NANETS2022 15th Annual Multidisciplinary NET Medical Symposium NANETS 2022 Other (12 abstracts)
Germline Pathogenic Variants in Patients with High-Grade (G3) Metastatic Gastroenteropancreatic (GEP) Neuroendocrine Neoplasms (NENs)
Farhana Moon 1 , Bryan Khuong Le 1 , Alan Paciorek 2 , Amie Blanco 3 , Adrienne Wakeling 3 , Claire K. Mulvey 4 , Li Zhang 2 , Nancy M. Joseph 5 & Emily Bergsland 4
1Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; 2Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA; 3Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA; 4Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA, USA; 5Department of Pathology, University of California San Francisco, San Francisco, CA, US.
Background: The incidence of germline pathogenic/likely pathogenic variants (P/LPV) is relatively well described in low grade well differentiated neuroendocrine tumors (NETs). However, germline findings in G3 NENs including grade 3 NETs (G3NET) and poorly differentiated neuroendocrine carcinoma (NEC) is gravely understudied, and guidance related to germline testing in G3NEN is lacking.
Methods: An IRB approved, single institution, retrospective chart review was performed in patients with metastatic G3NEN of gastro enteropancreatic (GEP) origin and unknown primary in whom both tumor DNA sequencing and germline testing were performed as part of clinical care. Pathology reports and clinical history were reviewed by one pathologist to best reclassify as G3NETs, NECs or ambiguous G3NEN. Data were collected from germline and tumor molecular sequencing reports. In patients harboring a germline P/LPV, somatic P/LPV were evaluated.
Results: Among 88 UCSF patients with G3NEN, 15 (17%) had germline P/LPV (14 patients with one and 1 with 2); see Table for details. Median age at the time of metastatic G3NEN was 58 years (range 26-84). Primary tumor sites: pancreas (n=30), colorectum (CR) (n=23), other gastrointestinal (GI) (n=14), and unknown (n=21). Histologic subtypes: 34 NEC, 24 G3NET, and 30 ambiguous G3NEN. Fifteen of 16 total germline P/LPV were also evaluable on somatic panels and 10 (67%) were present in the tumor with high mutant allele frequency (maf), suggesting a role in tumorigenesis. Five of 15 germline P/LPV (33%, 2 MUTYH, 1 BRCA1, 1 APC, and 1 PALB2) were not present or had significantly decreased maf in the tumor, arguing against a role in tumorigenesis.
| Gene | Mutated in germline (n) | Mutated in tumor (n) | Differentiation | Site |
| MUTYH | 4 | 2 | 1 NEC | 2 Pancreas |
| BRCA1 | 2 | 1 | 1 NEC | 1 Pancreas |
| APC | 2 | 1 | NEC | 1 CR |
| BRCA2 | 1 | 1 | Ambiguous | CR |
| MLH1 | 1 | 1 | NEC | CR |
| MSH6 | 1 | 1 | Ambiguous | CR |
| NTHL1** | 1 | ** | Ambiguous | Pancreas |
| PALB2 | 1 | 0 | NET | CR |
| ATM | 1 | 1 | NEC | GI |
| CHEK2 and MEN1 | 1 | 1 (CHEK2 & MEN1) | NET | Pancreas |
Conclusion: Germline P/LPV were identified in 17% of patients with GEP G3NENs, with 67% present at high maf in the tumor-supporting a role in G3NEN pathogenesis and with potential therapeutic implications in some cases. The findings suggest a role for germline genetic testing in all patients with G3NEN.
Abstract ID 21410
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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