{"title":"Serial single-cell RNA sequencing unveils drug resistance and metastatic traits in stage IV breast cancer","authors":"Kazutaka Otsuji, Yoko Takahashi, Tomo Osako, Takayuki Kobayashi, Toshimi Takano, Sumito Saeki, Liying Yang, Satoko Baba, Kohei Kumegawa, Hiromu Suzuki, Tetsuo Noda, Kengo Takeuchi, Shinji Ohno, Takayuki Ueno, Reo Maruyama","doi":"10.1038/s41698-024-00723-6","DOIUrl":"10.1038/s41698-024-00723-6","url":null,"abstract":"Metastasis is a complex process that remains poorly understood at the molecular levels. We profiled single-cell transcriptomic, genomic, and epigenomic changes associated with cancer cell progression, chemotherapy resistance, and metastasis from a Stage IV breast cancer patient. Pretreatment- and posttreatment-specimens from the primary tumor and distant metastases were collected for single-cell RNA sequencing and subsequent cell clustering, copy number variation (CNV) estimation, transcriptomic factor estimation, and pseudotime analyses. CNV analysis revealed that a small population of pretreatment cancer cells resisted chemotherapy and expanded. New clones including Metastatic Precursor Cells (MPCs), emerged in the posttreatment primary tumors in CNV similar to metastatic cells. MPCs exhibited expression profiles indicative of epithelial–mesenchymal transition. Comparison of MPCs with metastatic cancer cells also revealed dynamic changes in transcription factors and calcitonin pathway gene expression. These findings demonstrate the utility of single-patient clinical sample analysis for understanding tumor drug resistance, regrowth, and metastasis.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-15"},"PeriodicalIF":6.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372446","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}
Jinwei Li, Shengrong Long, Yang Zhang, Wei Wei, Shuangqi Yu, Quan Liu, Xuhui Hui, Xiang Li, Yinyan Wang
{"title":"Molecular mechanisms and diagnostic model of glioma-related epilepsy","authors":"Jinwei Li, Shengrong Long, Yang Zhang, Wei Wei, Shuangqi Yu, Quan Liu, Xuhui Hui, Xiang Li, Yinyan Wang","doi":"10.1038/s41698-024-00721-8","DOIUrl":"10.1038/s41698-024-00721-8","url":null,"abstract":"Epilepsy is one of the most common symptoms in patients with gliomas; however, the mechanisms underlying its interaction are not yet clear. Moreover, epidemiological studies have not accurately identified patients with glioma-related epilepsy (GRE), and there is an urgent need to identify the molecular mechanisms and markers of its occurrence. We analyzed the demographics, transcriptome, whole-genome, and methylation sequences of 997 patients with glioma, to determine the genetic differences between glioma and GRE patients and to determine the upregulated molecular function, cellular composition, biological processes involved, signaling pathways, and immune cell infiltration. Twelve machine learning algorithms were refined into 113 combinatorial algorithms for building diagnostic recognition models. A total of 342 patients with GRE were identified with WHO grade 2 (174), grade 3 (107), and grade 4 (61). The mean age of the patients with GREs, with IDH mutations (n = 217 [63%]) and 1p19q non-codeletion (n = 169 [49%]), was 38 years old. GRE molecular functions were mainly passive transmembrane transporter protein activity, ion channel activity, and gated channel activity. Cellular components were enriched in the cation-channel and transmembrane transporter complexes. Cerebral cortical development regulates the membrane potential and synaptic organization as major biological processes. The signaling pathways mainly focused on cholinergic, GABAergic, and glutamatergic synapses. LASSO, combined with Random Forest, was the best diagnostic model and identified nine diagnostic genes. This study provides new insights and future perspectives for resolving the molecular mechanisms of GRE.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-12"},"PeriodicalIF":6.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372444","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}
Christopher Godina, Michael N. Pollak, Helena Jernström
{"title":"Targeting IGF-IR improves neoadjuvant chemotherapy efficacy in breast cancers with low IGFBP7 expression","authors":"Christopher Godina, Michael N. Pollak, Helena Jernström","doi":"10.1038/s41698-024-00712-9","DOIUrl":"10.1038/s41698-024-00712-9","url":null,"abstract":"There has been a long-standing interest in targeting the type 1 insulin-like growth factor receptor (IGF-1R) signaling system in breast cancer due to its key role in neoplastic proliferation and survival. However, no IGF-1R targeting agent has shown substantial clinical benefit in controlled phase 3 trials, and no biomarker has been shown to have clinical utility in the prediction of benefit from an IGF-1R targeting agent. IGFBP7 is an atypical insulin-like growth factor binding protein as it has a higher affinity for the IGF-1R than IGF ligands. We report that low IGFBP7 gene expression identifies a subset of breast cancers for which the addition of ganitumab, an anti-IGF-1R monoclonal antibody, to neoadjuvant chemotherapy, substantially improved the pathological complete response rate compared to neoadjuvant chemotherapy alone. The pCR rate in the chemotherapy plus ganitumab arm was 46.9% in patients in the lowest quartile of IGFBP7 expression, in contrast to only 5.6% in the highest quartile. Furthermore, high IGFBP7 expression predicted increased distant metastasis risk. If our findings are confirmed, decisions to halt the development of IGF-1R targeting drugs, which were based on disappointing results of prior trials that did not use predictive biomarkers, should be reviewed.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-11"},"PeriodicalIF":6.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372447","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}
Quynh T. Tran, Alex Breuer, Tong Lin, Ruth Tatevossian, Sariah J. Allen, Michael Clay, Larissa V. Furtado, Mark Chen, Dale Hedges, Tylman Michael, Giles Robinson, Paul Northcott, Amar Gajjar, Elizabeth Azzato, Sheila Shurtleff, David W. Ellison, Stanley Pounds, Brent A. Orr
{"title":"Comparison of DNA methylation based classification models for precision diagnostics of central nervous system tumors","authors":"Quynh T. Tran, Alex Breuer, Tong Lin, Ruth Tatevossian, Sariah J. Allen, Michael Clay, Larissa V. Furtado, Mark Chen, Dale Hedges, Tylman Michael, Giles Robinson, Paul Northcott, Amar Gajjar, Elizabeth Azzato, Sheila Shurtleff, David W. Ellison, Stanley Pounds, Brent A. Orr","doi":"10.1038/s41698-024-00718-3","DOIUrl":"10.1038/s41698-024-00718-3","url":null,"abstract":"As part of the advancement in therapeutic decision-making for brain tumor patients at St. Jude Children’s Research Hospital (SJCRH), we developed three robust classifiers, a deep learning neural network (NN), k-nearest neighbor (kNN), and random forest (RF), trained on a reference series DNA-methylation profiles to classify central nervous system (CNS) tumor types. The models’ performance was rigorously validated against 2054 samples from two independent cohorts. In addition to classic metrics of model performance, we compared the robustness of the three models to reduced tumor purity, a critical consideration in the clinical utility of such classifiers. Our findings revealed that the NN model exhibited the highest accuracy and maintained a balance between precision and recall. The NN model was the most resistant to drops in performance associated with a reduction in tumor purity, showing good performance until the purity fell below 50%. Through rigorous validation, our study emphasizes the potential of DNA-methylation-based deep learning methods to improve precision medicine for brain tumor classification in the clinical setting.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-12"},"PeriodicalIF":6.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365972","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}
Divya Sahu, Jeffrey Shi, Isaac Andres Segura Rueda, Ajay Chatrath, Anindya Dutta
{"title":"Development of a polygenic score predicting drug resistance and patient outcome in breast cancer","authors":"Divya Sahu, Jeffrey Shi, Isaac Andres Segura Rueda, Ajay Chatrath, Anindya Dutta","doi":"10.1038/s41698-024-00714-7","DOIUrl":"10.1038/s41698-024-00714-7","url":null,"abstract":"Gene expression profiles of hundreds of cancer cell-lines and the cell-lines’ response to drug treatment were analyzed to identify genes whose expression correlated with drug resistance. In the GDSC dataset of 809 cancer cell lines, expression of 36 genes were associated with drug resistance (increased IC50) to many anti-cancer drugs. This was validated in the CTRP dataset of 860 cell lines. A polygenic score derived from the correlation coefficients of the 36 genes in cancer cell lines, UAB36, predicted resistance of cell lines to Tamoxifen. Although the 36 genes were selected from cell line behaviors, UAB36 successfully predicted survival of breast cancer patients in three different cohorts of patients treated with Tamoxifen. UAB36 outperforms two existing predictive gene signatures and is a predictor of outcome of breast cancer patients independent of the known clinical co-variates that affect outcome. This approach should provide promising polygenic biomarkers for resistance in many cancer types against specific drugs.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-11"},"PeriodicalIF":6.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365973","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}
Hamza Bakhtiar, Marina N. Sharifi, Kyle T. Helzer, Yue Shi, Matthew L. Bootsma, Tianfu A. Shang, Matthew R. Chrostek, Tracy J. Berg, S. Carson Callahan, Viridiana Carreno, Grace C. Blitzer, Malinda T. West, Ruth M. O’Regan, Kari B. Wisinski, Martin Sjöström, Shuang G. Zhao
{"title":"A phenocopy signature of TP53 loss predicts response to chemotherapy","authors":"Hamza Bakhtiar, Marina N. Sharifi, Kyle T. Helzer, Yue Shi, Matthew L. Bootsma, Tianfu A. Shang, Matthew R. Chrostek, Tracy J. Berg, S. Carson Callahan, Viridiana Carreno, Grace C. Blitzer, Malinda T. West, Ruth M. O’Regan, Kari B. Wisinski, Martin Sjöström, Shuang G. Zhao","doi":"10.1038/s41698-024-00722-7","DOIUrl":"10.1038/s41698-024-00722-7","url":null,"abstract":"In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-10"},"PeriodicalIF":6.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365971","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}
Qi-Dong Xia, Jian-Xuan Sun, Zhi-Peng Yao, Jun-Lin Lu, Chen-Qian Liu, Jin-Zhou Xu, Ye An, Meng-Yao Xu, Si-Han Zhang, Xing-Yu Zhong, Na Zeng, Si-Yang Ma, Hao-Dong He, Heng-Long Hu, Jia Hu, Yi Lu, Bing Li, Yao-Bing Chen, Zheng Liu, Shao-Gang Wang
{"title":"The role of TERT C228T and KDM6A alterations and TME in NMIBC treated with BCG","authors":"Qi-Dong Xia, Jian-Xuan Sun, Zhi-Peng Yao, Jun-Lin Lu, Chen-Qian Liu, Jin-Zhou Xu, Ye An, Meng-Yao Xu, Si-Han Zhang, Xing-Yu Zhong, Na Zeng, Si-Yang Ma, Hao-Dong He, Heng-Long Hu, Jia Hu, Yi Lu, Bing Li, Yao-Bing Chen, Zheng Liu, Shao-Gang Wang","doi":"10.1038/s41698-024-00725-4","DOIUrl":"10.1038/s41698-024-00725-4","url":null,"abstract":"We aimed to investigate the genomic and tumor microenvironmental (TME) profiles in non-muscle invasive bladder cancer (NMIBC) and explore potential predictive markers for Bacillus Calmette–Guérin (BCG) treatment response in high-risk NMIBC patients (according to European Association of Urology (EAU) risk stratification). 40 patients with high-risk NMIBC (cTis-T1N0M0) who underwent en bloc resection followed by BCG instillation were retrospectively enrolled. Surgical samples were subjected to Next Generation Sequencing (NGS) and multiplex immunofluorescence (mIF) assay. Genomic profiling revealed high prevalences of alterations in TERT (55%), KDM6A (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%) and ARID1A (20%). TME analysis showed different proportions of macrophages, NK cells, T cells subsets in tumoral and stromal compartment. Multivariate analysis identified TERT C228T and alteration in KDM6A as two independent factors associated with inferior RFS. The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-13"},"PeriodicalIF":6.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00725-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360070","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}
Lingzhi Hong, Sonia Patel, Leylah M. Drusbosky, Yuanyuan Xiong, Rongrong Chen, Ruixuan Geng, Simon Heeke, Monique Nilsson, Jia Wu, John V. Heymach, Yingyi Wang, Jianjun Zhang, Xiuning Le
{"title":"Molecular landscape of ERBB2 alterations in 3000 advanced NSCLC patients","authors":"Lingzhi Hong, Sonia Patel, Leylah M. Drusbosky, Yuanyuan Xiong, Rongrong Chen, Ruixuan Geng, Simon Heeke, Monique Nilsson, Jia Wu, John V. Heymach, Yingyi Wang, Jianjun Zhang, Xiuning Le","doi":"10.1038/s41698-024-00720-9","DOIUrl":"10.1038/s41698-024-00720-9","url":null,"abstract":"ERBB2 (HER2) represents a newly recognized actionable oncogenic driver in non-small cell lung cancer (NSCLC), with approved targeted therapy available. Understanding the landscape of ERBB2 alterations and co-occurring mutations is essential for guiding treatment decisions. We conducted an analysis involving 3000 NSCLC patients with all types of ERBB2 alterations, drawn from two extensive retrospective cohorts: 1281 from Geneplus (Chinese) and 1719 from Guardant360 (the United States, US). The incidence of all types of ERBB2 alterations was found to be 5.6% in the Chinese group and 5.2% in the US group. In both cohorts, among oncogenic alterations of ERBB2, exon 20 insertion Y772_A775dupYVMA was the most frequent alteration (58% vs 41.6% in the Chinese vs the US), followed by G776delinsVC/LC/VV/IC (10.7% vs 9.7%), and S310X (10.5% vs 15.4%). EGFR ex20 insertions were identified in the A767-V774 region, whereas ERBB2 ex20 insertions were observed in the Y772-P780 region. Notably, EGFR ex20 insertions exhibited greater insertion diversity. Clinical characteristics of EGFR and ERBB2 ex20 NSCLC were similar, characterized by low tumor mutation burden (TMB), a predominant never-smoker population, and a majority of lung adenocarcinoma cases.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-11"},"PeriodicalIF":6.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361797","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}
Jingyuan Wang, Joanne Xiu, Francesca Battaglin, Hiroyuki Arai, Shivani Soni, Wu Zhang, Richard M. Goldberg, Philip A. Philip, Andreas Seeber, Jimmy J. Hwang, Anthony F. Shields, John L. Marshall, Igor Astaturov, Tianshu Liu, A. Craig Lockhart, W. Michael Korn, Lin Shen, Heinz-Josef Lenz
{"title":"Large-scale analysis of CDH1 mutations defines a distinctive molecular subset with treatment implications in gastric cancer","authors":"Jingyuan Wang, Joanne Xiu, Francesca Battaglin, Hiroyuki Arai, Shivani Soni, Wu Zhang, Richard M. Goldberg, Philip A. Philip, Andreas Seeber, Jimmy J. Hwang, Anthony F. Shields, John L. Marshall, Igor Astaturov, Tianshu Liu, A. Craig Lockhart, W. Michael Korn, Lin Shen, Heinz-Josef Lenz","doi":"10.1038/s41698-024-00694-8","DOIUrl":"10.1038/s41698-024-00694-8","url":null,"abstract":"Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.7% (155 of 1596). CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score ≥1) than CDH1-wildtype (WT) GC (56.7% vs. 73.3%, p < 0.05). Compared to CDH1-WT GC, mutations of ARID1A, WRN, POT1, CDK12, and FANCC were significantly higher, while TP53 and APC were significantly lower in CDH1-MT GC (p < 0.05); The rates of KRAS and HER2 amplifications were significantly lower, while CRKL and IGF1R amplifications were significantly higher in CDH1-MT GC, compared to CDH1-WT GC (p < 0.05). Frequently altered genes in CDH1-MT GC were especially enriched in DNA damage repair and cell cycle checkpoint pathways. Inhibition of E-cadherin sensitized GC cell lines to PARP and Wee1 inhibitors by disrupting DNA damage repair pathway and cell cycle checkpoint. This is the largest study to investigate the distinct genomic landscape of CDH1-MT GC. Our data indicated GC patients with CDH1 mutations could potentially benefit from agents targeting PARP and Wee1.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-10"},"PeriodicalIF":6.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00694-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329433","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}
Megan L. Ludwig, David Moline, Alec Horrmann, Ella Boytim, Gabrianne Larson, Ali T. Arafa, Masooma Sayeda, John R. Lozada, Hannah E. Bergom, Abderrahman Day, Sandhyarani Dasaraju, Scott M. Dehm, Paari Murugan, Justin Hwang, Justin M. Drake, Emmanuel S. Antonarakis
{"title":"Integrated multi-omics assessment of lineage plasticity in a prostate cancer patient with brain and dural metastases","authors":"Megan L. Ludwig, David Moline, Alec Horrmann, Ella Boytim, Gabrianne Larson, Ali T. Arafa, Masooma Sayeda, John R. Lozada, Hannah E. Bergom, Abderrahman Day, Sandhyarani Dasaraju, Scott M. Dehm, Paari Murugan, Justin Hwang, Justin M. Drake, Emmanuel S. Antonarakis","doi":"10.1038/s41698-024-00713-8","DOIUrl":"10.1038/s41698-024-00713-8","url":null,"abstract":"Metastases to the brain are rare in prostate cancer. Here, we describe a patient with two treatment-emergent metastatic lesions, one to the brain with neuroendocrine prostate cancer (NEPC) histology and one to the dural membrane of adenocarcinoma histology. We performed genomic, transcriptomic, and proteomic characterization of these lesions and the primary tumor to investigate molecular features promoting these metastases. The two metastatic lesions had high genomic similarity, including TP53 mutation and PTEN deletion, with the most striking difference being the additional loss of RB1 in the NEPC lesion. Interestingly, the dural lesion expressed both androgen receptor and neuroendocrine markers, suggesting amphicrine carcinoma (AMPC). When analyzing pioneer transcription factors, the AMPC lesion exhibited elevated FOXA1 activity while the brain NEPC lesion showed elevated HOXC10, NFYB, and OTX2 expression suggesting novel roles in NEPC formation or brain tropism. Our results highlight the utility of performing multi-omic characterization, especially in rare cancer subtypes.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-9"},"PeriodicalIF":6.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00713-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329434","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}
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