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<p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, characterized by high metastatic potential and a&#xa0;marked resistance to therapy. Its development is driven by a&#xa0;complex interplay between environmental and lifestyle factors, genetic predisposition, and molecular as well as epigenetic alterations. Established precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), undergo a&#xa0;multistep progression marked by early <i>KRAS</i> mutations followed by alterations in tumor suppressor genes such as <i>CDKN2A</i>, <i>TP53</i>, and <i>SMAD4</i>. In addition to the classical linear progression model, non-linear tumor evolution with early dissemination and pronounced intratumoral heterogeneity is increasingly recognized. Molecular subtypes, particularly the classical and basal-like phenotypes, differ in terms of biology, prognosis, and therapeutic response. Furthermore, epigenetic mechanisms and non-coding RNAs play a&#xa0;crucial role in tumor development and offer promising opportunities for diagnostics and targeted therapies. Integrating etiological factors with molecular evolution provides deeper insight into PDAC pathogenesis and forms the basis for the development of precision medicine approaches.</p>

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Risikofaktoren und molekulare Evolution des Pankreaskarzinoms

  • 期刊论文

  • 发表日期：

    2026年7月24日

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  • Aslihan Yavas,
  • Rita Vesce,
  • Sebastian Matei Sabo,
  • Irene Esposito

摘要

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, characterized by high metastatic potential and a marked resistance to therapy. Its development is driven by a complex interplay between environmental and lifestyle factors, genetic predisposition, and molecular as well as epigenetic alterations. Established precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), undergo a multistep progression marked by early KRAS mutations followed by alterations in tumor suppressor genes such as CDKN2A, TP53, and SMAD4. In addition to the classical linear progression model, non-linear tumor evolution with early dissemination and pronounced intratumoral heterogeneity is increasingly recognized. Molecular subtypes, particularly the classical and basal-like phenotypes, differ in terms of biology, prognosis, and therapeutic response. Furthermore, epigenetic mechanisms and non-coding RNAs play a crucial role in tumor development and offer promising opportunities for diagnostics and targeted therapies. Integrating etiological factors with molecular evolution provides deeper insight into PDAC pathogenesis and forms the basis for the development of precision medicine approaches.