Pub Date : 2025-09-01Epub Date: 2025-07-26DOI: 10.1016/j.cancergen.2025.07.015
Diane M. Wilcock , Jian Zhao , H. Evin Gulbahce
Objectives
To assess the clinicopathologic features of breast cancers with complete CEP17 deletion and determine if alternative testing can resolve their HER2 status.
Methods
Cases with complete CEP17 deletion were identified, relevant clinicopathologic information was obtained, and fluorescence in-situ hybridization (FISH) was rerun with an alternative chromosome 17 control gene (RAI1, 17p11.2). One case was also evaluated by cytogenomic SNP microarray (CMA).
Results
Nine breast carcinoma cases were identified and displayed average HER2 copy numbers ranging from 1.1 to 4.7 (Average: 3.1). HER2 immunohistochemistry (IHC) result was available on 8/9 cases with 2/8 (25 %) displaying no staining, 2/8 (25 %%) displaying 1+ staining and 4/8 (50 %) with 2+ staining. ER and PR IHC were available on 8/9 cases 7/8 (87.5 %) were ER and/or PR positive. RAI1 was present in all cases and, if used in place of CEP17, the ASCO/CAP group classification would have been 2/9 (22.2 %) Group 1, 2/9 (22.2 %) Group 4, and 5/9 (55.6 %) Group 5. CMA confirmed complete CEP17 deletion in one case.
Conclusions
Alternative chromosome 17 markers and/or CMA may be needed to resolve HER2 status in patients with complete deletion of CEP17.
{"title":"Resolving HER2 status in breast carcinoma patients with complete deletion of CEP17 in fluorescence in-situ hybridization assays","authors":"Diane M. Wilcock , Jian Zhao , H. Evin Gulbahce","doi":"10.1016/j.cancergen.2025.07.015","DOIUrl":"10.1016/j.cancergen.2025.07.015","url":null,"abstract":"<div><h3>Objectives</h3><div>To assess the clinicopathologic features of breast cancers with complete CEP17 deletion and determine if alternative testing can resolve their HER2 status.</div></div><div><h3>Methods</h3><div>Cases with complete CEP17 deletion were identified, relevant clinicopathologic information was obtained, and fluorescence in-situ hybridization (FISH) was rerun with an alternative chromosome 17 control gene (RAI1, 17p11.2). One case was also evaluated by cytogenomic SNP microarray (CMA).</div></div><div><h3>Results</h3><div>Nine breast carcinoma cases were identified and displayed average <em>HER2</em> copy numbers ranging from 1.1 to 4.7 (Average: 3.1). HER2 immunohistochemistry (IHC) result was available on 8/9 cases with 2/8 (25 %) displaying no staining, 2/8 (25 %%) displaying 1+ staining and 4/8 (50 %) with 2+ staining. ER and PR IHC were available on 8/9 cases 7/8 (87.5 %) were ER and/or PR positive. RAI1 was present in all cases and, if used in place of CEP17, the ASCO/CAP group classification would have been 2/9 (22.2 %) Group 1, 2/9 (22.2 %) Group 4, and 5/9 (55.6 %) Group 5. CMA confirmed complete CEP17 deletion in one case.</div></div><div><h3>Conclusions</h3><div>Alternative chromosome 17 markers and/or CMA may be needed to resolve HER2 status in patients with complete deletion of CEP17.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 196-199"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721951","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}
Background: Cell division cycle 6 (Cdc6) is an oncogenic driver in cervical cancer, whose dysregulation accelerates S-phase entry and promotes genomic instability. As a key replication licensing factor, its overexpression creates a cancer-specific vulnerability, making it a promising therapeutic target.
Objective: To evaluate whether silencing Cdc6 via an adeno-associated virus serotype 2 (AAV2)-delivered shRNA can selectively inhibit cervical cancer growth while sparing normal cells.
Methods: We constructed an AAV2 vector encoding short hairpin RNA (shRNA) targeting Cdc6 and validated its efficacy in vitro using multiple cervical cancer cell lines and an immortalized epithelial cell line (HaCaT). Functional assays assessed cell cycle progression, apoptosis, and DNA damage. Antitumor efficacy was further assessed in xenograft mouse models.
Results: AAV2-shCdc6 transduction efficiently silenced Cdc6 expression, leading to G2/M phase arrest, increased γ-H2AX expression, and significant apoptosis in cervical cancer cells. In contrast, normal HaCaT cells exhibited only S-phase arrest without apoptosis. In vivo, AAV2-shCdc6 treatment significantly inhibited tumor growth in xenograft models without observable systemic toxicity.
Conclusion: AAV2-mediated Cdc6 knockdown selectively targets cervical cancer by exploiting a defined genetic vulnerability. This cancer genetics-based strategy offers a precise and well-tolerated approach for cervical cancer therapy.
{"title":"Genetic silencing of CDC6 via AAV2-Delivered shRNA as a novel cancer genetics-based therapy for cervical carcinoma.","authors":"Yajie Wang, Xiaofeng Li, Xiaoying Lian, Baihai Huang, Jing Jia, Changjun Zhu","doi":"10.1016/j.cancergen.2025.08.001","DOIUrl":"10.1016/j.cancergen.2025.08.001","url":null,"abstract":"<p><strong>Background: </strong>Cell division cycle 6 (Cdc6) is an oncogenic driver in cervical cancer, whose dysregulation accelerates S-phase entry and promotes genomic instability. As a key replication licensing factor, its overexpression creates a cancer-specific vulnerability, making it a promising therapeutic target.</p><p><strong>Objective: </strong>To evaluate whether silencing Cdc6 via an adeno-associated virus serotype 2 (AAV2)-delivered shRNA can selectively inhibit cervical cancer growth while sparing normal cells.</p><p><strong>Methods: </strong>We constructed an AAV2 vector encoding short hairpin RNA (shRNA) targeting Cdc6 and validated its efficacy in vitro using multiple cervical cancer cell lines and an immortalized epithelial cell line (HaCaT). Functional assays assessed cell cycle progression, apoptosis, and DNA damage. Antitumor efficacy was further assessed in xenograft mouse models.</p><p><strong>Results: </strong>AAV2-shCdc6 transduction efficiently silenced Cdc6 expression, leading to G2/M phase arrest, increased γ-H2AX expression, and significant apoptosis in cervical cancer cells. In contrast, normal HaCaT cells exhibited only S-phase arrest without apoptosis. In vivo, AAV2-shCdc6 treatment significantly inhibited tumor growth in xenograft models without observable systemic toxicity.</p><p><strong>Conclusion: </strong>AAV2-mediated Cdc6 knockdown selectively targets cervical cancer by exploiting a defined genetic vulnerability. This cancer genetics-based strategy offers a precise and well-tolerated approach for cervical cancer therapy.</p>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296-297 ","pages":"208-216"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800704","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 : 2025-09-01Epub Date: 2025-07-07DOI: 10.1016/j.cancergen.2025.07.002
B Aldrige Allister , Jonathan L Lühmann , Lena Wendeburg , Frank Dechend , Carmela Beger , Stefanie Tölle , Julia von Ehr , Tim Ripperger , Bernd Auber , Nataliya di Donato , Doris Steinemann
Large genomic rearrangements (LGRs) within the human genome are becoming more recognized by novel genome-wide technologies and may be underreported so far. This class of genomic variation includes copy number variations like duplications or triplications of coding or non-coding genomic regions. Here, we report two LGRs targeting BRCA1, a duplication of exons 18–19 and a triplication of exons 1–2 in two independent families. Utilizing Optical Genome Mapping (OGM), Whole Genome Sequencing (WGS) and cDNA analysis, we characterized the genomic organization and transcriptomic effects of these LGRs regarding its. We show that the tandem duplication ogm[GRCh38]dup(17)(q21.31q21.31)(43057052_43063373), targeting BRCA1 exon 18–19 is predicted to generate a premature termination codon, namely p.(His1732Metfs*10). The triplication of BRCA1 exon 1–2 ogm[GRCh38]trip(17)(q21.31q21.31)(43117155_43124115) is also sequentially arranged. The transcript shows an insertion of a small part of intron 2 (chr17:43,121,558–43,121,676) that theoretically will generate a premature termination codon as well. Collectively, OGM and WGS help elucidating the architecture of these LGRs. However, the final curation depends on how adequate the functional consequences of these LGR can be clarified. Deeper investigation of LGRs on transcript level is important to attain accurate conclusions with respect to therapeutic decisions.
{"title":"Tandem duplication and triplication in BRCA1: revisiting the large genomic rearrangements via optical genome mapping","authors":"B Aldrige Allister , Jonathan L Lühmann , Lena Wendeburg , Frank Dechend , Carmela Beger , Stefanie Tölle , Julia von Ehr , Tim Ripperger , Bernd Auber , Nataliya di Donato , Doris Steinemann","doi":"10.1016/j.cancergen.2025.07.002","DOIUrl":"10.1016/j.cancergen.2025.07.002","url":null,"abstract":"<div><div>Large genomic rearrangements (LGRs) within the human genome are becoming more recognized by novel genome-wide technologies and may be underreported so far. This class of genomic variation includes copy number variations like duplications or triplications of coding or non-coding genomic regions. Here, we report two LGRs targeting <em>BRCA1</em>, a duplication of exons 18–19 and a triplication of exons 1–2 in two independent families. Utilizing Optical Genome Mapping (OGM), Whole Genome Sequencing (WGS) and cDNA analysis, we characterized the genomic organization and transcriptomic effects of these LGRs regarding its. We show that the tandem duplication ogm[GRCh38]dup(17)(q21.31q21.31)(43057052_43063373), targeting <em>BRCA1</em> exon 18–19 is predicted to generate a premature termination codon, namely p.(His1732Metfs*10). The triplication of <em>BRCA1</em> exon 1–2 ogm[GRCh38]trip(17)(q21.31q21.31)(43117155_43124115) is also sequentially arranged. The transcript shows an insertion of a small part of intron 2 (chr17:43,121,558–43,121,676) that theoretically will generate a premature termination codon as well. Collectively, OGM and WGS help elucidating the architecture of these LGRs. However, the final curation depends on how adequate the functional consequences of these LGR can be clarified. Deeper investigation of LGRs on transcript level is important to attain accurate conclusions with respect to therapeutic decisions.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 125-129"},"PeriodicalIF":1.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614664","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 : 2025-09-01Epub Date: 2025-08-11DOI: 10.1016/j.cancergen.2025.08.002
Diane M. Wilcock , Jian Zhao , H. Evin Gulbahce
{"title":"Corrigendum to “Resolving HER2 status in breast carcinoma patients with complete deletion of CEP17 in fluorescence in-situ hybridization assays” [Cancer Genetics, 296–297, 2025, 196-199]","authors":"Diane M. Wilcock , Jian Zhao , H. Evin Gulbahce","doi":"10.1016/j.cancergen.2025.08.002","DOIUrl":"10.1016/j.cancergen.2025.08.002","url":null,"abstract":"","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Page 217"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810405","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 : 2025-09-01Epub Date: 2025-07-19DOI: 10.1016/j.cancergen.2025.07.011
Wei Li , Zishan Xu , Xiangyang Dong , Xiaoyu Yang , Gaoxiang Wang , Guoyang He
KRAS is the most frequently mutant human oncogene, with mutations present in more than 30% of colorectal cancer (CRC) cases. A rare somatic mutation in KRAS, NM_004985.5 : c.436G>A (p.Ala146Thr), was identified in carcinoma tissues from two CRC patients using Sanger sequencing. An alternative transcript of CDC37 was identified that retained intron 3. No splicing variant was detected within the coding exons and exon-intron boundaries of CDC37. The transcript encoded both truncated and full-length CDC37 proteins. Furthermore, KRAS, CDC37 and HSP90 interacted with each other. The expression levels of HSP90 and CDC37 in carcinoma tissues with the KRAS p.Ala146Thr mutation were higher than those in para-carcinoma tissues. Notably, the p.Ala146Thr mutation significantly upregulated the expression of CDK1, which in turn promoted CRC cell proliferation through activation of ERK signaling. These findings uncover a novel molecular mechanism underlying CRC pathogenesis associated with the KRAS p.Ala146Thr mutation and provide potential insights for developing targeted therapies for this subset of CRC.
{"title":"The KRAS p.Ala146Thr mutation promotes the proliferation of colorectal cancer cells via CDK1-mediated ERK signaling","authors":"Wei Li , Zishan Xu , Xiangyang Dong , Xiaoyu Yang , Gaoxiang Wang , Guoyang He","doi":"10.1016/j.cancergen.2025.07.011","DOIUrl":"10.1016/j.cancergen.2025.07.011","url":null,"abstract":"<div><div><em>KRAS</em> is the most frequently mutant human oncogene, with mutations present in more than 30% of colorectal cancer (CRC) cases. A rare somatic mutation in <em>KRAS</em>, NM_004985.5 : c.436G>A (p.Ala146Thr), was identified in carcinoma tissues from two CRC patients using Sanger sequencing. An alternative transcript of <em>CDC37</em> was identified that retained intron 3. No splicing variant was detected within the coding exons and exon-intron boundaries of <em>CDC37</em>. The transcript encoded both truncated and full-length CDC37 proteins. Furthermore, KRAS, CDC37 and HSP90 interacted with each other. The expression levels of HSP90 and CDC37 in carcinoma tissues with the <em>KRAS</em> p.Ala146Thr mutation were higher than those in para-carcinoma tissues. Notably, the p.Ala146Thr mutation significantly upregulated the expression of CDK1, which in turn promoted CRC cell proliferation through activation of ERK signaling. These findings uncover a novel molecular mechanism underlying CRC pathogenesis associated with the <em>KRAS</em> p.Ala146Thr mutation and provide potential insights for developing targeted therapies for this subset of CRC.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 154-162"},"PeriodicalIF":1.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685460","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":"2025-09-01","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 : 2025-09-01Epub Date: 2025-05-24DOI: 10.1016/j.cancergen.2025.05.005
Wan-Ru Chao , Ming-Yung Lee , Yi-Ju Lee , Gwo-Tarng Sheu , Hsiu-Hsiu Chiu , Huang-Pin Shen , Chih-Ping Han
Purpose
Dysregulated HER2-mediated RAS/MAPK and PI3K/AKT signaling drive uncontrolled cell growth and tumorigenesis. Following our prior report of frequent HER2 mutations in advanced uterine cervical neuroendocrine carcinoma (NEC), this study expands the genomic landscape by investigating KRAS and PIK3CA as potential therapeutic targets in a cohort of 12 Taiwanese women with cervical NEC.
Methods
We analyzed 12 histologically confirmed cervical NEC tumor samples from Taiwanese patients. Targeted next-generation sequencing (NGS) was performed using a custom Qiagen GeneRead DNAseq Targeted Panels V2, a clinically relevant tumor panel to detect mutations in key oncogenes. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissues, followed by variant analysis to identify pathogenic alterations.
Results
Beyond HER2 mutations (41.67 %, 5/12), we detected pathogenic alterations in KRAS (16.67 %, 2/12) and PIK3CA (16.67 %, 2/12) within the same cohort. Concurrent mutations were observed in HER2/KRAS (8.3 %, 1/12) and HER2/PIK3CA (8.3 %, 1/12), indicating potential cooperative effects.
Conclusion
This study identifies HER2, KRAS, and PIK3CA as potentially critical drivers in cervical NEC, with their co-occurrence highlighting the role of RAS/MAPK and PI3K/AKT pathways in pathogenesis. Dual pathway inhibition with multi-target therapies may enhance efficacy and address resistance in this aggressive, treatment-limited disease. Molecular profiling is essential for precision oncology, paving the way for validating these findings in larger cohorts and developing multi-pathway strategies to improve survival and quality of life.
{"title":"Profiling of HER2, KRAS, and PIK3CA mutations in uterine cervical neuroendocrine carcinoma and implications for oncogenic driver targeting therapy","authors":"Wan-Ru Chao , Ming-Yung Lee , Yi-Ju Lee , Gwo-Tarng Sheu , Hsiu-Hsiu Chiu , Huang-Pin Shen , Chih-Ping Han","doi":"10.1016/j.cancergen.2025.05.005","DOIUrl":"10.1016/j.cancergen.2025.05.005","url":null,"abstract":"<div><h3>Purpose</h3><div>Dysregulated HER2-mediated RAS/MAPK and PI3K/AKT signaling drive uncontrolled cell growth and tumorigenesis. Following our prior report of frequent HER2 mutations in advanced uterine cervical neuroendocrine carcinoma (NEC), this study expands the genomic landscape by investigating KRAS and PIK3CA as potential therapeutic targets in a cohort of 12 Taiwanese women with cervical NEC.</div></div><div><h3>Methods</h3><div>We analyzed 12 histologically confirmed cervical NEC tumor samples from Taiwanese patients. Targeted next-generation sequencing (NGS) was performed using a custom Qiagen GeneRead DNAseq Targeted Panels V2, a clinically relevant tumor panel to detect mutations in key oncogenes. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissues, followed by variant analysis to identify pathogenic alterations.</div></div><div><h3>Results</h3><div>Beyond <em>HER2</em> mutations (41.67 %, 5/12), we detected pathogenic alterations in <em>KRAS</em> (16.67 %, 2/12) and <em>PIK3CA</em> (16.67 %, 2/12) within the same cohort. Concurrent mutations were observed in <em>HER2</em>/<em>KRA</em>S (8.3 %, 1/12) and <em>HER2</em>/<em>PIK3CA</em> (8.3 %, 1/12), indicating potential cooperative effects.</div></div><div><h3>Conclusion</h3><div>This study identifies HER2, KRAS, and PIK3CA as potentially critical drivers in cervical NEC, with their co-occurrence highlighting the role of RAS/MAPK and PI3K/AKT pathways in pathogenesis. Dual pathway inhibition with multi-target therapies may enhance efficacy and address resistance in this aggressive, treatment-limited disease. Molecular profiling is essential for precision oncology, paving the way for validating these findings in larger cohorts and developing multi-pathway strategies to improve survival and quality of life.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 9-14"},"PeriodicalIF":1.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177700","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 : 2025-09-01Epub 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":"2025-09-01","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}
Pub Date : 2025-09-01Epub Date: 2025-07-16DOI: 10.1016/j.cancergen.2025.07.009
Qiong Wei , Yi Yang , Huimin Wang, Chun Li, Yuping Li
Objective
Ovarian cancer (OC) is the foremost cause of gynecological cancer-related mortality. Respecting the role of long noncoding RNAs (lncRNAs) in malignancies, we explored the mechanism of SSTR5-AS1 regulating OC cell ferroptosis resistance and immune escape via the signal transducer and activator of transcription 3 (STAT3)/solute carrier family 7a member 11 (SLC7A11) axis.
Methods
OC cells were treated with si-SSTR5-AS1, oe-SSTR5-AS1 and oe-SLC7A11 plasmids. SSTR5-AS1, STAT3 and SLC7A11 mRNA levels, and cell malignant behaviors were assessed by RT-qPCR, CCK-8 and Transwell assays. Fe2+, glutathione (GSH) and malondialdehyde (MDA) levels in Erastin-induced OC cells, and viability and apoptosis in OC cell-co-cultured CD8+T cells were determined using kits, and CCK-8 and flow cytometry. SSTR5-AS1 distribution was detected by subcellular fractionation assay. STAT3 and SLC7A11 protein levels were measured by Western blot. The protein interaction and binding relationship between SSTR5-AS1 and STAT3 were predicted by database and confirmed using RIP and verified using dual-luciferase assays.
Results
SSTR5-AS1 was up-regulated in OC cells. SSTR5-AS1 overexpression facilitated OC cell malignant behaviors, down-regulated Fe2+ and MDA levels and up-regulated the GSH level in Erastin-treated OC cells, and diminished viability and enhanced apoptosis in OC cell-co-cultured CD8+T cells, suggesting that SSTR5-AS1 overexpression promoted OC cell ferroptosis resistance and immune escape, which were inhibited by its downregulation. SSTR5-AS1 facilitated SLC7A11 transcription and expression by recruiting STAT3. SLC7A11 overexpression partially reversed the effects of SSTR5-AS1 knockdown on OC cells.
Conclusion
SSTR5-AS1 promoted SLC7A11 transcription and expression by recruiting STAT3, thereby promoting ferroptosis resistance and immune escape of OC cells.
{"title":"The mechanism of lncRNA SSTR5-AS1 promoting ferroptosis resistance and immune escape in ovarian cancer cells by recruiting STAT3 to regulate SLC7A11 expression","authors":"Qiong Wei , Yi Yang , Huimin Wang, Chun Li, Yuping Li","doi":"10.1016/j.cancergen.2025.07.009","DOIUrl":"10.1016/j.cancergen.2025.07.009","url":null,"abstract":"<div><h3>Objective</h3><div>Ovarian cancer (OC) is the foremost cause of gynecological cancer-related mortality. Respecting the role of long noncoding RNAs (lncRNAs) in malignancies, we explored the mechanism of SSTR5-AS1 regulating OC cell ferroptosis resistance and immune escape via the signal transducer and activator of transcription 3 (STAT3)/solute carrier family 7a member 11 (SLC7A11) axis.</div></div><div><h3>Methods</h3><div>OC cells were treated with si-SSTR5-AS1, oe-SSTR5-AS1 and oe-SLC7A11 plasmids. SSTR5-AS1, STAT3 and SLC7A11 mRNA levels, and cell malignant behaviors were assessed by RT-qPCR, CCK-8 and Transwell assays. Fe<sup>2+</sup>, glutathione (GSH) and malondialdehyde (MDA) levels in Erastin-induced OC cells, and viability and apoptosis in OC cell-co-cultured CD8<sup>+</sup><em>T</em> cells were determined using kits, and CCK-8 and flow cytometry. SSTR5-AS1 distribution was detected by subcellular fractionation assay. STAT3 and SLC7A11 protein levels were measured by Western blot. The protein interaction and binding relationship between SSTR5-AS1 and STAT3 were predicted by database and confirmed using RIP and verified using dual-luciferase assays.</div></div><div><h3>Results</h3><div>SSTR5-AS1 was up-regulated in OC cells. SSTR5-AS1 overexpression facilitated OC cell malignant behaviors, down-regulated Fe<sup>2+</sup> and MDA levels and up-regulated the GSH level in Erastin-treated OC cells, and diminished viability and enhanced apoptosis in OC cell-co-cultured CD8<sup>+</sup><em>T</em> cells, suggesting that SSTR5-AS1 overexpression promoted OC cell ferroptosis resistance and immune escape, which were inhibited by its downregulation. SSTR5-AS1 facilitated SLC7A11 transcription and expression by recruiting STAT3. SLC7A11 overexpression partially reversed the effects of SSTR5-AS1 knockdown on OC cells.</div></div><div><h3>Conclusion</h3><div>SSTR5-AS1 promoted SLC7A11 transcription and expression by recruiting STAT3, thereby promoting ferroptosis resistance and immune escape of OC cells.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 172-181"},"PeriodicalIF":1.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711966","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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