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<p>Despite improvements in the molecular profiling of pancreatic neuroendocrine tumors (PanNETs), predicting their clinical behavior and response to specific therapies remains challenging. We sought to elucidate the molecular basis underlying the broad phenotypic variations in these neoplasms through a genetic characterization of primary and metastatic PanNETs. Our findings revealed an enrichment of <i>CDKN2A</i> homozygous deletions and <i>TSC2</i> somatic mutations in metastatic PanNETs when compared to non-metastatic lesions. Tumor evolution analysis further revealed the acquisition of such genetic alterations as late events in the progression of these neoplasms, conferring poor survival outcomes to the affected patients. Biallelic loss of DNA damage repair genes, <i>ATRX</i> and/or <i>DAXX</i>, was associated with a high fraction of the genome altered in PanNETs, with pathogenic alterations affecting those genes also being associated with a homologous recombination deficiency signature. These findings highlight molecular mechanisms driving PanNET progression and underscore the need for further molecular characterization and tumor evolution studies to evaluate targeted therapies for such a challenging disease.</p>

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CDKN2A homozygous deletions and TSC2 somatic mutations in metastatic pancreatic neuroendocrine tumors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • Tito Teles Jesus,
  • Lorenzo Ferrando,
  • Lia Rodrigues,
  • Rui Sousa Martins,
  • Luís Cardoso,
  • José Manuel Lopes,
  • Paula Soares,
  • Arnaud Da Cruz Paula,
  • João Vinagre

摘要

Despite improvements in the molecular profiling of pancreatic neuroendocrine tumors (PanNETs), predicting their clinical behavior and response to specific therapies remains challenging. We sought to elucidate the molecular basis underlying the broad phenotypic variations in these neoplasms through a genetic characterization of primary and metastatic PanNETs. Our findings revealed an enrichment of CDKN2A homozygous deletions and TSC2 somatic mutations in metastatic PanNETs when compared to non-metastatic lesions. Tumor evolution analysis further revealed the acquisition of such genetic alterations as late events in the progression of these neoplasms, conferring poor survival outcomes to the affected patients. Biallelic loss of DNA damage repair genes, ATRX and/or DAXX, was associated with a high fraction of the genome altered in PanNETs, with pathogenic alterations affecting those genes also being associated with a homologous recombination deficiency signature. These findings highlight molecular mechanisms driving PanNET progression and underscore the need for further molecular characterization and tumor evolution studies to evaluate targeted therapies for such a challenging disease.