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

Sep 30, 2026

Molecular profiling of pancreatic neuroendocrine tumors (PanNETs) can be incomplete for predicting clinical behavior and therapy response. A genetic characterization of primary and metastatic PanNETs identified enrichment of CDKN2A homozygous deletions and TSC2 somatic mutations in metastatic lesions versus non-metastatic cases. Tumor evolution analyses indicated these alterations emerge as late events, linked to poor patient survival. Biallelic loss in DNA damage repair genes ATRX and/or DAXX correlated with a high genome-altered fraction and homologous recombination deficiency signatures, supporting mechanisms driving progression and guiding future targeted therapy studies.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Results

Clinical features of pancreatic neuroendocrine tumors

npj | precision oncology Article | Published in partnership with The Hormel Institute, University of Minnesota | | | | --- | --- | --- | | [https://doi.org/10.1038/s41698-025-01210-2](https://doi.org/10.1038/s41698-025-01210-2) | | | | CDKN2A homozygous deletions and TSC2 somatic mutations in metastatic pancreatic neuroendocrine tumors
Check for updates | | | | Tito Teles Jesus1,2, Lorenzo Ferrando3, Lia Rodrigues1,2,4, Rui Sousa Martins1,2,4, Luís Cardoso1,2,5, José Manuel Lopes1,2,4, Paula Soares1,2,4, Arnaud Da Cruz Paula1,2,6 & João Vinagre1,2,4,6 | | | | 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, ATRXand/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. Theseﬁndings 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. | | | | Pancreatic neuroendocrine tumors (PanNETs) are low-incidence diseases accounting for less than 3% of all pancreatic malignancies, but their prevalence is currently rising1. Patients with PanNET present metastases at diagnosis in 60–80% of cases1, and their prognosis differs widely, with some tumors having an indolent nature, with a reasonable length of survival even with a metastatic presentation, and others being extremely aggressive with a poor prognosis2. Recent advances in sequencing technologies have uncovered the molecular basis of numerous cancers and led to new prognostic classiﬁcation systems and actionable targets3. Indeed, it has been demonstrated that increasing numbers of molecular pathways are involved in the biology and clinical behavior of PanNETs, such as DNA damage repair, chromatin remodeling, telomere alteration, PI3K/AKT/mTORandp53/cell cycle signaling pathways3–5. DNA sequencing analysis of PanNETs hasidentiﬁed recurrent somatic mutations affecting MEN1, DAXX, and ATRX3–6. Loss of function of DAXX or ATRX, results in telomere dysfunction, due to the activation of homologous recombination in telomeric DNA, and consequently leads to genomic instability. The inactivation of these genesis also implicated in the activation of the alternative lengthening | oftelomeres(ALT)mechanism3,6,7. Additional mutations in the PI3K/AKT/ mTOR pathway were also found in these neoplasms, such as those affecting TSC1/2 and PTEN tumor suppressor genes, and pronounced losses of these genes were correlated with liver metastases, shorter time to progression, and shorter disease-free and overall survival5,6,8. More recently, high frequencies of CDKN2A copy number (CN) losses were observed in metastatic PanNETs9. Despite improvements in molecular proﬁling and prognostic grading and staging systems, it remains a challenge to predict the clinical behavior of PanNETs and the response to speciﬁc therapies, given the high degree of heterogeneity of these tumors. While most PanNETs present as advanced disease, the available systemic therapies provide modest beneﬁts. Therefore, there is a particular need to develop more effective systemic therapies based on the molecular proﬁle of PanNETs

FAQs

What genetic changes were enriched in metastatic PanNETs compared with non-metastatic lesions?

Metastatic PanNETs showed an enrichment of CDKN2A homozygous deletions and TSC2 somatic mutations relative to non-metastatic lesions.

When during tumor progression did CDKN2A and TSC2-associated alterations tend to arise?

Tumor evolution analysis indicated these genetic alterations were acquired as late events during progression.

How were ATRX and DAXX loss events linked to genome alteration and molecular signatures?

Biallelic loss of ATRX and/or DAXX was associated with a high fraction of the genome altered, and pathogenic alterations in these genes aligned with a homologous recombination deficiency signature.

Sep 30, 2026

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