NPJ Precision Oncology最新文献_第2页

Comprehensive analysis of targetable mutations and tumor microenvironment in urachal cancer.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-11 DOI: 10.1038/s41698-024-00795-4

David J Benjamin, Tolulope T Adeyelu, Andrew Elliott, Sourat Darabi, Thomas Lee, Rana R McKay, Matthew J Oberley, Arash Rezazadeh Kalebasty

{"title":"Comprehensive analysis of targetable mutations and tumor microenvironment in urachal cancer.","authors":"David J Benjamin, Tolulope T Adeyelu, Andrew Elliott, Sourat Darabi, Thomas Lee, Rana R McKay, Matthew J Oberley, Arash Rezazadeh Kalebasty","doi":"10.1038/s41698-024-00795-4","DOIUrl":"10.1038/s41698-024-00795-4","url":null,"abstract":"Urachal cancer, a rare malignancy, generally presents in the clinical setting with advanced stages of disease. Systemic treatment with chemotherapy is generally utilized in this setting. However, there remains a paucity of data on the effectiveness of immune checkpoint inhibitors or targeted therapies for urachal cancer. We analyzed the genomic profile of urachal cancer in order to identify potentially targetable mutations and evaluate the tumor microenvironment. 42 urachal samples were retrospectively analyzed. Our results showed that TP53, GNAS and KRAS mutations were common in urachal cancer with increased prevalence of TP53 mutation in urachal cohorts without MAPK-alterations. The tumor microenvironment demonstrated increased NK cells in MAPK-altered urachal cancer. Finally, we show that urachal cancer shares genomic and transcriptomic similarity with colorectal cancer compared to bladder cancer. This study provides new insights into the molecular profiles of urachal tumor samples and possibility of association with colorectal cancer that might guide future clinical trial design.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":"9 1","pages":"12"},"PeriodicalIF":6.8,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Accurate identification of primary site in tumors of unknown origin (TUO) using DNA methylation.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-10 DOI: 10.1038/s41698-025-00805-z

Drew Duckett, Erica R Vormittag-Nocito, Pouya Jamshidi, Madina Sukhanova, Stephanie Parker, Daniel J Brat, Lawrence J Jennings, Lucas Santana-Santos

{"title":"Accurate identification of primary site in tumors of unknown origin (TUO) using DNA methylation.","authors":"Drew Duckett, Erica R Vormittag-Nocito, Pouya Jamshidi, Madina Sukhanova, Stephanie Parker, Daniel J Brat, Lawrence J Jennings, Lucas Santana-Santos","doi":"10.1038/s41698-025-00805-z","DOIUrl":"10.1038/s41698-025-00805-z","url":null,"abstract":"Tumors of unknown origin (TUO) generally result in poor patient survival and are clinically difficult to address. Identification of the site of origin in TUO patients is paramount to their improved treatment and survival but is difficult to obtain with current methods. Here, we develop a random forest machine learning TUO methylation classifier using a large number of primary and metastatic tumor samples. Our classifier achieves high accuracy in primary site identification when applied to both publicly available and internal validation samples, with 97% of samples classified correctly and 85% receiving high probability scores (≥0.9). Moreover, by employing pathologist expertise and t-SNE visualization, the TUO classifier can assign samples to 46 different sites of origin/disease classes. This strategy also revealed multiple classes of yet unknown significance for future exploration. Overall, the presented TUO classifier represents a significant step forward in the diagnosis of TUO tumors.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":"9 1","pages":"8"},"PeriodicalIF":6.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11718252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Translational and clinical comparison of whole genome and transcriptome to panel sequencing in precision oncology.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-10 DOI: 10.1038/s41698-024-00788-3

Irina A Kerle, Thomas Gross, Anja Kögler, Jonas S Arnold, Maximilian Werner, Jan-Niklas Eckardt, Elena E Möhrmann, Marie Arlt, Barbara Hutter, Jennifer Hüllein, Daniela Richter, Martin M K Schneider, Mario Hlevnjak, Lino Möhrmann, Dorothea Hanf, Christoph E Heilig, Simon Kreutzfeldt, Maria-Veronica Teleanu, Evelin Schröck, Daniel Hübschmann, Peter Horak, Christoph Heining, Stefan Fröhling, Hanno Glimm

{"title":"Translational and clinical comparison of whole genome and transcriptome to panel sequencing in precision oncology.","authors":"Irina A Kerle, Thomas Gross, Anja Kögler, Jonas S Arnold, Maximilian Werner, Jan-Niklas Eckardt, Elena E Möhrmann, Marie Arlt, Barbara Hutter, Jennifer Hüllein, Daniela Richter, Martin M K Schneider, Mario Hlevnjak, Lino Möhrmann, Dorothea Hanf, Christoph E Heilig, Simon Kreutzfeldt, Maria-Veronica Teleanu, Evelin Schröck, Daniel Hübschmann, Peter Horak, Christoph Heining, Stefan Fröhling, Hanno Glimm","doi":"10.1038/s41698-024-00788-3","DOIUrl":"10.1038/s41698-024-00788-3","url":null,"abstract":"Precision oncology offers new cancer treatment options, yet sequencing methods vary in type and scope. In this study, we compared whole-exome/whole-genome (WES/WGS) and transcriptome sequencing (TS) with broad panel sequencing by resequencing the same tumor DNA and RNA as well as normal tissue DNA for germline assessment, from 20 patients with rare or advanced tumors, who were originally sequenced by WES/WGS ± TS within the DKFZ/NCT/DKTK MASTER program from 2015 to 2020. Molecular analyses resulted in a median number of 2.5 (gene panel) to 3.5 (WES/WGS ± TS) treatment recommendations per patient. Our results showed that approximately half of the therapy recommendations (TRs) of both sequencing programs were identical, while approximately one-third of the TRs in WES/WGS ± TS relied on biomarkers not covered by the panel. Eight of 10 molecularly informed therapy implementations were supported by the panel, the remaining two were based on biomarkers absent from the panel, highlighting the potential additional clinical benefit of WGS and TS.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":"9 1","pages":"9"},"PeriodicalIF":6.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-10 DOI: 10.1038/s41698-024-00792-7

Tong Chen, Huiyao Chen, Mingyang Xia, Yunfei Liao, Hao Li, Xinran Dong, Yifeng Lin, Wenhao Zhou

{"title":"In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma.","authors":"Tong Chen, Huiyao Chen, Mingyang Xia, Yunfei Liao, Hao Li, Xinran Dong, Yifeng Lin, Wenhao Zhou","doi":"10.1038/s41698-024-00792-7","DOIUrl":"10.1038/s41698-024-00792-7","url":null,"abstract":"Medulloblastoma (MB) is an aggressive pediatric brain tumor with distinct molecular heterogeneity. Identifying subtype-specific signatures within Group 3 and Group 4 remains challenging due to shared cytogenetic alterations and limitations of conventional differential gene expression analysis. To uncover the underlying molecular signatures and hidden regulators, we used the Cavalli transcriptomic profile of 470 Group 3 and Group 4 MB patients to reconstruct subtype-specific regulatory networks. A strong upregulation of the ribosomal pathway was linked to MYC amplification in Group 3, with Nucleophosmin 1 (NPM1) emerging as a key regulator. NPM1 upregulation defined a subset of Group3 and Group4 patients with poor prognosis. Inhibition of NPM1 led to apoptosis, reduced c-Myc stability, and impaired translation in MYC-amplified Group 3 MB cells. Together, our findings highlight NPM1 as a promising therapeutic target and provide new insights into the regulatory mechanisms in MB.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":"9 1","pages":"10"},"PeriodicalIF":6.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author Correction: Predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-09 DOI: 10.1038/s41698-024-00796-3

Sushant Patkar, Alex Chen, Alina Basnet, Amber Bixby, Rahul Rajendran, Rachel Chernet, Susan Faso, Prashanth Ashok Kumar, Devashish Desai, Ola El-Zammar, Christopher Curtiss, Saverio J Carello, Michel R Nasr, Peter Choyke, Stephanie Harmon, Baris Turkbey, Tamara Jamaspishvili

引用次数: 0

Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-09 DOI: 10.1038/s41698-024-00776-7

Edmond O'Donnell, Maria Muñoz, Ryan Davis, Jessica Bergonio, R Lor Randall, Clifford Tepper, Janai Carr-Ascher

{"title":"Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target.","authors":"Edmond O'Donnell, Maria Muñoz, Ryan Davis, Jessica Bergonio, R Lor Randall, Clifford Tepper, Janai Carr-Ascher","doi":"10.1038/s41698-024-00776-7","DOIUrl":"10.1038/s41698-024-00776-7","url":null,"abstract":"High-grade soft tissue sarcomas (STS) are a heterogeneous and aggressive set of cancers. Failure to respond anthracycline chemotherapy, standard first-line treatment, is associated with poor outcomes. We investigated the contribution of STS cancer stem cells (STS-CSCs) to doxorubicin resistance. We identified a positive correlation between CSC abundance and doxorubicin IC50. Utilizing patient-derived samples from five sarcoma subtypes we investigated if a common genetic signature across STS-CSCs could be targeted. We identified Enhancer of Zeste homolog 2 (EZH2), a member of the polycomb repressive complex 2 (PRC2) responsible for H3K27 methylation as being enriched in CSCs. EZH2 activity and a shared epigenetic profile was observed across subtypes and targeting of EZH2 ablated the STS-CSC population. Treatment of doxorubicin-resistant cell lines with tazemetostat resulted in a decrease in the STS-CSC population. These data confirm the presence of shared genetic programs across distinct subtypes of CSC-STS that can be therapeutically targeted.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":"9 1","pages":"7"},"PeriodicalIF":6.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Longitudinal genomic profiling using liquid biopsies in metastatic nonsquamous NSCLC following first line immunotherapy.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-08 DOI: 10.1038/s41698-024-00797-2

Haolun Ding, Min Yuan, Yaning Yang, Xu Steven Xu

{"title":"Longitudinal genomic profiling using liquid biopsies in metastatic nonsquamous NSCLC following first line immunotherapy.","authors":"Haolun Ding, Min Yuan, Yaning Yang, Xu Steven Xu","doi":"10.1038/s41698-024-00797-2","DOIUrl":"10.1038/s41698-024-00797-2","url":null,"abstract":"Tumor genomic profiling is often limited to one or two timepoints due to the invasiveness of tissue biopsies, but longitudinal profiling may provide deeper clinical insights. Using ctDNA data from IMpower150 study, we examined genetic changes in metastatic non-squamous NSCLC post-first-line immunotherapy. Mutations were most frequently detected in TP53, KRAS, SPTA1, FAT3, and LRP1B at baseline and during treatment. Mutation levels rose prior to radiographic progression in most progressing patients, with specific mutations (SPTA1, STK11, KEAP1, SMARCA4, TBX3, CDH2, and MLL3) significantly enriched in those with progression or nondurable response. However, ctDNA's role in detecting hyperprogression and pseudoprogression remains uncertain. STK11, SMARCA4, KRAS, SLT2, and KEAP1 mutations showed the strongest correlation with poorer overall survival, while SMARCA4, STK11, SPTA1, TBX3, and KEAP1 mutations correlated with shorter progression-free survival. Overall, longitudinal liquid biopsy profiling provided valuable insights into lung cancer biology post-immunotherapy, potentially guiding personalized therapies and future drug development.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":"9 1","pages":"5"},"PeriodicalIF":6.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-06 DOI: 10.1038/s41698-024-00793-6

Kohei Maruyama, Yuki Shimizu, Yumi Nomura, Tomoko Oh-Hara, Yuki Takahashi, Satoshi Nagayama, Naoya Fujita, Ryohei Katayama

{"title":"Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization.","authors":"Kohei Maruyama, Yuki Shimizu, Yumi Nomura, Tomoko Oh-Hara, Yuki Takahashi, Satoshi Nagayama, Naoya Fujita, Ryohei Katayama","doi":"10.1038/s41698-024-00793-6","DOIUrl":"https://doi.org/10.1038/s41698-024-00793-6","url":null,"abstract":"KRAS-specific inhibitors have shown promising antitumor effects, especially in non-small cell lung cancer, but limited efficacy in colorectal cancer (CRC) patients. Recent studies have shown that EGFR-mediated adaptive feedback mediates primary resistance to KRAS inhibitors, but the other resistance mechanisms have not been identified. In this study, we investigated intrinsic resistance mechanisms to KRAS inhibitors using patient-derived CRC cells (CRC-PDCs). We found that KRAS-mutated CRC-PDCs can be divided into at least an EGFR pathway-activated group and a PI3K/AKT pathway-activated group. In the latter group, PDCs with PIK3CA major mutation showed high sensitivity to PI3K+mTOR co-inhibition, and a PDC with Her2 amplification with PIK3CA minor mutation showed PI3K-AKT pathway dependency but lost KRAS-MAPK dependency by cytoplasmic localization of KRAS. In the PDC, Her2 knockout restored KRAS plasma membrane localization and KRAS inhibitor sensitivity. The current study provides insight into the mechanisms of primary resistance to KRAS inhibitors, including aberrant KRAS localization.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":"9 1","pages":"4"},"PeriodicalIF":6.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11704227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cyclin E1/CDK2 activation defines a key vulnerability to WEE1 kinase inhibition in gynecological cancers.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-04 DOI: 10.1038/s41698-024-00787-4

Daehwan Kim, Heekyung Chung, Wen Liu, Kangjin Jeong, Tugba Y Ozmen, Furkan Ozmen, Matthew J Rames, Sangyub Kim, Xiao Guo, Nathan Jameson, Petrus R de Jong, Steven Yea, Laurie Harford, Jiali Li, Cara A Mathews, Deborah B Doroshow, Vincent J Charles, Doris Kim, Kimberlee Fischer, Ahmed A Samatar, Adrian Jubb, Kevin D Bunker, Kimberly Blackwell, Fiona Simpkins, Funda Meric-Bernstam, Gordon B Mills, Olivier Harismendy, Jianhui Ma, Mark R Lackner

{"title":"Cyclin E1/CDK2 activation defines a key vulnerability to WEE1 kinase inhibition in gynecological cancers.","authors":"Daehwan Kim, Heekyung Chung, Wen Liu, Kangjin Jeong, Tugba Y Ozmen, Furkan Ozmen, Matthew J Rames, Sangyub Kim, Xiao Guo, Nathan Jameson, Petrus R de Jong, Steven Yea, Laurie Harford, Jiali Li, Cara A Mathews, Deborah B Doroshow, Vincent J Charles, Doris Kim, Kimberlee Fischer, Ahmed A Samatar, Adrian Jubb, Kevin D Bunker, Kimberly Blackwell, Fiona Simpkins, Funda Meric-Bernstam, Gordon B Mills, Olivier Harismendy, Jianhui Ma, Mark R Lackner","doi":"10.1038/s41698-024-00787-4","DOIUrl":"https://doi.org/10.1038/s41698-024-00787-4","url":null,"abstract":"Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib. We found that ovarian cancer cell lines with high levels of endogenous Cyclin E1 expression or forced overexpression were exquisitely sensitive to azenosertib and these results extended to in vivo models of ovarian and uterine serous carcinoma. Models with high Cyclin E1 expression showed higher baseline levels of replication stress and enhanced cellular responses to azenosertib treatment. We found azenosertib synergized with different classes of chemotherapy and described distinct underlying mechanisms. Finally, we provided early evidence from an ongoing phase I study demonstrating the clinical activity of monotherapy azenosertib in patients with Cyclin E1/CDK2-activated ovarian and uterine serous carcinomas.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":"9 1","pages":"3"},"PeriodicalIF":6.8,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A review of deep learning for brain tumor analysis in MRI.

IF 6.8 1区医学

NPJ Precision Oncology Pub Date : 2025-01-03 DOI: 10.1038/s41698-024-00789-2

Felix J Dorfner, Jay B Patel, Jayashree Kalpathy-Cramer, Elizabeth R Gerstner, Christopher P Bridge

引用次数: 0