Pancreatic neuroendocrine tumors and pathogenic variants: a multinational study
Background: Germline pathogenic variants (GPV) in MUTYH are rare in patients with pancreatic neuroendocrine tumors (PanNET). Objectives: We aimed to characterize PanNET patients with GPV and/or somatic pathogenic variants (SPV) in MUTYH . Design: Retrospective multicenter cohort. Methods: Patients w...
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SAGE Publishing
2025-07-01
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| Series: | Therapeutic Advances in Medical Oncology |
| Online Access: | https://doi.org/10.1177/17588359251356335 |
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| author | Rachel P. Riechelmann Giovana T. Torrezan Emily Bergsland Nitya Raj Jonathan Strosberg Farhana Moon Tiago C. Felismino Stian Knappskog Elena Trevizani Sara Cingarlini Halfdan Sorbye |
| author_facet | Rachel P. Riechelmann Giovana T. Torrezan Emily Bergsland Nitya Raj Jonathan Strosberg Farhana Moon Tiago C. Felismino Stian Knappskog Elena Trevizani Sara Cingarlini Halfdan Sorbye |
| author_sort | Rachel P. Riechelmann |
| collection | DOAJ |
| description | Background: Germline pathogenic variants (GPV) in MUTYH are rare in patients with pancreatic neuroendocrine tumors (PanNET). Objectives: We aimed to characterize PanNET patients with GPV and/or somatic pathogenic variants (SPV) in MUTYH . Design: Retrospective multicenter cohort. Methods: Patients with PanNET harboring MUTYH pathogenic variants ( MUTYH +) were identified from centers in Brazil, Europe, and the USA. Data were extracted from medical records. Germline or somatic variants were evaluated by targeted sequencing of cancer-associated genes. The primary endpoint was to clinically characterize these patients and the secondary endpoint was overall survival (OS). Aggressive behavior was defined as rapid progression, transformation to neuroendocrine carcinoma (NEC)-like histology and/or OS of <2 years from first-line treatment. All cases were diagnosed by expert pathologists. Results: In total, 23 patients with MUTYH +-associated PanNET were identified (17 germline; 4 somatic). Median age was 48 years (22–72), 65% were male, 12 (52%) had first-degree family history of cancer, and 70% had synchronic metastatic disease. Tumors were of G1, G2, and G3 in 17%, 52%, and 31%, of cases, respectively, and median KI-67 was 12% (2%–80%). Seven of 11 (64%) G1/G2 PanNET with tumor biopsy upon progression evolved to G3 (3 NEC-like). Median OS of 19 patients with metastases was 4.6 years (95% confidence interval (CI): 2.4–6.8), with 12 (63%) cases demonstrating aggressive behavior. MUTYH p.Gly396Asp and p.Tyr179Cys were the most frequent variants (mostly GPV). Of 13 tumors arising in patients with germline MUTYH mutations and tested for loss of heterozygosis of the wild allele, 6 (50%) exhibited a second hit event in MUTYH , with 4 demonstrating aggressive behavior. Tumor mutation burden (TMB) was low in the six treatment-naïve PanNET (TMB: 0–9) with this information, but three of seven tumors molecularly profiled after alkylating drugs and/or radioligand therapy had high TMB (TMB: 97, 65, and 728). Conclusion: MUTYH mutation-associated PanNET (germline and/or somatic) is associated with aggressive and high-grade disease when metastatic. |
| format | Article |
| id | doaj-art-65f514d218ef4fed9abd4e7c94775ad6 |
| institution | DOAJ |
| issn | 1758-8359 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Therapeutic Advances in Medical Oncology |
| spelling | doaj-art-65f514d218ef4fed9abd4e7c94775ad62025-08-20T03:13:45ZengSAGE PublishingTherapeutic Advances in Medical Oncology1758-83592025-07-011710.1177/17588359251356335Pancreatic neuroendocrine tumors and pathogenic variants: a multinational studyRachel P. RiechelmannGiovana T. TorrezanEmily BergslandNitya RajJonathan StrosbergFarhana MoonTiago C. FelisminoStian KnappskogElena TrevizaniSara CingarliniHalfdan SorbyeBackground: Germline pathogenic variants (GPV) in MUTYH are rare in patients with pancreatic neuroendocrine tumors (PanNET). Objectives: We aimed to characterize PanNET patients with GPV and/or somatic pathogenic variants (SPV) in MUTYH . Design: Retrospective multicenter cohort. Methods: Patients with PanNET harboring MUTYH pathogenic variants ( MUTYH +) were identified from centers in Brazil, Europe, and the USA. Data were extracted from medical records. Germline or somatic variants were evaluated by targeted sequencing of cancer-associated genes. The primary endpoint was to clinically characterize these patients and the secondary endpoint was overall survival (OS). Aggressive behavior was defined as rapid progression, transformation to neuroendocrine carcinoma (NEC)-like histology and/or OS of <2 years from first-line treatment. All cases were diagnosed by expert pathologists. Results: In total, 23 patients with MUTYH +-associated PanNET were identified (17 germline; 4 somatic). Median age was 48 years (22–72), 65% were male, 12 (52%) had first-degree family history of cancer, and 70% had synchronic metastatic disease. Tumors were of G1, G2, and G3 in 17%, 52%, and 31%, of cases, respectively, and median KI-67 was 12% (2%–80%). Seven of 11 (64%) G1/G2 PanNET with tumor biopsy upon progression evolved to G3 (3 NEC-like). Median OS of 19 patients with metastases was 4.6 years (95% confidence interval (CI): 2.4–6.8), with 12 (63%) cases demonstrating aggressive behavior. MUTYH p.Gly396Asp and p.Tyr179Cys were the most frequent variants (mostly GPV). Of 13 tumors arising in patients with germline MUTYH mutations and tested for loss of heterozygosis of the wild allele, 6 (50%) exhibited a second hit event in MUTYH , with 4 demonstrating aggressive behavior. Tumor mutation burden (TMB) was low in the six treatment-naïve PanNET (TMB: 0–9) with this information, but three of seven tumors molecularly profiled after alkylating drugs and/or radioligand therapy had high TMB (TMB: 97, 65, and 728). Conclusion: MUTYH mutation-associated PanNET (germline and/or somatic) is associated with aggressive and high-grade disease when metastatic.https://doi.org/10.1177/17588359251356335 |
| spellingShingle | Rachel P. Riechelmann Giovana T. Torrezan Emily Bergsland Nitya Raj Jonathan Strosberg Farhana Moon Tiago C. Felismino Stian Knappskog Elena Trevizani Sara Cingarlini Halfdan Sorbye Pancreatic neuroendocrine tumors and pathogenic variants: a multinational study Therapeutic Advances in Medical Oncology |
| title | Pancreatic neuroendocrine tumors and pathogenic variants: a multinational study |
| title_full | Pancreatic neuroendocrine tumors and pathogenic variants: a multinational study |
| title_fullStr | Pancreatic neuroendocrine tumors and pathogenic variants: a multinational study |
| title_full_unstemmed | Pancreatic neuroendocrine tumors and pathogenic variants: a multinational study |
| title_short | Pancreatic neuroendocrine tumors and pathogenic variants: a multinational study |
| title_sort | pancreatic neuroendocrine tumors and pathogenic variants a multinational study |
| url | https://doi.org/10.1177/17588359251356335 |
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