Cancer research communications最新文献

{"title":"Breast Cancer Risk Modification in Women with Pathogenic Variants in BRCA1, BRCA2, ATM, CHEK2, and PALB2.","authors":"Allison W Kurian, Elisha Hughes, Ryan Bernhisel, Eudora Hu, Eric C Polley, Siddhartha Yadav, Chunling Hu, Jennifer L Caswell-Jin, Esther M John, Aladdin H Shadyab, Rowan Chlebowski, Rami Nassir, Peter Kraft, Marcia L Stefanick, Fergus J Couch","doi":"10.1158/2767-9764.CRC-24-0592","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0592","url":null,"abstract":"<p><strong>Significance: </strong>There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":"5 5","pages":"783-791"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Subcutaneous Versus Orthotopic Implantations on Patient-Derived Xenograft Transcriptomic Profiles.","authors":"Yanghui Sheng, Zixuan Xie, Jingjing Wang, Xueying Yang, Mengtian Yao, Wubin Qian, Likun Zhang, Xiaobo Chen, Sheng Guo","doi":"10.1158/2767-9764.CRC-25-0008","DOIUrl":"10.1158/2767-9764.CRC-25-0008","url":null,"abstract":"<p><p>Patient-derived xenografts (PDX) are essential preclinical models, capturing the histologic and molecular features of human tumors. Subcutaneous (s.c.) and orthotopic (ortho) PDXs are widely used, but their comparative utility remains unclear, especially regarding tumor and stromal gene expression. This study analyzed 45 matched s.c. and ortho PDX models spanning five cancer types using bulk RNA sequencing. Tumor (human) gene expression was highly conserved between s.c. and ortho PDXs, with similar epithelial-mesenchymal transition, angiogenesis, and stemness scores. In contrast, stromal (mouse) gene expression varied by implantation site, with ortho models better reflecting native tissue environments. A conserved subset of stromal genes, consisting of histone and ribosomal protein genes and driven by tumor-intrinsic factors, exhibited stable expression patterns across implantation sites, indicating that tumor characteristics shape stromal responses. Differential expression analysis identified metastasis-related stromal genes in both PDX types, although no direct links to metastatic pathways were found. These findings highlight the stability of tumor-driven gene expression across implantation sites and reveal the impact of implantation location on stromal profiles, guiding model selection for future cancer research.</p><p><strong>Significance: </strong>This study reveals conserved tumor gene expression, distinct tumor microenvironment differences, and key stromal and metastasis-related genes in s.c. and ortho PDX models, providing valuable insights for oncology drug development.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"871-880"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeled Benefit of Individual Cancer Signal Origin Prediction for Multi-Cancer Early Detection.","authors":"Eric A Klein, Timothy R Church, Christina A Clarke, Earl Hubbell","doi":"10.1158/2767-9764.CRC-24-0351","DOIUrl":"10.1158/2767-9764.CRC-24-0351","url":null,"abstract":"<p><p>Multi-cancer early detection (MCED) tests may detect a broad spectrum of cancer types, including uncommon types that lack recommended screening. After a cancer signal is detected by an MCED test, some diagnostic process must definitively confirm the patient's cancer status. A commercially available blood-based MCED test detects a cancer signal and then predicts an anatomic location, a cancer signal origin (CSO), to guide the diagnostic process. We extended a preexisting model for MCED cancer screening, adding predicted CSO categories and a simple model of the diagnostic chain. We then predicted outcomes of the diagnostic chain for each predicted CSO and in populations with differing clinical risk factors. Typical positive predictive values were>40%, and using a minimal sufficient level of positive predictive value (>7%), (i) diagnostic workup based on any CSO was generally warranted, and (ii) continued workup for cancers in locations other than the CSO was justifiable. The benefit of prediction-directed workups was also observed via estimated clinical utility metrics, such as lives saved per diagnostic test, and remained applicable in populations with varying cancer risk, such as lung cancer prediction-directed workups in never-smokers. CSO predictions may enable most true-positive cases to be resolved by short and efficient diagnostic processes. The model predicted a large enough conditional benefit to warrant diagnostic workup based on any CSO prediction from an MCED test, assuming late-stage reduction by MCED leads to mortality reduction, which remains to be demonstrated.</p><p><strong>Significance: </strong>MCED tests may detect a signal from many cancers. Predicting an anatomic location from which the cancer signal may originate allows effective, usual diagnostic workup. In this study, we show that these predictions are beneficial to physicians choosing a diagnostic path, even for uncommon cancer types and among populations with differing cancer risks.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"814-824"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P4HA1 Mediates Hypoxia-Induced Invasion in Human Pancreatic Cancer Organoids.","authors":"Bernat Navarro-Serer, Maria F Wissler, Brandi K Glover, Michael G Lerner, Harsh H Oza, Vania Wang, Hidur Knutsdottir, Fatemeh Shojaeian, Kathleen Noller, Saravana Gowtham Baskaran, Sarah Hughes, Alana M Weaver, Daniel Wilentz, Oluwatobiloba Olayemi, Joel S Bader, Elana J Fertig, Daniele M Gilkes, Laura D Wood","doi":"10.1158/2767-9764.CRC-24-0025","DOIUrl":"10.1158/2767-9764.CRC-24-0025","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal prognosis. PDAC develops in a hypoxic environment in which cells adapt and activate processes to allow survival under low-oxygen conditions, some of which may enhance the ability of cancer cells to invade locally or metastasize distantly. Using human PDAC organoids, we determined that hypoxia consistently enhanced invasion across 11 patient-derived models. Using RNA sequencing of hypoxic invasive organoids (compared with matched invasive normoxic organoids from the same patients), we identified prolyl 4-hydroxylase subunit alpha 1 (P4HA1) as a potential regulator of PDAC invasion in hypoxia. Leveraging publicly available datasets from human tissue, we determined that P4HA1 is more highly expressed in PDAC compared with normal pancreatic tissue and that high P4HA1 expression correlates with poor patient prognosis. To further interrogate the role of P4HA1 in invasion of hypoxic patient-derived organoids, we quantified invasion in organoids modified to knockdown or overexpress P4HA1, demonstrating that P4HA1 is necessary for hypoxia-enhanced invasion and sufficient to increase invasion in normoxia in PDAC organoids. Our results identify P4HA1 as a driver of PDAC organoid invasion in hypoxia.</p><p><strong>Significance: </strong>This study demonstrates that hypoxia increases invasion across a cohort of human pancreatic cancer organoids and identifies the collagen-modifying enzyme P4HA1 as a driver of hypoxia-enhanced invasion. These results characterize a molecular mechanism by which the microenvironment alters tumor cell behavior and underscore new strategies to inhibit invasion.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"881-895"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Efficacy of a Selective Inhibitor of Cyclin-dependent Kinase 9 (KB-0742) in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma.","authors":"Glenn J Hanna, Gregory M Cote, Rashmi Chugh, Jacob S Thomas, Jyoti Malhotra, Richard E Cutler, Tressa Hood, Luis A Carvajal, Elizabeth A Olek, Miguel A Villalona-Calero","doi":"10.1158/2767-9764.CRC-25-0015","DOIUrl":"10.1158/2767-9764.CRC-25-0015","url":null,"abstract":"<p><strong>Purpose: </strong>Adenoid cystic carcinoma (ACC) is a rare salivary gland malignancy of the head and neck. Recurrent or metastatic ACC has very limited therapeutic options. Cyclin-dependent kinase 9 (CDK9) is a key factor in the oncogenic transcriptional regulatory network, and inhibition of CDK9 may prove beneficial in MYC-dependent tumors such as ACC.</p><p><strong>Patients and methods: </strong>A first-in-human, phase I, two-part dose-escalation and -expansion clinical trial (NCT04718675) enrolled patients with advanced solid tumors reliant on transcription factor activation to receive KB-0742, an oral selective inhibitor of CDK9. The primary endpoint was to establish safety/tolerability while nominating a recommended phase II dose (RP2D). Secondary endpoints included characterization of pharmacokinetics and assessment of preliminary efficacy.</p><p><strong>Results: </strong>Among 19 patients with ACC enrolled in dose expansion at the RP2D (60 mg orally 3 days on and 4 days off each week during a 28-day cycle), the regimen was well tolerated with mild gastrointestinal toxicity and fatigue; a single grade 3 treatment-related adverse event was observed (elevated γ-glutamyl transferase). One patient discontinued for gastrointestinal toxicity. Although no responses were observed, nine of 16 (56%) eligible patients had stable disease, with four experiencing >6 months of stability. Six-month progression-free survival was 37% (95% confidence interval, 14.2-59.8). Most patients had the more indolent type II ACC phenotype and 10 (53%) had MYB alterations.</p><p><strong>Conclusions: </strong>This dose-expansion cohort exploring the novel CDK9 inhibitor KB-0742 in patients with advanced ACC established favorable tolerability at the RP2D. Disease stabilization was observed in some patients despite a limited efficacy signal.</p><p><strong>Significance: </strong>A first-in-human, phase I trial explored the safety and preliminary efficacy of the CDK9 inhibitor KB-0742 in patients with advanced, transcription factor-dependent solid tumors including ACC. KB-0742 was well tolerated with evidence of disease stabilization observed among some patients with ACC, but overall therapeutic efficacy was limited.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":"5 5","pages":"767-773"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Activity of Datopotamab Deruxtecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2, in Uterine Serous Carcinoma.","authors":"Michelle Greenman, Cem Demirkiran, Stefania Bellone, Tobias M P Hartwich, Blair McNamara, Victoria M Ettorre, Niccolo G Santin, Namrata Sethi, Yang Yang-Hartwich, Katyayani Papatla, Elena Ratner, Alessandro D Santin","doi":"10.1158/2767-9764.CRC-25-0057","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0057","url":null,"abstract":"<p><p>Uterine serous carcinoma (USC) is a rare subset of endometrial cancer with a poor prognosis and high recurrence rate. Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate (ADC). The objective of this study was to evaluate the preclinical activity of Dato-DXd in USC in vitro against primary USC cell lines with various trophoblast cell-surface antigen 2 (TROP2) expression and in vivo in TROP2-overexpressing cell line-derived mice xenografts. USC primary tumor cell lines were treated with Dato-DXd and a control ADC (CTL ADC) to evaluate cell viability following exposure. Antibody-dependent cell-mediated cytotoxicity against TROP2-overexpressing and -nonexpressing cell lines was evaluated using a 4-hour chromium release assay. USC xenografts in mice were treated with Dato-DXd, CTL ADC, datopotamab, and vehicle to assess the in vivo effects via retro-orbital Dato-DXd administration. We found USC cell lines with TROP2 overexpression to be significantly more sensitive to killing induced by Dato-DXd compared with CTL ADC in vitro (e.g., IC50: 0.11 µmol/L vs. 30.07 µmol/L, P = 0.0074 and 0.11 µmol/L vs. 48.95 µmol/L, P = 0.0127, respectively). Dato-DXd induced antibody-dependent cell-mediated cytotoxicity in the presence of peripheral blood lymphocytes from healthy donors. TROP2-nonexpressing cell lines demonstrated minimal killing by Dato-DXd; however, when admixed with TROP2-overexpressing cells, a significant bystander effect was appreciated. In vivo, mice xenografts overexpressing TROP2 treated with Dato-DXd demonstrated tumor growth suppression and longer overall survival compared with CTL ADC-treated xenografts. These data demonstrate Dato-DXd to be highly active against TROP2-overexpressing USC in vitro and in vivo. Our preclinical activity results warrant future clinical trials for patients with advanced or recurrent USC.</p><p><strong>Significance: </strong>Targeted treatment of USC using the biomarker TROP2 represents a significant opportunity for further treatment options for patients already resistant to other lines of treatment. In this study, we present data showing preclinical evidence of effectiveness of this biomarker-targeted therapy in USC.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":"5 5","pages":"774-782"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-1 Blockade Mitigates Surgery-Induced Immunosuppression and Increases the Efficacy of Photodynamic Therapy for Pleural Mesothelioma.","authors":"Gwendolyn M Cramer, Richard W Davis, Emmanouil Papasavvas, Astero Klampatsa, Joann M Miller, Shirron Carter, Ruth Ikpe, Min Yuan, Sandy Widura, R Sonali Majumdar, Sally McNulty, Mary Putt, Andrew V Kossenkov, Luis J Montaner, Sunil Singhal, Edmund K Moon, Steven M Albelda, Keith A Cengel, Theresa M Busch","doi":"10.1158/2767-9764.CRC-24-0571","DOIUrl":"10.1158/2767-9764.CRC-24-0571","url":null,"abstract":"<p><p>Lung-sparing radical pleurectomy with intraoperative photodynamic therapy (PDT) demonstrates remarkable survival for patients with pleural mesothelioma. Nevertheless, most patients treated with this multimodal approach will develop local tumor recurrence. An understanding of potential causes of treatment failure is central to developing mitigation strategies. Surgery importantly reduces disease burden but also produces tumor-promoting inflammation, as demonstrated through transcriptomic analysis of pleural mesothelioma specimens. Using preclinical models in the setting of combination therapy, we separated the benefit of surgical resection from its counterproductive effects on therapeutic outcome. Specifically, we evaluated mechanisms by which surgically induced inflammation can be therapy-limiting in a murine model of tumor incision (TI) introduced by a surgical cut across the tumor. In this TI model, we identified distinct TI-altered patterns in innate and adaptive inflammatory cells in murine mesothelioma tumors, and we studied changes in these patterns with the addition of PDT. TI introduction of an immunosuppressive environment is established via upregulation of PD-1/PD-L1 expression on tumor cells, T cells, and myeloid cells that is partially resolved by PDT. Immune dysfunction is further mitigated by the addition of PD-1 blockade, leading to curative potential in a process that requires Ly6G+ neutrophils and CD8+ T cells. Overall, these studies suggest that, without PDT, surgical modulation of immune cell trafficking and functionality leads to systemic immunosuppression. This immunosuppressive state potentially interferes with the generation of antitumor immunity by PDT. However, targeted inhibition of surgery-induced signaling in the PD-l/PD-L1 pathway counteracts surgery's immunosuppressive outcomes to enhance PDT efficacy in the intraoperative setting.</p><p><strong>Significance: </strong>Surgery combined with PDT extends survival for patients with mesothelioma, but these patients are still at risk for tumor recurrence, in part due to the immunosuppressive effects of surgery. We find, in a mouse model, that combining surgery, PDT, and immune checkpoint blockade maximizes the efficacy of these therapies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"841-856"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiome Landscape and Association with Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors: A SCRUM-Japan MONSTAR-SCREEN Study.","authors":"Kentaro Sawada, Riu Yamashita, Shunsuke A Sakai, Satoshi Horasawa, Ayumu Yoshikawa, Takao Fujisawa, Shigenori Kadowaki, Ken Kato, Makoto Ueno, Eiji Oki, Yoshito Komatsu, Tatsuyuki Chiyoda, Yosuke Horita, Hisateru Yasui, Tadamichi Denda, Hironaga Satake, Taito Esaki, Taroh Satoh, Naoki Takahashi, Kentaro Yamazaki, Nobuhisa Matsuhashi, Tomohiro Nishina, Hiroyuki Takeda, Koushiro Ohtsubo, Takashi Ohta, Akihito Tsuji, Masahiro Goto, Takeshi Kato, Hideaki Bando, Katsuya Tsuchihara, Yoshiaki Nakamura, Takayuki Yoshino","doi":"10.1158/2767-9764.CRC-24-0543","DOIUrl":"10.1158/2767-9764.CRC-24-0543","url":null,"abstract":"<p><p>Although the gut microbiome is associated with cancer development and progression, little is known about the effects of the gut microbiome landscape and the efficacy of immune checkpoint inhibitors (ICI) across cancer types. We investigated the association between the microbiome, clinical features, and ICI efficacy across cancer types in a large nationwide screening project for solid tumors. Among 2,180 patients with advanced solid tumors enrolled in the SCRUM-Japan MONSTAR-SCREEN between October 2019 and September 2021, in the chemotherapy-naïve cohort (n = 817), a high prevalence of oral bacteria was observed in patients using proton pump inhibitors (PPI) and those with upper gastrointestinal cancers, particularly postoperative patients with gastric or pancreatic cancer. Among patients treated with ICIs (n = 333), a high abundance of sequence variants in the gut microbiome was not significantly associated with ICI efficacy across cancer types (HR = 0.94; 95% confidence interval, 0.73-1.21). However, high oral bacteria in feces significantly correlated with a shorter progression-free survival compared with low oral bacteria (median, 4.34 vs. 6.97 months; HR = 1.38; 95% confidence interval, 1.07-1.78). Notably, in patients using PPIs, a higher proportion of oral bacteria influenced progression-free survival outcomes of ICI treatment (median, 3.15 vs. 2.04 months; P = 0.08), unlike in PPI nonusers (median, 7.13 vs. 5.55 months; P = 0.74). This study of the gut microbiome has unveiled significant insights into its landscape and potential impact on ICI efficacy. It highlights that the abundance of oral bacteria in feces may play a critical role in diminishing ICI efficacy among patients using PPIs.</p><p><strong>Significance: </strong>As part of the MONSTAR-SCREEN, a prospective nationwide project for patients with solid tumors, we found that although gut microbiome diversity does not consistently predict ICI efficacy across cancer types, a high level of oral bacteria in the gut is linked to reduced ICI effectiveness, especially in patients using PPIs. These findings highlight the potential clinical impact of microbiome variations on cancer treatment outcomes.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"857-870"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clear-Cell Renal Cell Carcinoma Molecular Subtypes Differ by African and European Genetic Similarity.","authors":"Roy Elias, Thomas Nirschl, Michael Rezaee, Anirudh Yerrapragada, Shirley Wang, Joseph Cheaib, Ridwan Alam, Sunil Patel, Yuezhou Jing, Mohamad Allaf, David McKean, Alison P Klein, Elana J Fertig, Ezra Baraban, Yasser Ged, Srinivasan Yegnasubramanian, Nirmish Singla","doi":"10.1158/2767-9764.CRC-24-0624","DOIUrl":"10.1158/2767-9764.CRC-24-0624","url":null,"abstract":"<p><strong>Abstract: </strong>Self-reported Black (B) individuals remain underrepresented in molecular studies of clear-cell renal cell carcinoma (ccRCC) relative to White (W) individuals. We performed whole-exome and transcriptome sequencing on paired tumor and normal samples from 59 matched B and W patients undergoing nephrectomy for localized ccRCC, comparing molecular differences by estimated genetic similarity to African (AFR) and European (EUR) 1000 Genomes groups. We validated our findings with a propensity-matched subset of The Cancer Genome Atlas, yielding a final cohort of 254 patients (79 AFR and 175 EUR) with similar baseline clinical variables. Significant differences emerged in VHL mutation frequency (AFR: 23.4%, EUR: 57.5%; FDR = 0.0029) and chromosome 3p deletions (AFR: 59.2%, EUR: 82.6%; FDR = 0.086). Transcriptomic analyses identified 34 genes associated with genetic similarity, and gene set enrichment revealed inflammatory (IFN-γ/IFN-α, allograft rejection), proliferative (E2F targets, G2–M checkpoint), and metabolic (bile acid, fatty acid, glycolysis, MTORC1, peroxisome) pathway enrichment in EUR. We also observed differences in ccRCC molecular subtype distribution, with “Proliferative” and “Angio/Stromal” subtypes being more common in AFR (P = 0.018). Importantly, differential subtype membership explained most group-level differences. These results link EUR and AFR genetic similarity to distinct ccRCC molecular subtypes, underscoring the importance of molecular classifiers in disease stratification and the need to include diverse populations in molecular studies to improve our understanding and treatment of ccRCC.</p><p><strong>Significance: </strong>Our study shows that AFR genetic similarity correlates with distinct ccRCC molecular subtypes. Further research is needed to disentangle environmental and genetic influences. Identifying these differences underscores the critical importance of including racially and ethnically diverse populations in cancer research to ensure more equitable and sustainable outcomes worldwide for all patients.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"743-755"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOBEC3 Activity Promotes the Survival and Evolution of Drug-Tolerant Persister Cells during EGFR Inhibitor Resistance in Lung Cancer.","authors":"Nina Marie G Garcia, Jessica N Becerra, Sharan Srinivasan, Brock J McKinney, Ashley V DiMarco, Feinan Wu, Matthew Fitzgibbon, James V Alvarez","doi":"10.1158/2767-9764.CRC-24-0442","DOIUrl":"10.1158/2767-9764.CRC-24-0442","url":null,"abstract":"<p><p>APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTP) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through de novo acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor ΔNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of p63 in gefitinib-resistant cells reduces the expression of the ΔNp63 target genes IL-1α/β and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs and that approaches to target ΔNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.</p><p><strong>Significance: </strong>APOBEC mutagenesis is a common source of genetic heterogeneity in cancer, and APOBEC mutational signatures are enriched in metastatic and drug-resistant tumors. However, the mechanisms through which APOBEC3 enzymes promote tumor evolution remain unknown. In this study, we show that APOBEC3 activity contributes to the development of therapy-resistant cancer cells by promoting evolution of DTP cells. These findings offer insights into the role of APOBEC mutagenesis in cancer progression.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"825-840"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12093302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}