{"title":"Chemotherapy-associated mutational process signature and genomic alterations associated with outcome in metastatic pancreatic cancer.","authors":"Kaiqiang Wang, Linqiang Zhang, Qingkui Li, Qinghua Wang, Zhijia Jiang, Yaqing Wei, Tonghe Zhang, Zhaoyang Li, Zhan Jiang, Huitang Yang, Yandong Cai, Guoju Fan, Bo Chen, Hongwei Zhang, Yankui Li, Jinjin Sun","doi":"10.1007/s12094-025-03975-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Metastatic pancreatic cancer (mPAC) carries a dismal prognosis, and effective prognostic biomarkers are critically needed. This study aims to explore novel molecular prognostic markers for mPAC from the perspective of somatic mutations.</p><p><strong>Methods: </strong>We integrated clinical data and somatic mutation profiles from 820 mPAC patients. Prognosis-associated molecular markers were systematically explored from three perspectives: mutational process signatures, mutation activity-driven molecular subtypes, and genomic variations.</p><p><strong>Results: </strong>The median overall survival was 11.1 months (95% CI: 9.92-12.6). Liver metastasis was the most common site and associated with worse prognosis. Tumor mutational burden (TMB) and fraction genome alteration (FGA) were favorable prognostic biomarkers. Non-negative matrix factorization identified three distinct mutational process signatures (SBS1, SBS11, and SBS29). Notably, the presence of the temozolomide-associated signature (SBS11, characterized by C > T substitutions) was associated with improved survival. Consensus clustering of mutational activity defined seven molecular subtypes, one of which (Cluster 4) demonstrated the most favorable prognosis. Genomic profiling revealed that patients harboring KRAS p.G12V mutations had the poorest survival outcomes and significantly reduced immunogenicity. Furthermore, copy-number deletions in KRAS, AKT2, and MYC were identified as biomarkers of adverse prognosis.</p><p><strong>Conclusions: </strong>By deciphering the somatic mutational landscape of mPAC, this study identified potential molecular biomarkers associated with survival outcomes, providing a scientific foundation for prognostic prediction and informing clinical treatment strategies for mPAC.</p>","PeriodicalId":50685,"journal":{"name":"Clinical & Translational Oncology","volume":" ","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical & Translational Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12094-025-03975-1","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Objective: Metastatic pancreatic cancer (mPAC) carries a dismal prognosis, and effective prognostic biomarkers are critically needed. This study aims to explore novel molecular prognostic markers for mPAC from the perspective of somatic mutations.
Methods: We integrated clinical data and somatic mutation profiles from 820 mPAC patients. Prognosis-associated molecular markers were systematically explored from three perspectives: mutational process signatures, mutation activity-driven molecular subtypes, and genomic variations.
Results: The median overall survival was 11.1 months (95% CI: 9.92-12.6). Liver metastasis was the most common site and associated with worse prognosis. Tumor mutational burden (TMB) and fraction genome alteration (FGA) were favorable prognostic biomarkers. Non-negative matrix factorization identified three distinct mutational process signatures (SBS1, SBS11, and SBS29). Notably, the presence of the temozolomide-associated signature (SBS11, characterized by C > T substitutions) was associated with improved survival. Consensus clustering of mutational activity defined seven molecular subtypes, one of which (Cluster 4) demonstrated the most favorable prognosis. Genomic profiling revealed that patients harboring KRAS p.G12V mutations had the poorest survival outcomes and significantly reduced immunogenicity. Furthermore, copy-number deletions in KRAS, AKT2, and MYC were identified as biomarkers of adverse prognosis.
Conclusions: By deciphering the somatic mutational landscape of mPAC, this study identified potential molecular biomarkers associated with survival outcomes, providing a scientific foundation for prognostic prediction and informing clinical treatment strategies for mPAC.
期刊介绍：
Clinical and Translational Oncology is an international journal devoted to fostering interaction between experimental and clinical oncology. It covers all aspects of research on cancer, from the more basic discoveries dealing with both cell and molecular biology of tumour cells, to the most advanced clinical assays of conventional and new drugs. In addition, the journal has a strong commitment to facilitating the transfer of knowledge from the basic laboratory to the clinical practice, with the publication of educational series devoted to closing the gap between molecular and clinical oncologists. Molecular biology of tumours, identification of new targets for cancer therapy, and new technologies for research and treatment of cancer are the major themes covered by the educational series. Full research articles on a broad spectrum of subjects, including the molecular and cellular bases of disease, aetiology, pathophysiology, pathology, epidemiology, clinical features, and the diagnosis, prognosis and treatment of cancer, will be considered for publication.
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