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Updated: May 3, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Pancreatic neuroendocrine tumors and MUTYH pathogenic variants: a multinational study
Rachel P Riechelmann1, Giovana T Torrezan2,3, Emily Bergsland4
1Department of Clinical Oncology and Neuroendocrine Tumors Reference Center, AC Camargo Cancer Center, Rua Antônio Prudente 211, São Paulo 01509-010, Brazil.
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.
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