Pub Date : 2025-08-16DOI: 10.1016/j.cancergen.2025.08.004
Ying Zhang , Jack Reid , Deepa Jeyakumar , Kapitolina Semenova , Naqvi Kiran , Lisa Lee , Angela Fleishman , Sherif Rezk , Xiaohui Zhao , Fabiola Quintero-Rivera
The occurrence of additional specific chromosomal abnormalities in Philadelphia chromosome-positive (pH+) cells is associated with disease progression in chronic myeloid leukemia (CML), and is considered a marker that defines the accelerated/blast phase of CML. Both DEK::NUP214 fusion and CBFB rearrangement are extremely rare in CML, and their prognostic significance is unknown. Here we present two CML cases, with one case having concurrent translocation 6;9 [t(6;9)] leading to DEK::NUP214 fusion, and the other one presenting with concurrent inversion 16 -inv(16)- leading to CBFB::MYH11 fusion. The t(6;9) is usually associated with poor prognosis in acute myeloid leukemia (AML) patients. In this case, the patient failed to achieve remission and expired. This suggests that the t(6;9) is also associated with poor prognosis in CML. However, more data is needed to verify this association. Detection of inv(16) by karyotyping is technically challenging. In addition, FISH for CBFB is not usually run in the context of CML, thus raising the possibility that similar cases may have been underdiagnosed. With the routine use of next-generation sequencing (NGS) for gene fusion detection, more patients like this one should be diagnosed and treated accordingly. These cases illustrate the importance of a comprehensive molecular/cytogenetic diagnostic work-up.
{"title":"Unfavorable disease progression in patients with chronic myeloid leukemia and concurrent t(6;9) translocation (DEK::NUP214 fusion) or inversion 16 (CBFB::MYH11 fusion)","authors":"Ying Zhang , Jack Reid , Deepa Jeyakumar , Kapitolina Semenova , Naqvi Kiran , Lisa Lee , Angela Fleishman , Sherif Rezk , Xiaohui Zhao , Fabiola Quintero-Rivera","doi":"10.1016/j.cancergen.2025.08.004","DOIUrl":"10.1016/j.cancergen.2025.08.004","url":null,"abstract":"<div><div>The occurrence of additional specific chromosomal abnormalities in Philadelphia chromosome-positive (pH+) cells is associated with disease progression in chronic myeloid leukemia (CML), and is considered a marker that defines the accelerated/blast phase of CML. Both DEK::NUP214 fusion and CBFB rearrangement are extremely rare in CML, and their prognostic significance is unknown. Here we present two CML cases, with one case having concurrent translocation 6;9 [t(6;9)] leading to DEK::NUP214 fusion, and the other one presenting with concurrent inversion 16 -inv(16)- leading to CBFB::MYH11 fusion. The t(6;9) is usually associated with poor prognosis in acute myeloid leukemia (AML) patients. In this case, the patient failed to achieve remission and expired. This suggests that the t(6;9) is also associated with poor prognosis in CML. However, more data is needed to verify this association. Detection of inv(16) by karyotyping is technically challenging. In addition, FISH for CBFB is not usually run in the context of CML, thus raising the possibility that similar cases may have been underdiagnosed. With the routine use of next-generation sequencing (NGS) for gene fusion detection, more patients like this one should be diagnosed and treated accordingly. These cases illustrate the importance of a comprehensive molecular/cytogenetic diagnostic work-up.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 20-26"},"PeriodicalIF":2.1,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908235","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 : 2025-08-14DOI: 10.1016/j.cancergen.2025.08.005
Andrea Mariani , Mika Sampo , Harri Sihto , Tom Böhling , Omar Youssef
YEATS4 resides within the 12q13–15 chromosomal region, where it is frequently co-amplified with MDM2 and CDK4 in liposarcomas (LPS). However, its independent role in LPS progression and dedifferentiation remains poorly defined. In this study, YEATS4 expression was analyzed in 57 formalin-fixed paraffin-embedded (FFPE) LPS samples using quantitative real-time PCR and compared across histological subtypes. MDM2 amplification status was determined by fluorescence in situ hybridization (FISH). The functional relevance of YEATS4 was assessed via siRNA-mediated knockdown in two well-differentiated LPS (WDLPS) cell lines, GOT-3 and 93T449. Relative YEATS4 mRNA expression was significantly higher in MDM2-positive compared to MDM2-negative tumors (median = 0.413 vs. 0.007; p = 0.008). Using the median YEATS4 expression value (0.227) – calculated from WDLPS and DDLPS cases only – as a threshold, high YEATS4 expression was observed in 64% of high-grade dedifferentiated LPS (DDLPS), 54% of low-grade DDLPS, and 29% of WDLPS cases (p = 0.302). Functionally, YEATS4 silencing significantly reduced cell viability in 93T449 cells at Days 5 (24.1%) and Day 7 (22.1%) compared to control (p < 0.001). In GOT3 cells, a slight reduction was noted at Day 3 (7.6%) which was not sustained. In summary, YEATS4 could contribute to LPS progression in a subset of MDM2-amplified tumors, particularly in high-grade DDLPS. Its variable functional impact across models highlights the complexity of the 12q13–15 amplicon and supports further investigation into YEATS4 as a potential molecular marker and therapeutic target in LPS.
YEATS4位于12q13-15染色体区域，在脂肉瘤（LPS）中，它经常与MDM2和CDK4共同扩增。然而，其在LPS进展和去分化中的独立作用仍不明确。在本研究中，采用实时荧光定量PCR分析了57份福尔马林固定石蜡包埋（FFPE） LPS样品中YEATS4的表达，并比较了不同组织学亚型。采用荧光原位杂交法（FISH）检测MDM2扩增状态。在两种分化良好的脂多糖（WDLPS）细胞系GOT-3和93T449中，通过sirna介导的敲低来评估YEATS4的功能相关性。与mdm2阴性肿瘤相比，mdm2阳性肿瘤中YEATS4 mRNA的相对表达量显著升高（中位数= 0.413 vs. 0.007; p = 0.008）。使用YEATS4中位表达值（0.227）（仅从WDLPS和DDLPS病例计算）作为阈值，在64%的高级别去分化LPS （DDLPS）、54%的低级别DDLPS和29%的WDLPS病例中观察到高水平的YEATS4表达（p = 0.302）。在功能上，与对照组相比，YEATS4沉默显著降低了93T449细胞在第5天（24.1%）和第7天（22.1%）的细胞活力（p < 0.001）。在GOT3细胞中，在第3天注意到轻微的减少（7.6%），但没有持续。总之，YEATS4可能在mdm2扩增的肿瘤亚群中促进LPS进展，特别是在高级别DDLPS中。它在不同模型中的不同功能影响突出了12q13-15扩增子的复杂性，并支持进一步研究YEATS4作为LPS的潜在分子标记和治疗靶点。
{"title":"High YEATS4 expression characterizes MDM2-amplified liposarcoma","authors":"Andrea Mariani , Mika Sampo , Harri Sihto , Tom Böhling , Omar Youssef","doi":"10.1016/j.cancergen.2025.08.005","DOIUrl":"10.1016/j.cancergen.2025.08.005","url":null,"abstract":"<div><div><em>YEATS4</em> resides within the 12q13–15 chromosomal region, where it is frequently co-amplified with <em>MDM2</em> and <em>CDK4</em> in liposarcomas (LPS). However, its independent role in LPS progression and dedifferentiation remains poorly defined. In this study, <em>YEATS4</em> expression was analyzed in 57 formalin-fixed paraffin-embedded (FFPE) LPS samples using quantitative real-time PCR and compared across histological subtypes. <em>MDM2</em> amplification status was determined by fluorescence in situ hybridization (FISH). The functional relevance of <em>YEATS4</em> was assessed via siRNA-mediated knockdown in two well-differentiated LPS (WDLPS) cell lines, GOT-3 and 93T449. Relative <em>YEATS4</em> mRNA expression was significantly higher in <em>MDM2</em>-positive compared to <em>MDM2</em>-negative tumors (median = 0.413 vs. 0.007; <em>p</em> = 0.008). Using the median <em>YEATS4</em> expression value (0.227) – calculated from WDLPS and DDLPS cases only – as a threshold, high <em>YEATS4</em> expression was observed in 64% of high-grade dedifferentiated LPS (DDLPS), 54% of low-grade DDLPS, and 29% of WDLPS cases (<em>p</em> = 0.302). Functionally, <em>YEATS4</em> silencing significantly reduced cell viability in 93T449 cells at Days 5 (24.1%) and Day 7 (22.1%) compared to control (<em>p</em> < 0.001). In GOT3 cells, a slight reduction was noted at Day 3 (7.6%) which was not sustained. In summary, <em>YEATS4</em> could contribute to LPS progression in a subset of <em>MDM2</em>-amplified tumors, particularly in high-grade DDLPS. Its variable functional impact across models highlights the complexity of the 12q13–15 amplicon and supports further investigation into <em>YEATS4</em> as a potential molecular marker and therapeutic target in LPS.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 10-15"},"PeriodicalIF":2.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865487","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 : 2025-08-12DOI: 10.1016/j.cancergen.2025.08.003
Leila Jahangiri
Breast cancer is a significant health problem across the world, and a better understanding of the cellular and molecular properties of the microenvironment in which the breast cancer cells reside is paramount. Breast cancer cells exhibit an intricate bilateral interaction with the tumour microenvironment, which can contribute to tumour progression. This tumour microenvironment comprises a host of proteins, proteoglycans, glycoproteins, signalling molecules, stromal and immune cells, in addition to extracellular vesicles. Extracellular vesicles encompass a range of vesicles that facilitate cell-to-cell communication and signal relay. Examples of these extracellular vesicles include microvesicles, exosomes and apoptotic bodies. Other categorisations divide extracellular vesicles into exosomes and ectosomes based on their biogenesis. The content of extracellular vesicles can be DNA, RNA, miRNA, proteins, glycans and lipids. This content can affect the tumour microenvironment and tumour metastasis and progression. As such, this review article aims to understand the content of extracellular vesicles and those that promote invasion and metastasis in the context of the tumour microenvironment. The implications of these extracellular vesicles for breast cancer therapeutics will be addressed. Finally, the genes indicated in these processes will be discussed.
{"title":"The impact of extracellular vesicles on breast cancer metastasis and therapeutics: genetic considerations","authors":"Leila Jahangiri","doi":"10.1016/j.cancergen.2025.08.003","DOIUrl":"10.1016/j.cancergen.2025.08.003","url":null,"abstract":"<div><div>Breast cancer is a significant health problem across the world, and a better understanding of the cellular and molecular properties of the microenvironment in which the breast cancer cells reside is paramount. Breast cancer cells exhibit an intricate bilateral interaction with the tumour microenvironment, which can contribute to tumour progression. This tumour microenvironment comprises a host of proteins, proteoglycans, glycoproteins, signalling molecules, stromal and immune cells, in addition to extracellular vesicles. Extracellular vesicles encompass a range of vesicles that facilitate cell-to-cell communication and signal relay. Examples of these extracellular vesicles include microvesicles, exosomes and apoptotic bodies. Other categorisations divide extracellular vesicles into exosomes and ectosomes based on their biogenesis. The content of extracellular vesicles can be DNA, RNA, miRNA, proteins, glycans and lipids. This content can affect the tumour microenvironment and tumour metastasis and progression. As such, this review article aims to understand the content of extracellular vesicles and those that promote invasion and metastasis in the context of the tumour microenvironment. The implications of these extracellular vesicles for breast cancer therapeutics will be addressed. Finally, the genes indicated in these processes will be discussed.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 1-9"},"PeriodicalIF":2.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841528","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 : 2025-08-11DOI: 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":"2025-08-11","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 : 2025-07-26DOI: 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":"2025-07-26","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}
Universal cancer screening based on methylation analysis of circulating cell-free DNA (cfDNA) enables multi-organ cancer detection, thereby reducing all-cause mortality and preventing cancer misdiagnosed by guideline-based cancer-specific screening. This study aims to establish a gene methylation panel for blood-based multi-cancer early detection.
Materials and methods
Bioinformatics analysis and in-house DNA sequencing of various human cancer cell lines and blood from healthy persons were carried out to identify candidate pan-cancer methylation sites. Methylation-sensitive restriction enzymes-quantitative PCR (MSRE-qPCR) was then used for DNA methylation analysis. Blood cfDNA from 103 patients with diverse cancer types and 40 healthy subjects was extracted for methylation analysis.
Results
By bioinformatics analysis and in-house DNA sequencing, we identified two candidates pan-cancer methylation sites, HIST1H4F and CDO1. A long stretch of methylation was found on the promoters of HIST1H4F and CDO1 across various cancer cell lines, while these genomic regions are unmethylated in healthy persons. When tested with clinical samples, the detection sensitivity and specificity of our gene methylation panel in detecting pan-cancer were 47.57 % and 90.00 %, respectively. When analyzed by cancer subtypes, the detection sensitivity was the highest in lung cancer (76.92 %), followed by colorectal cancer (63.64 %) and gastric cancer (50.00 %).
Conclusions
Our newly established gene methylation panel provides an alternative assay for multi-cancer screening tests. As no bisulfite conversion and invasive procedures are required, it can accelerate cancer diagnosis and streamline the operation for pan-cancer screening.
{"title":"Pan-cancer methylation analysis of circulating cell-free DNA","authors":"Wenjiao Dong , Cia-Hin Lau , Jiaqi Li , Zhihao Huang , Jiahui Li , Weidong Wu , Xiaoqing Chen , Yumei Huang , Xiaojun Huang , Meijing Xu , Haibao Zhu , Yuanlin Ding","doi":"10.1016/j.cancergen.2025.07.014","DOIUrl":"10.1016/j.cancergen.2025.07.014","url":null,"abstract":"<div><h3>Background</h3><div>Universal cancer screening based on methylation analysis of circulating cell-free DNA (cfDNA) enables multi-organ cancer detection, thereby reducing all-cause mortality and preventing cancer misdiagnosed by guideline-based cancer-specific screening. This study aims to establish a gene methylation panel for blood-based multi-cancer early detection.</div></div><div><h3>Materials and methods</h3><div>Bioinformatics analysis and in-house DNA sequencing of various human cancer cell lines and blood from healthy persons were carried out to identify candidate pan-cancer methylation sites. Methylation-sensitive restriction enzymes-quantitative PCR (MSRE-qPCR) was then used for DNA methylation analysis. Blood cfDNA from 103 patients with diverse cancer types and 40 healthy subjects was extracted for methylation analysis.</div></div><div><h3>Results</h3><div>By bioinformatics analysis and in-house DNA sequencing, we identified two candidates pan-cancer methylation sites, <em>HIST1H4F</em> and <em>CDO1</em>. A long stretch of methylation was found on the promoters of <em>HIST1H4F</em> and <em>CDO1</em> across various cancer cell lines, while these genomic regions are unmethylated in healthy persons. When tested with clinical samples, the detection sensitivity and specificity of our gene methylation panel in detecting pan-cancer were 47.57 % and 90.00 %, respectively. When analyzed by cancer subtypes, the detection sensitivity was the highest in lung cancer (76.92 %), followed by colorectal cancer (63.64 %) and gastric cancer (50.00 %).</div></div><div><h3>Conclusions</h3><div>Our newly established gene methylation panel provides an alternative assay for multi-cancer screening tests. As no bisulfite conversion and invasive procedures are required, it can accelerate cancer diagnosis and streamline the operation for pan-cancer screening.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 182-195"},"PeriodicalIF":2.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721987","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}
DICER1 syndrome is a tumor-predisposition disorder caused by a germline pathogenic variant in DICER1. Pathogenic variants of DICER1 are the monogenic cause of various tumors including pleuropulmonary blastoma (PPB), ovarian sex cord-stromal tumors, and multinodular goiters. We present a family with a novel DICER1 pathogenic variant c.5528–2del who presents with development of isolated thyroid goiters/follicular adenoma. A 44 year old female presents with a past medical history of total thyroidectomy along with her 14-year-old son with a past history of multinodular thyroid goiter confirmed as multifocal follicular adenoma with papillary architecture and her 12-year-old daughter with a past history of multinodular thyroid goiter confirmed as diffuse nodular thyroid hyperplasia. No additional DICER1 syndrome presentations were observed. A genetics panel revealed that the mother, the 14-year-old son, and the 12-year-old daughter share a heterozygous DICER1 c.5528–2del variant, which has not been previously reported. In addition to our direct clinical observations from this family, genetic analysis via in silico prediction models, segregation analysis, and ACMG classification support this variant to be pathogenic. Given the absence of other DICER1 syndrome manifestations through human genetics evidence, this variant may be specifically associated with isolated multinodular goiters/follicular adenoma. Our findings contribute to the expanding genotype-phenotype correlation in DICER1 syndrome, providing new insights into its variable clinical presentation. Since not all variants are identical, reporting of these observations will advance precision medicine and benefit future patients through more accurate diagnosis, prognosis and personalized management strategies.
{"title":"Isolated multinodular goiter and follicular adenoma associated with a novel germline DICER1 variant: A benign presentation","authors":"Joshua Chang , Rachel Rabenn , Aditi Parikh , Chen-Han Wilfred Wu","doi":"10.1016/j.cancergen.2025.07.013","DOIUrl":"10.1016/j.cancergen.2025.07.013","url":null,"abstract":"<div><div><em>DICER1</em> syndrome is a tumor-predisposition disorder caused by a germline pathogenic variant in <em>DICER1</em>. Pathogenic variants of <em>DICER1</em> are the monogenic cause of various tumors including pleuropulmonary blastoma (PPB), ovarian sex cord-stromal tumors, and multinodular goiters. We present a family with a novel <em>DICER1</em> pathogenic variant c.5528–2del who presents with development of isolated thyroid goiters/follicular adenoma. A 44 year old female presents with a past medical history of total thyroidectomy along with her 14-year-old son with a past history of multinodular thyroid goiter confirmed as multifocal follicular adenoma with papillary architecture and her 12-year-old daughter with a past history of multinodular thyroid goiter confirmed as diffuse nodular thyroid hyperplasia. No additional <em>DICER1</em> syndrome presentations were observed. A genetics panel revealed that the mother, the 14-year-old son, and the 12-year-old daughter share a heterozygous <em>DICER1</em> c.5528–2del variant, which has not been previously reported. In addition to our direct clinical observations from this family, genetic analysis via in silico prediction models, segregation analysis, and ACMG classification support this variant to be pathogenic. Given the absence of other <em>DICER1</em> syndrome manifestations through human genetics evidence, this variant may be specifically associated with isolated multinodular goiters/follicular adenoma. Our findings contribute to the expanding genotype-phenotype correlation in <em>DICER1</em> syndrome, providing new insights into its variable clinical presentation. Since not all variants are identical, reporting of these observations will advance precision medicine and benefit future patients through more accurate diagnosis, prognosis and personalized management strategies.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 200-204"},"PeriodicalIF":2.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724597","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}
Development of multiple distinct, synchronous cancer types in a pediatric patient is very rare and should raise suspicion for an underlying genetic predisposition to cancer.
Case presentation
We present a previously healthy seven-year-old male who was diagnosed with diffuse large B cell lymphoma after a ruptured appendicitis. During the same hospitalization, he was diagnosed with a high-grade glioma. He underwent subsequent genetic testing, which showed compound heterozygosity for PMS2. He was ultimately diagnosed with Mismatch Repair Cancer Syndrome-4, a subtype of Constitutional Mismatch Repair Deficiency syndrome. His newly discovered cancer predisposition syndrome led to multiple additional family members receiving the same diagnosis, which was especially important in a sibling with leukemia who received hematopoietic stem cell transplantation from an unaffected sibling donor.
Conclusion
While rare, cancer predisposition syndromes should be suspected in pediatric patients presenting with two or more synchronous, distinct cancer types.
{"title":"Mismatch Repair Cancer Syndrome presenting as synchronous high-grade glioma and diffuse large B cell lymphoma in a pediatric patient","authors":"Margaret Massett , Nicole Kendel , Abdulrazak Alali , Erin Wright","doi":"10.1016/j.cancergen.2025.07.012","DOIUrl":"10.1016/j.cancergen.2025.07.012","url":null,"abstract":"<div><h3>Background</h3><div>Development of multiple distinct, synchronous cancer types in a pediatric patient is very rare and should raise suspicion for an underlying genetic predisposition to cancer.</div></div><div><h3>Case presentation</h3><div>We present a previously healthy seven-year-old male who was diagnosed with diffuse large B cell lymphoma after a ruptured appendicitis. During the same hospitalization, he was diagnosed with a high-grade glioma. He underwent subsequent genetic testing, which showed compound heterozygosity for <em>PMS2</em>. He was ultimately diagnosed with Mismatch Repair Cancer Syndrome-4, a subtype of Constitutional Mismatch Repair Deficiency syndrome. His newly discovered cancer predisposition syndrome led to multiple additional family members receiving the same diagnosis, which was especially important in a sibling with leukemia who received hematopoietic stem cell transplantation from an unaffected sibling donor.</div></div><div><h3>Conclusion</h3><div>While rare, cancer predisposition syndromes should be suspected in pediatric patients presenting with two or more synchronous, distinct cancer types.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 205-207"},"PeriodicalIF":2.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724598","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 : 2025-07-19DOI: 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":"2025-07-19","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}
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