Genes, Chromosomes & Cancer最新文献

{"title":"Roles and interactions of tumor microenvironment components in medulloblastoma with implications for novel therapeutics","authors":"Hanjie Yang,&nbsp;Min Li,&nbsp;Yuhao Deng,&nbsp;Huantao Wen,&nbsp;Minjie Luo,&nbsp;Wangming Zhang","doi":"10.1002/gcc.23233","DOIUrl":"https://doi.org/10.1002/gcc.23233","url":null,"abstract":"<p>Medulloblastomas, the most common malignant pediatric brain tumors, can be classified into the wingless, sonic hedgehog (SHH), group 3, and group 4 subgroups. Among them, the SHH subgroup with the <i>TP53</i> mutation and group 3 generally present with the worst patient outcomes due to their high rates of recurrence and metastasis. A novel and effective treatment for refractory medulloblastomas is urgently needed. To date, the tumor microenvironment (TME) has been shown to influence tumor growth, recurrence, and metastasis through immunosuppression, angiogenesis, and chronic inflammation. Treatments targeting TME components have emerged as promising approaches to the treatment of solid tumors. In this review, we summarize progress in research on medulloblastoma microenvironment components and their interactions. We also discuss challenges and future research directions for TME-targeting medulloblastoma therapy.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma","authors":"Henry de Traux De Wardin,&nbsp;Joanna Cyrta,&nbsp;Josephine K. Dermawan,&nbsp;Delphine Guillemot,&nbsp;Daniel Orbach,&nbsp;Isabelle Aerts,&nbsp;Gaelle Pierron,&nbsp;Cristina R. Antonescu","doi":"10.1002/gcc.23232","DOIUrl":"https://doi.org/10.1002/gcc.23232","url":null,"abstract":"<p>The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as <i>PAX3</i>/<i>7::FOXO1</i> in alveolar RMS (ARMS) and fusions involving <i>VGLL2</i> or <i>NCOA2</i> in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel <i>FGFR1::ANK1</i> fusion, we reviewed our molecular files for cases harboring <i>FGFR1</i>-related fusions. One additional case with an <i>FGFR1::TACC1</i> fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in <i>TP53</i> or <i>DICER1</i> on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic <i>TP53</i> and <i>TET2</i> mutations. Two additional RMS cases (one unclassified, one ERMS) with <i>FGFR1</i> overexpression but lacking <i>FGFR1</i> fusions were identified by RNA sequencing. These two cases and the <i>FGFR1::TACC1</i>-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent <i>FGFR1</i> fusions. However, it remains unclear if <i>FGFR1</i> fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140546657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adolescent presentation of FGFR1::EBF2 gene fusion mesenchymal tumor","authors":"Omar Jaber,&nbsp;Iyad Sultan","doi":"10.1002/gcc.23234","DOIUrl":"https://doi.org/10.1002/gcc.23234","url":null,"abstract":"","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140541070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spindle cell neoplasms with novel LTK fusion – Expanding the spectrum of kinase fusion-positive soft tissue tumors","authors":"Maximus C. F. Yeung,&nbsp;Josephine K. Dermawan,&nbsp;Anthony P. Y. Liu,&nbsp;Albert Y. L. Lam,&nbsp;Cristina R. Antonescu,&nbsp;Tony W. H. Shek","doi":"10.1002/gcc.23227","DOIUrl":"10.1002/gcc.23227","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Kinase fusion-positive soft tissue tumors represent an emerging, molecularly defined group of mesenchymal tumors with a wide morphologic spectrum and diverse activating kinases. Here, we present two cases of soft tissue tumors with novel <i>LTK</i> fusions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>Both cases presented as acral skin nodules (big toe and middle finger) in pediatric patients (17-year-old girl and 2-year-old boy). The tumors measured 2 and 3 cm in greatest dimension. Histologically, both cases exhibited bland-looking spindle cells infiltrating adipose tissue and accompanied by collagenous stroma. One case additionally displayed perivascular hyalinization and band-like stromal collagen. Both cases exhibited focal S100 staining, and one case had patchy coexpression of CD34. Targeted RNA-seq revealed the presence of novel in-frame <i>MYH9::LTK</i> and <i>MYH10::LTK</i> fusions, resulting in upregulation of <i>LTK</i> expression. Of interest, DNA methylation-based unsupervised clustering analysis in one case showed that the tumor clustered with dermatofibrosarcoma protuberans (DFSP). One tumor was excised with amputation with no local recurrence or distant metastasis at 18-month follow-up. The other case was initially marginally excised with local recurrence after one year, followed by wide local excision, with no evidence of disease at 10 years of follow-up.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This is the first reported case series of soft tissue tumors harboring <i>LTK</i> fusion, expanding the molecular landscape of soft tissue tumors driven by activating kinase fusions. Furthermore, studies involving a larger number of cases and integrated genomic analyses will be warranted to fully elucidate the pathogenesis and classification of these tumors.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.23227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140184159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation","authors":"Quitterie Fontanges,&nbsp;Paul Dubos,&nbsp;Tom Lesluyes,&nbsp;Yec'han Laizet,&nbsp;Valérie Velasco,&nbsp;Bárbara Meléndez,&nbsp;Nicky D'Haene,&nbsp;Esther Oliva,&nbsp;Robert H. Young,&nbsp;Laetitia Mayeur,&nbsp;Flora Rebier,&nbsp;Mélissa Alamé,&nbsp;Claire Larmonier,&nbsp;Mojgan Devouassoux-Shisheboran,&nbsp;Laurent Arnould,&nbsp;Isabelle Soubeyran,&nbsp;Camille Chakiba,&nbsp;Anne Floquet,&nbsp;Guillaume Babin,&nbsp;Frédéric Guyon,&nbsp;Eliane Mery,&nbsp;Sophie Le Guellec,&nbsp;Jean-Christophe Noël,&nbsp;Sabrina Croce,&nbsp;Frédéric Chibon","doi":"10.1002/gcc.23229","DOIUrl":"10.1002/gcc.23229","url":null,"abstract":"<p>A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, <i>p</i> &lt; 0.001). We described three groups: (1) a group with <i>FH</i> deletion (24/58) with low GI (mean GI: 11 vs. 22,4, <i>p</i> = 0.02), (2) a group with <i>TP53</i> deletion (17/58) with higher GI (22.4 vs. 11 <i>p</i> = 0.02), and (3) a group without genomic events on <i>FH</i> or <i>TP53</i> genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI &lt;10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI &gt;10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC<b>®</b> signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel MED15::ATF1 fusion in a pediatric melanoma with spitzoid features and aggressive presentation","authors":"Larissa V. Furtado,&nbsp;Maria Cardenas,&nbsp;Teresa Santiago,&nbsp;Robert E. Ruiz,&nbsp;Zonggao Shi,&nbsp;Alberto Pappo,&nbsp;Marija Kacar","doi":"10.1002/gcc.23230","DOIUrl":"10.1002/gcc.23230","url":null,"abstract":"<p>Childhood melanoma is a rare and biologically heterogeneous pediatric malignancy. The differential diagnosis of pediatric melanoma is usually broad, including a wide variety of spindle cell or epithelioid neoplasms. Different molecular alterations affecting the MAPK and PI3K/AKT/mTOR pathways, tumor suppressor genes, and telomerase reactivation have been implicated in melanoma tumorigenesis and progression. Here, we report a novel <i>MED15::ATF1</i> fusion in a pediatric melanoma with spitzoid features and an aggressive clinical course.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140068333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal origin and genomic diversity in Lynch syndrome-associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of MLH1 p.L582H","authors":"Kotaro Takahashi,&nbsp;Nozomi Yachida,&nbsp;Ryo Tamura,&nbsp;Sosuke Adachi,&nbsp;Shuhei Kondo,&nbsp;Tatsuya Abé,&nbsp;Hajime Umezu,&nbsp;Hiromi Nyuzuki,&nbsp;Shujiro Okuda,&nbsp;Hirofumi Nakaoka,&nbsp;Kosuke Yoshihara","doi":"10.1002/gcc.23231","DOIUrl":"10.1002/gcc.23231","url":null,"abstract":"<p>Lynch syndrome-associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27-year-old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, <i>MLH1</i> p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome-associated cancers in three generations of the family and identified consistent <i>MLH1</i> loss. Whole-exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy-neutral loss of heterozygosity (LOH) occurring at the <i>MLH1</i> position in all tumors. This indicated that the germline variant and the copy-neutral LOH led to biallelic loss of <i>MLH1</i> and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as <i>ARID1A</i> and <i>PIK3CA</i>. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.23231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140068332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epithelioid hemangioendothelioma (EHE) with WWTR1::TFE3 gene fusion, a novel fusion variant","authors":"Shuo Li,&nbsp;Josephine K. Dermawan,&nbsp;Caleb N. Seavey,&nbsp;Shuang Ma,&nbsp;Cristina R. Antonescu,&nbsp;Brian P. Rubin","doi":"10.1002/gcc.23226","DOIUrl":"10.1002/gcc.23226","url":null,"abstract":"<p>Epithelioid hemangioendothelioma (EHE) is a rare endothelial sarcoma associated with a high incidence of metastases and for which there are no standard treatment options. Based on disease-defining mutations, most EHEs are classified into two subtypes: <i>WWTR1::CAMTA1</i>-fused EHE or <i>YAP1::TFE3-</i>fused EHE. However, rare non-canonical fusions have been identified in clinical samples of EHE cases and are challenging to classify. In this study, we report the identification of a novel <i>WWTR1::TFE3</i> fusion variant in an EHE patient using targeted RNA sequencing. Histologically, the tumor exhibited hybrid morphological characteristics between <i>WWTR1::CAMTA1</i>-fused EHE and <i>YAP1::TFE3-</i>fused EHE. In addition to the driver fusion, there were six additional secondary mutations identified, including a loss-of-function <i>FANCA</i> mutation. Furthermore, in vitro studies were conducted to investigate the tumorigenic function of the WWTR1::TFE3 fusion protein in NIH3T3 cells and demonstrated that WWTR1::TFE3 promotes colony formation in soft agar. Finally, as the wild-type WWTR1 protein relies on binding the TEAD family of transcription factors to affect gene transcription, mutation of the WWTR1 domain of the fusion protein to inhibit such binding abrogates the transformative effect of WWTR1::TFE3. Overall, we describe a novel gene fusion in EHE with a hybrid histological appearance between the two major genetic subtypes of EHE. Further cases of this very rare subtype of EHE will need to be identified to fully elucidate the clinical and pathological characteristics of this unusual subtype of EHE.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.23226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD30 expression in an emerging group of mesenchymal spindle cell neoplasms with ALK fusion detected by flow cytometry and immunohistochemistry","authors":"Akari Iwakoshi,&nbsp;Hajime Kikui,&nbsp;Ryosuke Nakashima,&nbsp;Yuya Goto,&nbsp;Daisuke Ichikawa,&nbsp;Eiichi Sasaki,&nbsp;Masahiro Sekimizu,&nbsp;Hiroyoshi Hattori,&nbsp;Naoko Maeda","doi":"10.1002/gcc.23228","DOIUrl":"10.1002/gcc.23228","url":null,"abstract":"<p>An emerging group of spindle cell neoplasms harboring fusions involving <i>NTRK</i> or non-<i>NTRK</i> kinase genes often share characteristic S100 and/or CD34 expression; however, the diagnostic utility of immunohistochemical stains is not well established in this family owing to their lack of specificity. Recently, CD30 expression in spindle cell neoplasms with kinase gene fusions, such as <i>NTRK</i>, <i>BRAF</i>, <i>RAF1</i>, and <i>RET</i>, has been increasingly identified. We herein report a 10-year-old girl with high-grade spindle cell sarcoma of the neck. Prior to histopathological evaluation, flow cytometry (FCM) analysis and touch smear cytology of the tumor tissue revealed CD34+ and dimCD30+ spindle cell populations. Histopathologically, the case was characterized by monomorphic spindle-shaped cytomorphology with CD30, S100, and CD34 positivity and harbored close similarities with spindle cell neoplasms with <i>NTRK</i> or non-<i>NTRK</i> gene fusions. Subsequently, a comprehensive next-generation sequencing sarcoma panel identified a rare <i>PLEKHH2::ALK</i> fusion, and a diagnosis of <i>ALK</i>-rearranged spindle cell neoplasm was made. The patient showed significant tumor response to single-agent treatment with alectinib, an ALK-tyrosine kinase inhibitor. This case supports that CD30 is expressed in an <i>ALK</i>-rearranged mesenchymal neoplasm. The benefit of the early detection of CD30 expression by FCM for a prompt diagnosis and treatment is highlighted in the context of an aggressive clinical course. This case represents a learning experience regarding the need to the check the status of CD30 expression in these tumors and suggests the potential clinical benefits of CD30-targeted therapy.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric NCOA3-rearranged low-grade fibroblastic tumor with nuclear beta-catenin immunoreactivity","authors":"Faizan Malik,&nbsp;Larissa V. Furtado,&nbsp;Mohammad K. Eldomery,&nbsp;Zonggao Shi,&nbsp;Selene C. Koo","doi":"10.1002/gcc.23223","DOIUrl":"10.1002/gcc.23223","url":null,"abstract":"","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139716021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}