Sydney A Skupa, Kathryn M Cooper, Audrey L Smith, Erin M Drengler, Alexandria P Eiken, Elizabeth Schmitz, Grace M Waldron, Grinu Mathew, Mark Primeaux, Punita Dhawan, Geoffrey A Talmon, Christopher R D'Angelo, Dalia El-Gamal
{"title":"Gut Microbiome Profiling in Eμ-TCL1 Mice Reveals Intestinal Changes and a Dysbiotic Signature Specific to Chronic Lymphocytic Leukemia.","authors":"Sydney A Skupa, Kathryn M Cooper, Audrey L Smith, Erin M Drengler, Alexandria P Eiken, Elizabeth Schmitz, Grace M Waldron, Grinu Mathew, Mark Primeaux, Punita Dhawan, Geoffrey A Talmon, Christopher R D'Angelo, Dalia El-Gamal","doi":"10.1158/2767-9764.CRC-25-0022","DOIUrl":"10.1158/2767-9764.CRC-25-0022","url":null,"abstract":"<p><p>The gut microbiome's role in the pathogenesis of hematologic malignancies is actively being explored; yet studies on chronic lymphocytic leukemia (CLL) are limited. Using the Eμ-TCL1 murine model of CLL, we identify a unique and dysbiotic disease-associated gut microbiome that develops in mice over time. Leukemic mice show an increase in abundance of pathogenic bacteria, specifically members of the Proteobacteria phylum. We found that this dysbiotic microenvironment is associated with CLL involvement within the intestinal tract and high levels of markers indicative of altered tight junction permeability (e.g., claudin-2, soluble CD14, and zonulin). Moreover, utilizing the syngeneic model of CLL in tandem with an antibiotic-mediated microflora ablation approach, we found that leukemic mice receiving microflora-ablating antibiotics show marked changes to the gut microbiome and a delayed disease onset compared with mice receiving antibiotic-free water. Immunophenotyping of murine spleens showed that this delay in disease was accompanied by more tumor-reactive CD8+ T cells that coexpressed fewer inhibitory receptors (e.g., PD-1, LAG-3, and TIM-3). These findings confirm that a dysbiotic gut microbiome develops during CLL disease and demonstrate unique intestinal involvement and potential immune dysregulation occurring during CLL progression that may be influencing the overall microbial signature.</p><p><strong>Significance: </strong>There is a growing appreciation for the gut microbiome's role in hematologic malignancies. Despite this, its role in CLL remains obscure. This study demonstrates a dysbiotic microbiome within CLL that may contribute to further intestinal and immune dysregulation present during CLL progression.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1344-1358"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755197","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}
Caretia J Washington, Chayil C Lattimore, Jimmy J Brown, Natalie L Silver, Dejana Braithwaite, Kristianna M Fredenburg, Shama D Karanth
{"title":"Treatment Outcomes Differ for Racial and Ethnic Minorities with Advanced-Stage Laryngeal Cancer: A Florida Cancer Data System Analysis.","authors":"Caretia J Washington, Chayil C Lattimore, Jimmy J Brown, Natalie L Silver, Dejana Braithwaite, Kristianna M Fredenburg, Shama D Karanth","doi":"10.1158/2767-9764.CRC-25-0239","DOIUrl":"10.1158/2767-9764.CRC-25-0239","url":null,"abstract":"<p><p>A disparity persists in advanced-stage laryngeal cancer outcomes, in which Black patients experience lower survival rates. We examined real-world treatment patterns and outcomes by race and ethnicity in patients with advanced-stage laryngeal cancer in Florida. Data were abstracted from the Florida Cancer Data System on non-Hispanic (NH)-White, Hispanic, and NH-Black patients with advanced-stage laryngeal cancer from 2009 to 2020. Kaplan-Meier curves estimated survival by race and ethnicity. Multivariable Cox proportional hazard models calculated HRs and 95% confidence intervals (95% CI) to examine the association of race and ethnicity with treatment receipt and mortality. Cox proportional hazard models were adjusted for sociodemographic and tumor characteristics. A total of 4,316 participants with advanced-stage laryngeal cancer (75.3% NH-White, 13.1% Hispanic, and 11.6% NH-Black) were included in the analysis. In age- and sex-adjusted models, NH-Black patients had a higher risk of death (HR = 1.21; 95% CI, 1.08-1.35) compared with NH-White patients, whereas Hispanic patients had a lower risk (HR = 0.80; 95% CI, 0.71-0.90). After controlling for sociodemographic factors, mortality differences between NH-Black and NH-White patients were not statistically significant (HR = 1.12; 95% CI, 1.00-1.26). However, in treatment-stratified analyses, specifically in patients who received chemoradiation, NH-Black patients had a higher risk of death (HR = 1.25; 95% CI, 1.02-1.52) compared with NH-White patients. In conclusion, NH-Black patients with advanced-stage laryngeal cancer who underwent chemoradiation had higher mortality compared with NH-White patients, whereas Hispanic patients had lower mortality. Investigating factors such as healthcare access, comorbidities, and treatment response may help address these disparities.</p><p><strong>Significance: </strong>This study provides important insight into racial and ethnic disparities in treatment outcomes and mortality risk among patients with advanced-stage laryngeal cancer in a real-world setting. Our findings underscore the need for a comprehensive approach to understanding outcome differences, considering the interplay of healthcare access, clinical factors, and treatment quality that influence patient care and survival.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1310-1318"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12336365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692592","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}
Jessica D Daley, Elina Mukherjee, David Ferraro, A Carolina Tufino, Nathanael Bailey, Shanthi Bhaskar, Nivitha Periyapatna, Ian MacFawn, Sean Hartwick, Sheryl Kunning, Cynthia Hinck, Tullia C Bruno, Adam C Olson, Linda M McAllister-Lucas, Andrew P Hinck, Kristine Cooper, Riyue Bao, Anthony R Cillo, Kelly M Bailey
{"title":"TGFβ Inhibition during Radiotherapy Enhances Immune Cell Infiltration and Decreases Metastases in Ewing Sarcoma.","authors":"Jessica D Daley, Elina Mukherjee, David Ferraro, A Carolina Tufino, Nathanael Bailey, Shanthi Bhaskar, Nivitha Periyapatna, Ian MacFawn, Sean Hartwick, Sheryl Kunning, Cynthia Hinck, Tullia C Bruno, Adam C Olson, Linda M McAllister-Lucas, Andrew P Hinck, Kristine Cooper, Riyue Bao, Anthony R Cillo, Kelly M Bailey","doi":"10.1158/2767-9764.CRC-24-0346","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0346","url":null,"abstract":"<p><p>Ewing sarcoma is an aggressive cancer diagnosed in adolescents and young adults. Inhibition of TGFβ is being tested in limited clinical trials for relapsed Ewing sarcoma. TGFβ is an immunosuppressive cytokine that exists in latent and active states. The functional impact of TGFβ inhibition on the Ewing tumor microenvironment (TME) and on Ewing tumor behavior remains largely unknown. In this study, we use single-cell RNA sequencing analysis of human Ewing tumors to demonstrate that immune cells are the largest contributors of TGFB1 expression in the human Ewing TME. We utilize a humanized mouse model of Ewing sarcoma to demonstrate that TME signatures in these models differ significantly from Ewing sarcoma tumors developed in immunodeficient mice. Using this humanized model, we investigate the effect of TGFβ inhibition on the Ewing sarcoma TME during radiotherapy, a treatment that is commonly used to treat unresectable, metastatic, and relapsed/refractory Ewing sarcoma that is known to enhance TGFβ activation in multiple cancers. Utilizing a trivalent ligand TGFβ trap to inhibit TGFβ, we demonstrate that in combination with radiotherapy, TGFβ inhibition both increases Ewing sarcoma immune cell infiltration and decreases lung metastatic burden in vivo. These data demonstrate the value of immunocompetent models to address immune-biological preclinical questions in Ewing sarcoma and demonstrate that TGFβ inhibition during radiotherapy is a promising strategy to enhance antitumor immune response and improve treatment efficacy for metastatic Ewing sarcoma.</p><p><strong>Significance: </strong>This work demonstrates the importance of disrupting immunosuppression during radiotherapy to reduce lung metastatic potential in Ewing sarcoma. Humanized mouse models of Ewing sarcoma are also established as an immunocompetent preclinical tool to ask therapeutic questions about the Ewing TME.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":"5 8","pages":"1441-1457"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980812","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}
Jared Sipes, Didi Zha, Sagar Rayamajhi, Leonidas E Bantis, Rashna Madan, Amrita Mitra, Rajni V Puri, Mohammod Mahmudur Rahman, Foyez Ahmmed, Harsh B Pathak, Angela Russo, Mihaela Sardiu, Brett C Isenberg, Brian P Cain, Jonathan Coppeta, Pamoda M Galhenage, Shailja Pathania, Shannon MacLaughlan David, Joanna E Burdette, Andrew K Godwin
{"title":"Defining the Ovarian Cancer Precancerous Landscape through Modeling Fallopian Tube Epithelium Reprogramming Driven by Extracellular Vesicles.","authors":"Jared Sipes, Didi Zha, Sagar Rayamajhi, Leonidas E Bantis, Rashna Madan, Amrita Mitra, Rajni V Puri, Mohammod Mahmudur Rahman, Foyez Ahmmed, Harsh B Pathak, Angela Russo, Mihaela Sardiu, Brett C Isenberg, Brian P Cain, Jonathan Coppeta, Pamoda M Galhenage, Shailja Pathania, Shannon MacLaughlan David, Joanna E Burdette, Andrew K Godwin","doi":"10.1158/2767-9764.CRC-25-0064","DOIUrl":"10.1158/2767-9764.CRC-25-0064","url":null,"abstract":"<p><p>Serous tubal intraepithelial carcinomas (lesions) in the human fallopian tube epithelium (hFTE) are theorized to give rise to high-grade serous ovarian cancers. Small extracellular vesicles (sEV) are known to mediate key signaling in both normal and cancerous tissues, but few ex vivo systems exist for studying the impact of sEV on hFTE tissue. In this study, we present a microfluidic tissue culture platform with combined spatial transcriptomic and proteomic readouts that allows us to profile dual responses in tissue exposed to sEV \"messages\"-capturing both short-term transcriptomic shifts in the tissue and long-term changes in protein cargo of secreted EVs (the \"reply\"). Using spatial transcriptomics, we show that the short-term 1-day exposure to ovarian cancer-derived sEVs alters expression of 68 transcripts in secretory cells, the progenitor of high-grade serous ovarian cancer, notably upregulating immune-related mRNA, including CXCL family chemokines, VCAM1, and pro-inflammatory mediators (NFKB1, IL1B, and IFNA7/17). Additionally, we observed that the long-term 14-day exposure to sEVs alters the expression of seven transcripts and 25 EV cargo proteins of fallopian tube-derived EVs (\"secondary release EVs\") following stimulus from cancer EVs. Together, tissue transcriptomics and tissue-derived EV proteomics indicate that ovarian cancer-derived sEVs rewire target cell signaling to modify the tubal immune landscape. This study provides insights into the early molecular changes associated with the pathogenesis of ovarian cancer in its tissue of origin, providing a platform to study EV-tissue interactions and identify how sEVs drive cell signaling reprogramming in hFTE.</p><p><strong>Significance: </strong>We model the fallopian tube preneoplastic landscape using a microfluidic platform to study EV-induced stress and show that cancer EVs promote immune signaling changes representing the earliest stages of ovarian cancer pathogenesis.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1266-1281"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12319521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676709","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}
Guadalupe Nibeyro, Verónica M Baronetto, Agustín Nava, María R Girotti, Laura Prato, Gabriel Morón, Elmer A Fernández
{"title":"Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade-Treated Advanced Melanoma: A Retrospective Analysis.","authors":"Guadalupe Nibeyro, Verónica M Baronetto, Agustín Nava, María R Girotti, Laura Prato, Gabriel Morón, Elmer A Fernández","doi":"10.1158/2767-9764.CRC-25-0204","DOIUrl":"10.1158/2767-9764.CRC-25-0204","url":null,"abstract":"<p><p>Advanced melanoma, characterized by its aggressiveness and genomic complexity, demands improved prognostic and therapeutic strategies, particularly for patients with limited response to immune checkpoint blockade (ICB). Gene fusions, proposed as enhancers of tumor immunogenicity through neoantigens, also reflect chromosomal instability, which influences tumor evolution and therapy outcomes. However, their impact on melanoma remains unexplored. By retrospectively analyzing baseline tumors from 222 ICB-treated patients, we found a high tumor fusion burden (TFB-H) correlation with poor RECIST response, reduced overall survival (time-dependent ROC > 0.6, P << 0.01), and increased mortality risk (HR = 2, P < 0.01). TFB-H was found to be strongly associated with chromosomal instability (β = 0.72, P < 0.01), heightened proliferation, and diminished immune cytolytic activity. TFB-H was also linked to poor prognosis and immune impairment in nonadvanced melanoma tumors (n = 441) that have not received ICB treatment. These findings suggest that TFB-H tumors may exhibit an aggressive phenotype insensitive to ICB, probably due to immune evasion caused by intratumoral heterogeneity. Additionally, we identified targetable fusions, such as KIAA1549::BRAF, which represent therapeutic opportunities for advanced melanoma, including novel type II RAF inhibitors with potent activity against kinase fusions. Integrating gene fusion profiling into clinical practice may guide precision medicine strategies to overcome the limitations of ICB in advanced melanoma, offering prognostic insights and expanding therapeutic options, particularly with emerging fusion-specific inhibitors.</p><p><strong>Significance: </strong>The evidence of this work supports the idea that gene fusion profiling may serve as both a prognostic marker and a guide for alternative therapeutic strategies, including targeted fusion inhibitors, in patients less likely to benefit from ICB.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1332-1343"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12344778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755185","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}
Hyun Jung Lee, Roman Gulati, Erolcan Sayar, Radhika A Patel, Pushpa Itagi, Helen M Richards, Thomas Persse, Sonali Arora, Ilsa Coleman, Mohamed Adil, Samantha L Schuster, Farinaz Shokri, Jonathan L Wright, Evan Y Yu, Lawrence D True, Meagan Chambers, Jessica E Hawley, Heather H Cheng, Michael T Schweizer, Petros Grivas, Peter S Nelson, R Bruce Montgomery, Andrew C Hsieh, Funda Vakar-Lopez, Colm Morrissey, Hung-Ming Lam, Gavin Ha, Maria S Tretiakova, Michael C Haffner, Ruben Raychaudhuri
{"title":"Patterns of HER2 Expression in Metastatic Prostate and Urothelial Cancers: Implications for HER2-Targeted Therapies.","authors":"Hyun Jung Lee, Roman Gulati, Erolcan Sayar, Radhika A Patel, Pushpa Itagi, Helen M Richards, Thomas Persse, Sonali Arora, Ilsa Coleman, Mohamed Adil, Samantha L Schuster, Farinaz Shokri, Jonathan L Wright, Evan Y Yu, Lawrence D True, Meagan Chambers, Jessica E Hawley, Heather H Cheng, Michael T Schweizer, Petros Grivas, Peter S Nelson, R Bruce Montgomery, Andrew C Hsieh, Funda Vakar-Lopez, Colm Morrissey, Hung-Ming Lam, Gavin Ha, Maria S Tretiakova, Michael C Haffner, Ruben Raychaudhuri","doi":"10.1158/2767-9764.CRC-25-0069","DOIUrl":"10.1158/2767-9764.CRC-25-0069","url":null,"abstract":"<p><p>HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. Although HER2-directed therapies like fam-trastuzumab deruxtecan are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer and urothelial carcinoma remains inadequately characterized. We evaluated HER2 protein expression in metastatic prostate cancer and urothelial carcinoma using a validated IHC assay on tissue microarrays constructed from the University of Washington Tissue Acquisition Necropsy Program. HER2 expression was scored using standardized gastric cancer criteria. Genomic analysis of ERBB2 alterations was conducted on a subset of samples. HER2 expression heterogeneity and its relationship with other surface markers were also evaluated. In the prostate cancer cohort (n = 52 patients, 1-19 tumors per patient), HER2 expression was low, with no 3+ expression observed and only five (10%) patients exhibiting 2+ expression. Low-level ERBB2 copy-number gains were observed in some tumors but did not correlate with HER2 protein expression (P = 0.2). In urothelial carcinoma (n = 20, 2-6 tumors per patient), HER2 expression was more frequent, with ≥2+ expression observed in six (30%) cases and 3+ expression observed in three (15%) cases in at least one tumor. Urothelial carcinoma samples showed less heterogeneity, with more consistent expression across metastases. HER2 overexpression is rare and heterogeneous in metastatic prostate cancer, limiting its utility as a therapeutic target. HER2 expression is more prevalent and uniform in urothelial carcinoma. These findings underscore the importance of comprehensive HER2 assessment in advanced urothelial carcinoma and suggest that success of HER2-directed therapies in prostate cancer will require careful case selection.</p><p><strong>Significance: </strong>This study demonstrates that HER2 is rarely overexpressed in metastatic prostate cancer but is more common and consistent in urothelial carcinoma. These findings highlight the need for HER2 testing in urothelial cancer and suggest that HER2-targeted therapies in prostate cancer will require careful patient selection.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1419-1428"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790887","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}
Jeffrey Chee-Hong Goh, Chyong-Huey Lai, Efren Javier Domingo, Jae Hoon Kim, Carmel Spiteri, Danny Hsu, Soo Yeon Ihm, Peng Peng
{"title":"Metastatic Cervical Cancer in the Asia-Pacific Region: Current Treatment Landscape and Barriers.","authors":"Jeffrey Chee-Hong Goh, Chyong-Huey Lai, Efren Javier Domingo, Jae Hoon Kim, Carmel Spiteri, Danny Hsu, Soo Yeon Ihm, Peng Peng","doi":"10.1158/2767-9764.CRC-24-0647","DOIUrl":"10.1158/2767-9764.CRC-24-0647","url":null,"abstract":"<p><p>Despite treatment advances for metastatic cervical cancer (mCC), the Asia-Pacific region faces significant barriers in treatment accessibility, availability, and healthcare infrastructure. This study explored the treatment landscape and barriers for mCC in the Asia-Pacific. A descriptive, cross-sectional, web-based study evaluating cervical cancer treatment patterns was conducted among medical, radiation, and gynecologic oncologists and gynecologists in the Chinese mainland (n = 80), Australia, the Philippines, South Korea, and Taiwan (n = 20 each). Eligible respondents were primarily involved in direct patient care (≥60%) and were key treatment deciders with ≥5 years of experience. Among patients with cervical cancer of 160 physicians, 10.9% had metastatic disease, of which 50.3% were aged 41 to 60 years and had Eastern Cooperative Oncology Group scores of 0 to 2 (78.7%). Top treatment modalities included systemic therapy (ST) alone (43.6%) and radiotherapy + ST (33.4%). Top first-line regimens were carboplatin/cisplatin + paclitaxel ± bevacizumab (42.3% and 33.1%, respectively), and the top second-line treatment regimens were carboplatin + paclitaxel + bevacizumab (12.0%) and cisplatin + paclitaxel + bevacizumab (11.5%). PD-L1 testing was more common in South Korea (80.8%) than in the Chinese mainland (48.8%) and Taiwan (26.4%). Treatment drivers included National Comprehensive Cancer Network guidelines (82.7%), disease stage (87.4%), Eastern Cooperative Oncology Group status (83.5%), comorbidities (59.1%), drug efficacy (88.2%), safety (84.3%), and accessibility (66.9%). Treatment challenges included poor prognosis (26.8%), patient affordability (21.3%), and limited treatment option availability (19.7%). In bevacizumab-reimbursed locations, patient tolerability and insufficient medical resources persisted. In conclusion, approximately 11% of cervical cancer cases were metastatic. Treatment preferences were radiotherapy and ST, with funding, cost, accessibility, and availability challenges. Policies supporting reimbursement and accessibility could encourage the adoption of effective alternative therapies.</p><p><strong>Significance: </strong>The findings offer valuable insights about current treatments and the related unmet needs in funding, cost, accessibility, and availability across the Asia-Pacific region. These further highlight areas of importance and the need for implementing reimbursement policies and enhancing accessibility to support the adoption of effective, advanced treatments.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1429-1440"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12378444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692590","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}
Aaron Chevalier, Tao Guo, Natasha Q Gurevich, Jingwen Xu, Masanao Yajima, Joshua D Campbell
{"title":"Characterization of Mutational Signatures in Tumors from a Large Chinese Population.","authors":"Aaron Chevalier, Tao Guo, Natasha Q Gurevich, Jingwen Xu, Masanao Yajima, Joshua D Campbell","doi":"10.1158/2767-9764.CRC-24-0496","DOIUrl":"10.1158/2767-9764.CRC-24-0496","url":null,"abstract":"<p><p>The majority of mutational signatures have been characterized in tumors from American and European countries, and the degree to which mutational signatures are similar to or different from those in Chinese populations has not been fully explored. We leveraged a large-scale clinical sequencing cohort of tumors from the Chinese population developed by OrigiMed (OM). A total of 2,115 tumors from 25 major tumor types that had at least 10 single-base substitutions (SBS) were used for mutational signature analysis. Sixteen mutational signatures from the Catalogue of Somatic Mutations in Cancer (COSMIC) database were identified in the OM cohort using the musicatk package. The activity levels for most of the signatures were similar to those in a cohort from Memorial Sloan Kettering in the United States. The activity level for the apolipoprotein B mRNA editing catalytic polypeptide-like-related signature SBS2 was significantly lower in breast tumors in the OM cohort. The aristolochic acid signature SBS22 was observed in four soft-tissue sarcomas, and the POLE-associated signature SBS10 was observed in a gallbladder carcinoma. In lung adenocarcinoma, the polycyclic aromatic hydrocarbon signature SBS4 was significantly higher in males compared with females but not associated with smoking status. UV-related mutations were significantly lower in cutaneous melanomas from the Chinese cohort compared with the American cohort and may contribute to lower response rates to immunotherapy observed in this population. Overall, these results add to our understanding of the mutational processes that contribute to tumors from the Chinese population.</p><p><strong>Significance: </strong>Analysis of a large Chinese cohort from 25 tumor types reveals similarities and differences in the activity of mutational signatures compared with other populations.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1466-1476"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144801081","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}
Jun Li, Zoe Welham, Benita Tse, Chahaya Gauci, Shila Ghazanfar, Pratibha Panwar, Alexander Engel, Mark P Molloy
{"title":"Mutational Analysis of Early, Low-Grade Bowel Polyps Defines a Subgroup with Concurrent, High-Risk Oncogenic Drivers Independent of Polyp Size.","authors":"Jun Li, Zoe Welham, Benita Tse, Chahaya Gauci, Shila Ghazanfar, Pratibha Panwar, Alexander Engel, Mark P Molloy","doi":"10.1158/2767-9764.CRC-25-0182","DOIUrl":"10.1158/2767-9764.CRC-25-0182","url":null,"abstract":"<p><p>The accumulation of pathogenic mutations in premalignant colorectal neoplasms is critical for colorectal cancer development; however, the frequency and diversity of pathogenic driver mutations in early-stage colorectal polyps is incompletely known. We investigated this by whole-exome sequencing of low-grade dysplasia (LGD) colorectal polyps and paired germline DNA. Interestingly, in these early lesions, there was no association with mutational burden and the known risk factor of polyp size (range, 3-15 mm). However, a subset of LGD polyps harbored concurrent, oncogenic alterations in colorectal cancer-causing pathways of WNT/β-catenin, p53, or RTK-RAS. Further analysis suggested that the concurrent mutation signature was associated with increased polyp burden. Spatial transcriptomic analysis revealed that immune effectors, including NF-κB signaling, were a characteristic of LGD polyps with concurrent pathogenic mutations. Together, these observations suggest that some small-sized, early colorectal neoplasms have enhanced oncogenic potential and highlight that nonadvanced colorectal adenoma may not be universally considered a low-risk finding.</p><p><strong>Significance: </strong>Through whole-exome sequencing of early colorectal polyps characterized by LGD, we demonstrate that polyp size poorly correlates with mutational burden. Some small-sized (<10 mm polyps) early polyps harbored concurrent driver gene mutations commonly seen in adenocarcinoma. Sequencing of key driver genes in early polyps may identify risky lesions that cannot be detected by histology alone.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1372-1383"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777047","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}
Samantha I Liang, Zoe Quandt, Sara Wienke, Jing Wang, Sean Gordon, Reagan M Barnett, Jude Masannat, Kyle Chang, Carin R Espenschied, Katie J Quinn, Kimberly C Banks, Enjun Yang, John E Connolly
{"title":"Methylation-Based ctDNA Tumor Fraction Changes Predict Long-Term Clinical Benefit From Immune Checkpoint Inhibitors in RADIOHEAD, a Real-World Pan-Cancer Study.","authors":"Samantha I Liang, Zoe Quandt, Sara Wienke, Jing Wang, Sean Gordon, Reagan M Barnett, Jude Masannat, Kyle Chang, Carin R Espenschied, Katie J Quinn, Kimberly C Banks, Enjun Yang, John E Connolly","doi":"10.1158/2767-9764.CRC-25-0151","DOIUrl":"10.1158/2767-9764.CRC-25-0151","url":null,"abstract":"<p><p>Current response evaluation methods have accuracy limitations. Monitoring with a ctDNA methylation-based tumor fraction (TF) may provide a more accurate assessment of tumor burden across solid tumors. In this study, we evaluate a tissue-free, methylation-based TF and explore the association with treatment outcomes in RADIOHEAD, a cohort of 1,070 patients with solid tumors receiving standard-of-care immune checkpoint inhibition (ICI) regimens, with blood samples collected prospectively for retrospective analysis. A total of 1,997 baseline and serial on-treatment plasma samples from 627 patients with stage IV cancer were analyzed with an analytically validated next-generation sequencing methylation-based ctDNA assay (Guardant Reveal). The primary outcome measure was real-world progression-free survival (rwPFS). Secondary outcomes included real-world overall survival (rwOS) and the lead time between nonmolecular response (nMR) to rwPFS event. Patients with any decrease in TF while receiving ICI had superior outcomes. Patients with ≥80% decrease in TF at two timepoints or TF below the limit of quantification had longer rwPFS and rwOS than those with <80% decrease [nMR; rwPFS HR, 0.24 (95% confidence interval, 0.19-0.32) P < 0.005; rwOS HR, 0.28 (95% confidence interval, 0.21-0.38) P < 0.005]. nMR was detected prior to clinical progression in 209 patients with a median lead time of 3.03 months. Among 627 patients with stage IV cancer receiving standard-of-care ICI, monitoring with methylation-based TF identified patients who have significantly longer rwPFS and rwOS. Changes in TF on ICI can provide additional response data earlier than imaging alone and support the potential of serial monitoring to inform treatment decisions.</p><p><strong>Significance: </strong>This study found that early decreases in tumor DNA levels in the blood are linked to longer survival in patients with cancer treated with immunotherapy. These findings support the use of blood-based monitoring to help predict treatment response and improve decision-making in real-world cancer care.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1384-1395"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12365632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144735839","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}