> = 287). Median overall survival (OS) was borderline improved (12 vs. 8 months, HR 0.74, <em>p</em> = 0.06). Reasons for non-MMT management were low GA targetability (40 %), drug unavailability (30 %), clinical decline (23 %), and clinician preference (7 %). Patients with ≤3 prior therapies, ECOG performance status 0–1, and molecular tumor board discussion saw significant OS gains with MMT even for ESCAT III-V GA (5 vs. 18 months, HR 0.25, <em>p</em> < 0.01).</div></div><div><h3>Conclusion</h3><div>MMT following CMP offers clinical benefit for selected patients, even with ESCAT III-V GA, underscoring its potential in personalized oncology.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 45-52"},"PeriodicalIF":1.4,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298167","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}
This report presents a rare case of metastatic castration-resistant prostate cancer (CRPC) in an adult patient characterized by dual molecular alterations: microsatellite instability-high (MSI-H) and a BRCA2 mutation. Despite initial treatment with castration, Abiraterone, and sequential chemotherapy with docetaxel and cabazitaxel, the patient progressed to CRPC. Genetic testing revealed MSI-H and a BRCA2 mutation, prompting pembrolizumab therapy. The treatment led to a dramatic prostate-specific antigen (PSA) reduction .
This case underscores the importance of comprehensive genomic profiling for advanced prostate cancer. MSI-H tumors often respond to immune checkpoint inhibitors (ICIs) such as pembrolizumab, while BRCA2 mutations are associated with poly(ADP-ribose) polymerase inhibitors (PARPi) sensitivity. This dual alteration presents therapeutic challenges, as evidenced by pembrolizumab’s remarkable efficacy in this patient, highlighting its potential as a treatment option for MSI-H and BRCA-positive CRPC. Moreover, next-generation sequencing (NGS) played a crucial role in identifying actionable biomarkers not detected by earlier BRCA analyses, emphasizing the necessity of thorough genetic testing.
Further research is needed to optimize treatment strategies for cases with coexisting MSI-H and BRCA mutations, including exploring the synergistic effects of ICIs and PARP i. This case demonstrates the promise of pembrolizumab and advances the understanding of genetic testing’s role in tailoring therapies for complex molecular profiles in prostate cancer.
{"title":"Efficacy of pembrolizumab in MSI-high and BRCA-positive castration-resistant prostate cancer","authors":"Keita Higa , Satoshi Yamamoto , Koichiro Kurokawa , Koki Watanabe , Hiroki Bamba , Sanji Kanaoka , Kazuyoshi Nakamura","doi":"10.1016/j.cancergen.2025.06.002","DOIUrl":"10.1016/j.cancergen.2025.06.002","url":null,"abstract":"<div><div>This report presents a rare case of metastatic castration-resistant prostate cancer (CRPC) in an adult patient characterized by dual molecular alterations: microsatellite instability-high (MSI-H) and a BRCA2 mutation. Despite initial treatment with castration, Abiraterone, and sequential chemotherapy with docetaxel and cabazitaxel, the patient progressed to CRPC. Genetic testing revealed MSI-H and a BRCA2 mutation, prompting pembrolizumab therapy. The treatment led to a dramatic prostate-specific antigen (PSA) reduction .</div><div>This case underscores the importance of comprehensive genomic profiling for advanced prostate cancer. MSI-H tumors often respond to immune checkpoint inhibitors (ICIs) such as pembrolizumab, while BRCA2 mutations are associated with poly(ADP-ribose) polymerase inhibitors (PARPi) sensitivity. This dual alteration presents therapeutic challenges, as evidenced by pembrolizumab’s remarkable efficacy in this patient, highlighting its potential as a treatment option for MSI-H and BRCA-positive CRPC. Moreover, next-generation sequencing (NGS) played a crucial role in identifying actionable biomarkers not detected by earlier BRCA analyses, emphasizing the necessity of thorough genetic testing.</div><div>Further research is needed to optimize treatment strategies for cases with coexisting MSI-H and BRCA mutations, including exploring the synergistic effects of ICIs and PARP i. This case demonstrates the promise of pembrolizumab and advances the understanding of genetic testing’s role in tailoring therapies for complex molecular profiles in prostate cancer.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 41-44"},"PeriodicalIF":1.4,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298162","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 : 2025-06-01DOI: 10.1016/j.cancergen.2025.05.007
Kirthik Roshan M , Rituparna Pal , Subhadra Kumari, Santosh Kumar, Srinivasan Muthuswamy
Chemoresistance is an obstacle to the efficacy of chemotherapy in cancer. Numerous preclinical and clinical investigations have concentrated on mitigating drug resistance; nevertheless, chemoresistance remains a predominant challenge. Recent findings strongly suggest that ferroptosis, a form of non-apoptotic cell death characterized by lipid peroxidation, has been associated with resistance to cancer therapies, and the induction of ferroptosis has been shown to reverse drug resistance. The most common epitranscriptomic modification N6-methyladenosine (m6A) regulates cancer progression by enhancing the stability of oncogenes. Recent evidence suggests that dynamic m6A modifying factors play a role in chemosensitization by increasing the ferroptosis susceptibility. This review explores the mechanisms and significance of ferroptosis, including the role of m6A modifications in regulating ferroptosis-related genes. We discuss potential strategies for enhancing m6A-mediated ferroptosis to increase the effectiveness of chemotherapeutic treatments. Understanding the role of m6A modifications in regulating ferroptosis and their impact on the tumor cell response to chemotherapy could lead to identifying novel therapeutic targets, enhancing the effectiveness of chemotherapy and potentially overcoming chemoresistance.
{"title":"The Interplay of N6-Methyladenosine and Ferroptosis in Cancer: A Promising Therapeutic Avenue","authors":"Kirthik Roshan M , Rituparna Pal , Subhadra Kumari, Santosh Kumar, Srinivasan Muthuswamy","doi":"10.1016/j.cancergen.2025.05.007","DOIUrl":"10.1016/j.cancergen.2025.05.007","url":null,"abstract":"<div><div>Chemoresistance is an obstacle to the efficacy of chemotherapy in cancer. Numerous preclinical and clinical investigations have concentrated on mitigating drug resistance; nevertheless, chemoresistance remains a predominant challenge. Recent findings strongly suggest that ferroptosis, a form of non-apoptotic cell death characterized by lipid peroxidation, has been associated with resistance to cancer therapies, and the induction of ferroptosis has been shown to reverse drug resistance. The most common epitranscriptomic modification N6-methyladenosine (m6A) regulates cancer progression by enhancing the stability of oncogenes. Recent evidence suggests that dynamic m6A modifying factors play a role in chemosensitization by increasing the ferroptosis susceptibility. This review explores the mechanisms and significance of ferroptosis, including the role of m6A modifications in regulating ferroptosis-related genes. We discuss potential strategies for enhancing m6A-mediated ferroptosis to increase the effectiveness of chemotherapeutic treatments. Understanding the role of m6A modifications in regulating ferroptosis and their impact on the tumor cell response to chemotherapy could lead to identifying novel therapeutic targets, enhancing the effectiveness of chemotherapy and potentially overcoming chemoresistance.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 15-24"},"PeriodicalIF":1.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232604","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}
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