Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms.

Venizelos, Andreas; Sorbye, Halfdan; Elvebakken, Hege; Perren, Aurel; Lothe, Inger Marie B; Couvelard, Anne; Hjortland, Geir Olav; Sundlöv, Anna; Svensson, Johanna; Garresori, Harrish; Kersten, Christian; Hofsli, Eva; Detlefsen, Sönke; Vestermark, Lene W; Ladekarl, Morten; Tabaksblat, Elizaveta Mitkina; Knappskog, Stian (2023). Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms. Endocrine-related cancer, 30(10) BioScientifica 10.1530/ERC-23-0057

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High-grade gastroenteropancreatic (HG-GEP) NEN are highly aggressive cancers. The molecular etiology of these tumors remains unclear and the prevalence of pathogenic germline variants in patients with HG-GEP-NEN is unknown. We assessed sequencing data of 360 cancer genes in normal tissue, from 240 patients with HG GEP-NEN; 198 patients with NEC and 42 with NET G3. Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in 3 patients and a recurrent MUTYH variant in 2 patients, indicating that these genes may be important underlying risk factors for HG-GEP-NEN, when mutated. Further, germline variants were found in canonical tumor suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in-silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP-NEC. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG GEP-NEN with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG GEP-NEN.

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