As a key regulatory enzyme in mitochondria, YME1L is crucial for regulation of mitochondrial dynamic balance and metabolic plasticity in tumors. Yet its role in non-small cell lung cancer (NACLC) and underlying mechanism are still unclear. In this study, we found YME1L was highly expressed at both protein and RNA levels in NSCLC tissues, which was consistent with the result of database analysis. The bioinformatics analysis also showed that YME1L expression negatively correlated with survival rate. The significance of YME1L was investigated through gain- and loss-of-function studies in vivo and vitro. As expected, the protease activity was consistent with the expression of YME1L. Knockdown of YME1L significantly inhibited mitochondrial activity, proliferation and migration of NACLC cell lines, and suppressed the growth of xenografted tumors in nude mice. While over-expression of YME1L promoted the development of tumors. Further study revealed that YME1L increased the proportion of S-phase and reduced the number of G0/G1 ratio in NSCLC cells, suggesting the strong proliferation activity. Mechanically, knockdown of YME1L decreased the expression of Gαi1 and the phosphorylation of Akt, and on the contrary, YME1L over-expression increased the Gαi1 expression and Akt activation, which in turn stimulated cell proliferation, migration and survival, and promoted the progression of NSCLC. In this study, we revealed that YME1L played a novel oncogenic role in promoting NSCLC tumorigenesis and progression via the mitochondria-Gαi1-AKT axis, providing a new target for the treatment of lung cancer.
作为线粒体的关键调控酶，YME1L在肿瘤组织中对线粒体动态平衡和代谢可塑性的调控起着至关重要的作用。但其在非小细胞肺癌（nclc）中的作用及其机制尚不清楚。本研究中，我们发现YME1L在NSCLC组织中蛋白和RNA水平均高表达，这与数据库分析结果一致。生物信息学分析也显示YME1L表达与存活率呈负相关。通过体内和体外的功能获得和功能丧失研究来研究YME1L的意义。正如预期的那样，蛋白酶活性与YME1L的表达一致。敲低YME1L可显著抑制nclc细胞系线粒体活性、增殖和迁移，抑制裸鼠异种移植肿瘤的生长。而过表达YME1L则促进肿瘤的发展。进一步研究发现，YME1L增加了NSCLC细胞s期比例，降低了G0/G1比，提示其具有较强的增殖活性。机械上，YME1L的下调降低了Gαi1的表达和Akt的磷酸化，相反，YME1L的过表达增加了Gαi1的表达和Akt的激活，从而刺激细胞的增殖、迁移和存活，促进NSCLC的进展。在本研究中，我们发现YME1L通过线粒体- g - αi1- akt轴在促进NSCLC肿瘤发生和进展中发挥了新的致瘤作用，为肺癌的治疗提供了新的靶点。
{"title":"YME1L facilitates the development of non-small cell lung cancer by promoting activation of mitochondria-Gαi1-Akt pathway","authors":"MinDan Wu , WenXia Qian , MeiJie Xu, JieRu Zhang, Feng Gao, LiXiu Chen, SongHua Huang","doi":"10.1016/j.cancergen.2025.10.101","DOIUrl":"10.1016/j.cancergen.2025.10.101","url":null,"abstract":"<div><div>As a key regulatory enzyme in mitochondria, YME1L is crucial for regulation of mitochondrial dynamic balance and metabolic plasticity in tumors. Yet its role in non-small cell lung cancer (NACLC) and underlying mechanism are still unclear. In this study, we found YME1L was highly expressed at both protein and RNA levels in NSCLC tissues, which was consistent with the result of database analysis. The bioinformatics analysis also showed that YME1L expression negatively correlated with survival rate. The significance of YME1L was investigated through gain- and loss-of-function studies in vivo and vitro. As expected, the protease activity was consistent with the expression of YME1L. Knockdown of YME1L significantly inhibited mitochondrial activity, proliferation and migration of NACLC cell lines, and suppressed the growth of xenografted tumors in nude mice. While over-expression of YME1L promoted the development of tumors. Further study revealed that YME1L increased the proportion of S-phase and reduced the number of G0/G1 ratio in NSCLC cells, suggesting the strong proliferation activity. Mechanically, knockdown of YME1L decreased the expression of Gαi1 and the phosphorylation of Akt, and on the contrary, YME1L over-expression increased the Gαi1 expression and Akt activation, which in turn stimulated cell proliferation, migration and survival, and promoted the progression of NSCLC. In this study, we revealed that YME1L played a novel oncogenic role in promoting NSCLC tumorigenesis and progression via the mitochondria-Gαi1-AKT axis, providing a new target for the treatment of lung cancer.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 212-220"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145410670","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 : 2025-11-01DOI: 10.1016/j.cancergen.2025.10.104
Haohui Li , Chenting Jin , Fangfang Zhou , Man Bao , Canliang Tan , Zhenchao Luo , Ninglei Li , Yiyi Jin , Luzhe Han , Gang Xiao , Jian Yan
Background
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and a leading cause of cancer-related mortality. Tumor progression and metastasis, particularly to the lymph nodes, are critical factors contributing to poor patient outcomes. Identifying molecular markers that predict disease progression and patient survival is essential for improving CRC prognosis and therapeutic strategies.
Objective
This study aims to investigate the clinical significance of PHLDA2 expression in CRC and its potential as a prognostic marker.
Methods
PHLDA2 expression levels in CRC tissues were analyzed using Oncomine database and validated through immunohistochemistry. Mean optical density (MOD) scores were used to quantify PHLDA2 protein expression, and mRNA levels were analyzed in tissue samples. Kaplan-Meier survival analysis was performed to determine the effect of PHLDA2 expression on overall survival (OS). The impact of PHLDA2 on CRC cell behavior was examined by knocking out PHLDA2 in HCT 116 and DLD-1 cell lines, followed by assessments of cell proliferation, migration, invasion, and colony formation in vitro. Additionally, the effects of PHLDA2 knockout were evaluated in xenograft models.
Results
PHLDA2 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues. Elevated PHLDA2 levels were associated with lymph node metastasis, with a high expression in 69.23% of rectal cancer patients with metastasis compared to 33.33% in those without metastasis (p = 0.0363). Patients with higher PHLDA2 expression (2+/3+) had significantly worse OS than those with low or no expression (p < 0.05). Functional assays revealed that PHLDA2 knockout significantly reduced proliferation, migration, invasion, and colony formation in HCT 116 and DLD-1 cells. In vivo, PHLDA2 knockout markedly decreased tumor growth in xenograft models.
Conclusions
Increased PHLDA2 expression is associated with more advanced CRC, particularly in cases with lymph node metastasis, and is linked to poorer survival outcomes. These findings suggest that PHLDA2 may be a valuable prognostic marker in CRC.
{"title":"Expression and clinical significance of the imprinted gene PHLDA2 in colorectal cancer","authors":"Haohui Li , Chenting Jin , Fangfang Zhou , Man Bao , Canliang Tan , Zhenchao Luo , Ninglei Li , Yiyi Jin , Luzhe Han , Gang Xiao , Jian Yan","doi":"10.1016/j.cancergen.2025.10.104","DOIUrl":"10.1016/j.cancergen.2025.10.104","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and a leading cause of cancer-related mortality. Tumor progression and metastasis, particularly to the lymph nodes, are critical factors contributing to poor patient outcomes. Identifying molecular markers that predict disease progression and patient survival is essential for improving CRC prognosis and therapeutic strategies.</div></div><div><h3>Objective</h3><div>This study aims to investigate the clinical significance of PHLDA2 expression in CRC and its potential as a prognostic marker.</div></div><div><h3>Methods</h3><div>PHLDA2 expression levels in CRC tissues were analyzed using Oncomine database and validated through immunohistochemistry. Mean optical density (MOD) scores were used to quantify PHLDA2 protein expression, and mRNA levels were analyzed in tissue samples. Kaplan-Meier survival analysis was performed to determine the effect of PHLDA2 expression on overall survival (OS). The impact of PHLDA2 on CRC cell behavior was examined by knocking out PHLDA2 in HCT 116 and DLD-1 cell lines, followed by assessments of cell proliferation, migration, invasion, and colony formation in vitro. Additionally, the effects of PHLDA2 knockout were evaluated in xenograft models.</div></div><div><h3>Results</h3><div>PHLDA2 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues. Elevated PHLDA2 levels were associated with lymph node metastasis, with a high expression in 69.23% of rectal cancer patients with metastasis compared to 33.33% in those without metastasis (p = 0.0363). Patients with higher PHLDA2 expression (2+/3+) had significantly worse OS than those with low or no expression (p < 0.05). Functional assays revealed that PHLDA2 knockout significantly reduced proliferation, migration, invasion, and colony formation in HCT 116 and DLD-1 cells. In vivo, PHLDA2 knockout markedly decreased tumor growth in xenograft models.</div></div><div><h3>Conclusions</h3><div>Increased PHLDA2 expression is associated with more advanced CRC, particularly in cases with lymph node metastasis, and is linked to poorer survival outcomes. These findings suggest that PHLDA2 may be a valuable prognostic marker in CRC.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 227-236"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145439194","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 : 2025-11-01DOI: 10.1016/j.cancergen.2025.11.003
Dongjun Luo , Chen Wang , Beicheng Sun , Zhu Xu
Adjuvant transcatheter arterial chemoembolization (TACE) has traditionally been performed as an effective treatment for hepatocellular carcinoma (HCC). The present study aims to explore key genes associated with TACE treatment for HCC. We used weighted gene co-expression network analysis (WGCNA) to identify the core gene related to the efficacy of TACE for HCC. The raw data of GSE104580 were downloaded from the Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were analyzed. WGCNA was used to identify the key modules related to the efficacy of TACE for HCC, and the protein-protein interaction (PPI) network was used to screen the core genes. Villin1 (VIL1) was identified as a core gene for predicting TACE response. VIL1 was highly expressed in HCC compared to normal tissues, and high expression of VIL1 was strongly correlated with the poor prognosis of HCC patients. Finally, we used one cohort from our center to validate that high expression of VIL1 was closely related to low TACE efficacy in HCC patients. Our study identified the Villin1 gene that may play an important role in the efficacy of TACE for HCC and may become a potential predictive biomarker for evaluating the efficacy of TACE in HCC patients.
辅助经导管动脉化疗栓塞（TACE）传统上被认为是治疗肝细胞癌（HCC）的有效方法。本研究旨在探索与肝癌TACE治疗相关的关键基因。我们使用加权基因共表达网络分析（WGCNA）来确定与TACE治疗HCC疗效相关的核心基因。从Gene Expression Omnibus （GEO）下载GSE104580的原始数据，分析其差异表达基因（differential Expression genes, DEGs）。利用WGCNA鉴定与TACE治疗HCC疗效相关的关键模块，利用蛋白-蛋白相互作用（PPI）网络筛选核心基因。Villin1 （VIL1）被确定为预测TACE反应的核心基因。与正常组织相比，VIL1在HCC中高表达，且VIL1的高表达与HCC患者预后不良密切相关。最后，我们使用本中心的一个队列来验证HCC患者中VIL1的高表达与低TACE疗效密切相关。我们的研究发现，Villin1基因可能在TACE治疗HCC的疗效中发挥重要作用，并可能成为评估TACE治疗HCC患者疗效的潜在预测性生物标志物。
{"title":"Villin1 predicts survival and adjuvant TACE response in hepatocellular carcinoma","authors":"Dongjun Luo , Chen Wang , Beicheng Sun , Zhu Xu","doi":"10.1016/j.cancergen.2025.11.003","DOIUrl":"10.1016/j.cancergen.2025.11.003","url":null,"abstract":"<div><div>Adjuvant transcatheter arterial chemoembolization (TACE) has traditionally been performed as an effective treatment for hepatocellular carcinoma (HCC). The present study aims to explore key genes associated with TACE treatment for HCC. We used weighted gene co-expression network analysis (WGCNA) to identify the core gene related to the efficacy of TACE for HCC. The raw data of GSE104580 were downloaded from the Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were analyzed. WGCNA was used to identify the key modules related to the efficacy of TACE for HCC, and the protein-protein interaction (PPI) network was used to screen the core genes. Villin1 (VIL1) was identified as a core gene for predicting TACE response. VIL1 was highly expressed in HCC compared to normal tissues, and high expression of VIL1 was strongly correlated with the poor prognosis of HCC patients. Finally, we used one cohort from our center to validate that high expression of VIL1 was closely related to low TACE efficacy in HCC patients. Our study identified the Villin1 gene that may play an important role in the efficacy of TACE for HCC and may become a potential predictive biomarker for evaluating the efficacy of TACE in HCC patients.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 280-284"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519826","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}
Li-Fraumeni syndrome (LFS) is an autosomal dominant disease caused by heterozygous germline pathogenic variant in TP53 gene and frequently predisposes to a broad spectrum of cancers including early-onset cancers. To date, clinical and genetic features of LFS are largely unknown in Algerian population. In this study, we performed germline variants screening in TP53 gene in an Algerian LFS family and we have reclassified the TP53 germline missense variant c.314G>T/ (p.Gly105Val).
Patients and Methods
We selected an LFS family with strong history of cancer along three generations that meets updated Chompret clinical criteria. Four family members were affected with various tumors. The proband in this family, a 4-year-old girl has been diagnosed with rhabdomyosarcoma at age 3 years old and she developed a secondary cancer in the right lung after radiotherapy. Her mother developed an early-onset breast cancer at age 30 years old, her maternal grandmother and her maternal aunt have also been diagnosed with breast cancer at age 33 and 27 years, respectively. We screened TP53 exons 3–11 using PCR-Sanger sequencing in 4 members of this LFS family: the proband, her mother and her father (trio) and her kid brother aged of 2 years old, respectively.
Results
The analysis identified the rare germline missense variant TP53 c.314G>T/ (p.Gly105Val) in heterozygous status in three members of the LFS family: the proband, her mother and her kid brother, respectively. The father has been tested negative for the variant. As the TP53 missense germline variant c.314G>T co-segregates within cancer in our LFS family along two generations, we can classify it for the first time as Class 4 variant with the status “Likely Pathogenic” according to ACMG nomenclature.
Conclusions
Our study highlights the importance of the identification, the interpretation and the reclassification of TP53 missense variants detected in carriers in order to improve prognosis, treatment strategies, and LFS patients monitoring and identifying high risk family members.
{"title":"Segregation of the rare TP53 germline missense variant c.314G>T, p.Gly105Val in Algerian family with Li-Fraumeni Syndrome: First report","authors":"Farid Cherbal , Djamel-Eddine Seddik , Mouchira Saidi , Fatiha Gachi","doi":"10.1016/j.cancergen.2025.11.001","DOIUrl":"10.1016/j.cancergen.2025.11.001","url":null,"abstract":"<div><h3>Background</h3><div>Li-Fraumeni syndrome (LFS) is an autosomal dominant disease caused by heterozygous germline pathogenic variant in <em>TP53</em> gene and frequently predisposes to a broad spectrum of cancers including early-onset cancers. To date, clinical and genetic features of LFS are largely unknown in Algerian population. In this study, we performed germline variants screening in <em>TP53</em> gene in an Algerian LFS family and we have reclassified the <em>TP53</em> germline missense variant c.314G><em>T</em>/ (p.Gly105Val).</div></div><div><h3>Patients and Methods</h3><div>We selected an LFS family with strong history of cancer along three generations that meets updated Chompret clinical criteria. Four family members were affected with various tumors. The proband in this family, a 4-year-old girl has been diagnosed with rhabdomyosarcoma at age 3 years old and she developed a secondary cancer in the right lung after radiotherapy. Her mother developed an early-onset breast cancer at age 30 years old, her maternal grandmother and her maternal aunt have also been diagnosed with breast cancer at age 33 and 27 years, respectively. We screened <em>TP53</em> exons 3–11 using PCR-Sanger sequencing in 4 members of this LFS family: the proband, her mother and her father (trio) and her kid brother aged of 2 years old, respectively.</div></div><div><h3>Results</h3><div>The analysis identified the rare germline missense variant <em>TP53</em> c.314G><em>T</em>/ (p.Gly105Val) in heterozygous status in three members of the LFS family: the proband, her mother and her kid brother, respectively. The father has been tested negative for the variant. As the <em>TP53</em> missense germline variant c.314G><em>T</em> co-segregates within cancer in our LFS family along two generations, we can classify it for the first time as Class 4 variant with the status “Likely Pathogenic” according to ACMG nomenclature.</div></div><div><h3>Conclusions</h3><div>Our study highlights the importance of the identification, the interpretation and the reclassification of <em>TP53</em> missense variants detected in carriers in order to improve prognosis, treatment strategies, and LFS patients monitoring and identifying high risk family members.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 268-273"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514372","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 : 2025-11-01DOI: 10.1016/j.cancergen.2025.11.002
Mei Ling Chong , Sok Meng Evelyn Ng , Hongyan Chai , Autumn Diadamo , Aron Flagg , Nicole Marie Owen , Peining Li , Jiadi Wen
B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous hematologic malignancy caused by diverse genetic alterations. While cytogenetic methods such as karyotyping and FISH are routinely used in diagnostics, cryptic and novel oncogenic gene fusions often go undetected. We report a 15-year-old male diagnosed with high-risk B-ALL, presenting with anemia, leukocytosis, and significant lymphoblast burden. Initial karyotyping identified an abnormal clone with a t(7;20)(q34;q13.3) and FISH detected a partial deletion of the ABL1 gene. Chromosome microarray analysis revealed a deletion at 9p21.3 encompassing CDKN2A/CDKN2B and several contiguous copy number aberrations at 9q34.12q34.2. Further long-read genomic sequencing uncovered cryptic NUP214::ABL1 and ABL1::TSC1 fusions, as well as a novel VAPB::TRBV30 rearrangement from the t(7;20). RNA sequencing confirmed the transcripts for both ABL1 fusions and a noncoding rearrangement involving the TCRB locus. Notably, the presence of NUP214::ABL1 identified a clinically actionable target, supporting the use of tyrosine kinase inhibitors (TKIs) such as imatinib. This case underscores the critical role of integrated sequencing approaches in identifying cryptic genetic alterations in B-ALL for precise classification of oncogenic drivers and for targeted therapeutic strategies to improve patient outcomes.
{"title":"Decoding the genetic complexity in a pediatric case of B-ALL through long-read genomic sequencing and RNA sequencing","authors":"Mei Ling Chong , Sok Meng Evelyn Ng , Hongyan Chai , Autumn Diadamo , Aron Flagg , Nicole Marie Owen , Peining Li , Jiadi Wen","doi":"10.1016/j.cancergen.2025.11.002","DOIUrl":"10.1016/j.cancergen.2025.11.002","url":null,"abstract":"<div><div>B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous hematologic malignancy caused by diverse genetic alterations. While cytogenetic methods such as karyotyping and FISH are routinely used in diagnostics, cryptic and novel oncogenic gene fusions often go undetected. We report a 15-year-old male diagnosed with high-risk B-ALL, presenting with anemia, leukocytosis, and significant lymphoblast burden. Initial karyotyping identified an abnormal clone with a t(7;20)(q34;q13.3) and FISH detected a partial deletion of the <em>ABL1</em> gene. Chromosome microarray analysis revealed a deletion at 9p21.3 encompassing <em>CDKN2A</em>/<em>CDKN2B</em> and several contiguous copy number aberrations at 9q34.12q34.2. Further long-read genomic sequencing uncovered cryptic <em>NUP214::ABL1</em> and <em>ABL1::TSC1</em> fusions, as well as a novel <em>VAPB::TRBV30</em> rearrangement from the t(7;20). RNA sequencing confirmed the transcripts for both <em>ABL1</em> fusions and a noncoding rearrangement involving the TCRB locus. Notably, the presence of <em>NUP214::ABL1</em> identified a clinically actionable target, supporting the use of tyrosine kinase inhibitors (TKIs) such as imatinib. This case underscores the critical role of integrated sequencing approaches in identifying cryptic genetic alterations in B-ALL for precise classification of oncogenic drivers and for targeted therapeutic strategies to improve patient outcomes.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 274-279"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514415","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 : 2025-11-01DOI: 10.1016/j.cancergen.2025.11.010
Mohammad Sina , Keivan Majidzadeh-A , Shiva Zarinfam , Rosalba Monica Ferraro , Elena Laura Mazzoldi , Seyedeh Zahra Mousavi , Silvia Clara Giliani
Lynch syndrome is an inherited autosomal-dominant cancer-predisposition condition that results from germline defects in the DNA mismatch-repair (MMR) pathway or inactivation of the EPCAM gene. Variants involving EPCAM are detected in roughly 1–3 % of Lynch syndrome cases, whereas combined EPCAM–MSH2 deletions remain very uncommon. We investigated two Iranian families from the same village, each with multiple members affected by colorectal cancer (CRC), to identify the underlying genetic causes. In Family A, colon tumor immunohistochemistry showed loss of MSH2 and MSH6 expression in formalin-fixed paraffin-embedded tissue. Despite negative Sanger sequencing results for MSH2, whole-exome sequencing (WES) followed by copy number variant (CNV) analysis using CNVkit and ExomeDepth identified a large CNV across EPCAM and MSH2. Breakpoints were confirmed by MLPA and SYBR Green qPCR. A second family from the same village showed multi-generational CRC; Family B was therefore tested by MLPA/qPCR for the same CNV. We identified a heterozygous ∼76.7 kb deletion spanning EPCAM exons 1–9 and MSH2 exons 1–8. In Family A, 15/23 tested relatives were carriers; six carriers had CRC at 35–53 years, and no extracolonic tumors were observed. The CRC affected proband of Family B harbored the identical deletion. Cascade testing achieved remarkable uptake, with >20 relatives tested in family A—over tenfold higher than typical reports—facilitated by direct clinician contact and streamlined logistics such as convenient blood collection. This is the first documented EPCAM–MSH2 deletion reported from the Middle East and North Africa region (MENA).
Lynch综合征是一种遗传性常染色体显性癌症易感性疾病，由DNA错配修复（MMR）途径的种系缺陷或EPCAM基因失活引起。大约1 - 3%的Lynch综合征病例中检测到涉及EPCAM的变异，而EPCAM - msh2联合缺失仍然非常罕见。我们调查了来自同一村庄的两个伊朗家庭，每个家庭都有多名成员患有结直肠癌（CRC），以确定潜在的遗传原因。在A家族中，结肠肿瘤免疫组化显示在福尔马林固定石蜡包埋组织中MSH2和MSH6的表达缺失。尽管MSH2的Sanger测序结果为阴性，但使用CNVkit和ExomeDepth进行全外显子组测序（WES）和拷贝数变异（CNV）分析后，发现EPCAM和MSH2之间存在较大的拷贝数变异。采用MLPA和SYBR Green qPCR检测断点。同一村庄的第二个家庭表现出多代结直肠癌；因此，用MLPA/qPCR检测B家族相同的CNV。我们发现了一个杂合子- 76.7 kb的缺失，横跨EPCAM外显子1-9和MSH2外显子1-8。A家族有15/23的检测亲属为携带者；6名携带者在35-53岁时发生结直肠癌，未见结肠外肿瘤。B家族受结直肠癌影响的先证者也有相同的缺失。级联检测取得了显著成效，a家族有20名亲属接受检测，比典型报告高出10倍以上，这得益于直接与临床医生接触，以及便捷的采血等流程化的物流。这是中东和北非地区（MENA）首次报道的EPCAM-MSH2缺失。
{"title":"First Middle East and North Africa report of an EPCAM–MSH2 deletion in two Iranian Lynch syndrome families: a case report","authors":"Mohammad Sina , Keivan Majidzadeh-A , Shiva Zarinfam , Rosalba Monica Ferraro , Elena Laura Mazzoldi , Seyedeh Zahra Mousavi , Silvia Clara Giliani","doi":"10.1016/j.cancergen.2025.11.010","DOIUrl":"10.1016/j.cancergen.2025.11.010","url":null,"abstract":"<div><div>Lynch syndrome is an inherited autosomal-dominant cancer-predisposition condition that results from germline defects in the DNA mismatch-repair (MMR) pathway or inactivation of the <em>EPCAM</em> gene. Variants involving <em>EPCAM</em> are detected in roughly 1–3 % of Lynch syndrome cases, whereas combined <em>EPCAM–MSH2</em> deletions remain very uncommon. We investigated two Iranian families from the same village, each with multiple members affected by colorectal cancer (CRC), to identify the underlying genetic causes. In Family A, colon tumor immunohistochemistry showed loss of MSH2 and MSH6 expression in formalin-fixed paraffin-embedded tissue. Despite negative Sanger sequencing results for <em>MSH2</em>, whole-exome sequencing (WES) followed by copy number variant (CNV) analysis using CNVkit and ExomeDepth identified a large CNV across <em>EPCAM</em> and <em>MSH2</em>. Breakpoints were confirmed by MLPA and SYBR Green qPCR. A second family from the same village showed multi-generational CRC; Family B was therefore tested by MLPA/qPCR for the same CNV. We identified a heterozygous ∼76.7 kb deletion spanning <em>EPCAM</em> exons 1–9 and <em>MSH2</em> exons 1–8. In Family A, 15/23 tested relatives were carriers; six carriers had CRC at 35–53 years, and no extracolonic tumors were observed. The CRC affected proband of Family B harbored the identical deletion. Cascade testing achieved remarkable uptake, with >20 relatives tested in family A—over tenfold higher than typical reports—facilitated by direct clinician contact and streamlined logistics such as convenient blood collection. This is the first documented <em>EPCAM–MSH2</em> deletion reported from the Middle East and North Africa region (MENA).</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 315-320"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617932","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 : 2025-11-01DOI: 10.1016/j.cancergen.2025.10.100
Jun Jiang , Xiaoshuai Chen , Xinjie Dong , Yanfang Wang , Jixuan Liu , Ting Liu , Xiaolei Bian , Ming Li , Yafang Liu
{"title":"Corrigendum to “RNF121 Promotes the Proliferation, Migration, and Invasion of Non-Small-Cell lung cancer cell lines” [Cancer Genetics 298-299 (2025) 193-197]","authors":"Jun Jiang , Xiaoshuai Chen , Xinjie Dong , Yanfang Wang , Jixuan Liu , Ting Liu , Xiaolei Bian , Ming Li , Yafang Liu","doi":"10.1016/j.cancergen.2025.10.100","DOIUrl":"10.1016/j.cancergen.2025.10.100","url":null,"abstract":"","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Page 226"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145439257","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}
Sub-Saharan African women often develop breast cancer at a younger age, with a high prevalence of aggressive subtypes such as triple-negative breast cancer and elevated mortality. Genetic factors may underlie these patterns, but African populations remain underrepresented in genomic research. As an initial step toward addressing this gap, we evaluated DNA extracted from formalin-fixed paraffin-embedded (FFPE) breast cancer blocks collected in anatomic pathology laboratories in Gabon, Togo, and Benin. Although DNA could be successfully extracted, its functional quality was significantly impaired. Quantitative PCR revealed progressive degradation, with poor amplification efficiency for larger fragments, and next-generation sequencing (NGS) libraries exhibited degraded electropherogram profiles, low coverage, and elevated duplication rates. These limitations likely stem from socio-economic constraints, including delayed processing and prolonged formalin fixation, which promote nucleic acid fragmentation and crosslinking. To overcome these barriers, we established a preservation protocol adapted to the resource and infrastructural limitations of the region: storage of biopsies in physiological saline at –20 °C. This method requires only basic equipment widely available in local hospitals, yet yielded DNA of high integrity, enabled efficient library construction, and produced significantly superior NGS performance compared with FFPE-derived DNA. This cost-effective and scalable approach provides a feasible solution for genomic research in resource-limited settings. Future efforts should focus on complementary strategies for RNA preservation and tumor enrichment to enable comprehensive molecular profiling and advance precision oncology in West Africa.
{"title":"DNA quality challenges in breast cancer samples from three low-middle income African countries: a straightforward protocol for research in cancer genomics","authors":"Mohamad Chkeir , Freddy Gnangnon , Patrice Dangbemey , Gilbert Fassinou , Sylvain Lacorre , Maeva Chaumet , Mahiné Ivanga , Rosa-Maria Fassinou , Romulus Takin , Sidonie Nguizi Ogoula , Arnaud Agbanlinsou , Lionel Forestier , Nathalie Duprat , Karine Durand , Alain Chaunavel , Pierre-Marie Preux , Tchin Darré , Edgard Brice Ngoungou , Dieu donné Gnonlonfoun , Simon Azonbakin , Alexis Parenté","doi":"10.1016/j.cancergen.2025.11.005","DOIUrl":"10.1016/j.cancergen.2025.11.005","url":null,"abstract":"<div><div>Sub-Saharan African women often develop breast cancer at a younger age, with a high prevalence of aggressive subtypes such as triple-negative breast cancer and elevated mortality. Genetic factors may underlie these patterns, but African populations remain underrepresented in genomic research. As an initial step toward addressing this gap, we evaluated DNA extracted from formalin-fixed paraffin-embedded (FFPE) breast cancer blocks collected in anatomic pathology laboratories in Gabon, Togo, and Benin. Although DNA could be successfully extracted, its functional quality was significantly impaired. Quantitative PCR revealed progressive degradation, with poor amplification efficiency for larger fragments, and next-generation sequencing (NGS) libraries exhibited degraded electropherogram profiles, low coverage, and elevated duplication rates. These limitations likely stem from socio-economic constraints, including delayed processing and prolonged formalin fixation, which promote nucleic acid fragmentation and crosslinking. To overcome these barriers, we established a preservation protocol adapted to the resource and infrastructural limitations of the region: storage of biopsies in physiological saline at –20 °C. This method requires only basic equipment widely available in local hospitals, yet yielded DNA of high integrity, enabled efficient library construction, and produced significantly superior NGS performance compared with FFPE-derived DNA. This cost-effective and scalable approach provides a feasible solution for genomic research in resource-limited settings. Future efforts should focus on complementary strategies for RNA preservation and tumor enrichment to enable comprehensive molecular profiling and advance precision oncology in West Africa.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 295-301"},"PeriodicalIF":2.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568681","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}
Despite the significant role of genetic mutations in colorectal cancer (CRC), there is considerable variability in the reported prevalence of TP53, APC, and PIK3CA mutations across different populations and CRC subtypes. Thus, this systematic review and meta-analysis aimed to assess the prevalence of TP53, APC, and PIK3CA gene mutations in CRC patients.
Methods
A systematic search was done in Medline/PubMed, Scopus, Embase, Web of Science, and Google Scholar from their dates of inception until September 2024. Obsevational studies reported TP53, APC, and PIK3CA mutations in CRC patients were included. The quality of the evidence was assessed using the Joanna Briggs Institute (JBI) instrument. The prevalence of each mutated gene and its 95 % confidence interval (CI) were calculated using the random effects model.
Results
A total of 32 studies were included comprising 7765 participants with JBI scores ranging from 7 to 9. Our findings showed that TP53 mutations were the most prevalent, detected in 51 % (95 % CI: 41–60) of cases, with a significantly higher prevalence in M-CRC (81 %, 95 % CI: 76–85), followed by APC (33 %, 95 % CI: 13–52), and PIK3CA (19 %, 95 % CI: 10–28).
Conclusion
This meta-analysis showed the high prevalence of TP53, PIK3CA, and APC mutations among CRC patients, with TP53 mutations being the most common among these three genes.
{"title":"The prevalence of TP53, APC, and PIK3CA gene mutations in colorectal cancer patients: A Systematic Review and Meta-analysis","authors":"Mobina Gheibi , Sogand Sadeghi , Amirhossein Hessami , Zahra Erfani , Erfan Ghadirzadeh , Mahmood Moosazadeh","doi":"10.1016/j.cancergen.2025.10.003","DOIUrl":"10.1016/j.cancergen.2025.10.003","url":null,"abstract":"<div><h3>Background</h3><div>Despite the significant role of genetic mutations in colorectal cancer (CRC), there is considerable variability in the reported prevalence of TP53, APC, and PIK3CA mutations across different populations and CRC subtypes. Thus, this systematic review and meta-analysis aimed to assess the prevalence of TP53, APC, and PIK3CA gene mutations in CRC patients.</div></div><div><h3>Methods</h3><div>A systematic search was done in Medline/PubMed, Scopus, Embase, Web of Science, and Google Scholar from their dates of inception until September 2024. Obsevational studies reported TP53, APC, and PIK3CA mutations in CRC patients were included. The quality of the evidence was assessed using the Joanna Briggs Institute (JBI) instrument. The prevalence of each mutated gene and its 95 % confidence interval (CI) were calculated using the random effects model.</div></div><div><h3>Results</h3><div>A total of 32 studies were included comprising 7765 participants with JBI scores ranging from 7 to 9. Our findings showed that TP53 mutations were the most prevalent, detected in 51 % (95 % CI: 41–60) of cases, with a significantly higher prevalence in M-CRC (81 %, 95 % CI: 76–85), followed by APC (33 %, 95 % CI: 13–52), and PIK3CA (19 %, 95 % CI: 10–28).</div></div><div><h3>Conclusion</h3><div>This meta-analysis showed the high prevalence of TP53, PIK3CA, and APC mutations among CRC patients, with TP53 mutations being the most common among these three genes.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 198-207"},"PeriodicalIF":2.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145362093","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 : 2025-10-09DOI: 10.1016/j.cancergen.2025.10.002
Jun Jiang, Xiaoshuai Chen, Xinjie Dong, Yanfang Wang, Jixuan Liu, Ting Liu, Xiaolei Bian, Ming Li, Yafang Liu
Objectives
RING finger proteins are a large family of proteins within the human genome that play essential roles in the regulation of physiological processes and have been implicated in cancer progression. However, the relationships among RING Finger Protein 121 (RNF121), E3 ubiquitin ligase, and tumorigenesis have yet to be determined. In this study, we aimed to comprehensively elucidate the functions of RNF121 in non-small cell lung cancer (NSCLC).
Methods
On the basis of MTT, colony formation, and Transwell assays, we evaluated RNF121-specific functions that were found to be closely associated with clinicopathological features.
Results
RNF121 expression was demonstrated to be closely associated with different diseases. By altering the levels of this protein in the A549 and H1299 cell lines, we discovered that this protein promotes cell proliferation, migration, and invasion.
Conclusion
This study is the first to demonstrate that RNF121 plays a prominent role in driving NSCLC progression and that its expression is correlated with clinicopathological features. Accordingly, this gene would serve not only as a key prognostic indicator but also as a novel potential therapeutic target for the treatment of NSCLC.
目的：无名指蛋白是人类基因组中的一个大家族蛋白，在生理过程的调节中发挥重要作用，并与癌症进展有关。然而，RING Finger Protein 121 （RNF121）、E3泛素连接酶与肿瘤发生之间的关系尚不明确。在本研究中，我们旨在全面阐明RNF121在非小细胞肺癌（NSCLC）中的功能。方法：基于MTT、菌落形成和Transwell试验，我们评估了与临床病理特征密切相关的rnf121特异性功能。结果：RNF121的表达与不同疾病密切相关。通过改变A549和H1299细胞系中这种蛋白的水平，我们发现这种蛋白促进细胞增殖、迁移和侵袭。结论：本研究首次证实RNF121在推动NSCLC进展中发挥突出作用，其表达与临床病理特征相关。因此，该基因不仅可以作为关键的预后指标，而且可以作为治疗非小细胞肺癌的新的潜在治疗靶点。
{"title":"RNF121 promotes the proliferation, migration, and invasion of lung cancer cell lines","authors":"Jun Jiang, Xiaoshuai Chen, Xinjie Dong, Yanfang Wang, Jixuan Liu, Ting Liu, Xiaolei Bian, Ming Li, Yafang Liu","doi":"10.1016/j.cancergen.2025.10.002","DOIUrl":"10.1016/j.cancergen.2025.10.002","url":null,"abstract":"<div><h3>Objectives</h3><div>RING finger proteins are a large family of proteins within the human genome that play essential roles in the regulation of physiological processes and have been implicated in cancer progression. However, the relationships among RING Finger Protein 121 (RNF121), E3 ubiquitin ligase, and tumorigenesis have yet to be determined. In this study, we aimed to comprehensively elucidate the functions of <em>RNF121</em> in non-small cell lung cancer (NSCLC).</div></div><div><h3>Methods</h3><div>On the basis of MTT, colony formation, and Transwell assays, we evaluated <em>RNF121</em>-specific functions that were found to be closely associated with clinicopathological features.</div></div><div><h3>Results</h3><div><em>RNF121</em> expression was demonstrated to be closely associated with different diseases. By altering the levels of this protein in the A549 and H1299 cell lines, we discovered that this protein promotes cell proliferation, migration, and invasion.</div></div><div><h3>Conclusion</h3><div>This study is the first to demonstrate that <em>RNF121</em> plays a prominent role in driving NSCLC progression and that its expression is correlated with clinicopathological features. Accordingly, this gene would serve not only as a key prognostic indicator but also as a novel potential therapeutic target for the treatment of NSCLC.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 193-197"},"PeriodicalIF":2.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304214","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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