Data from Germline Testing Identifies Pathogenic/Likely Pathogenic Variants in Patients with Pancreatic Neuroendocrine Tumors

Abstract

<div>Abstract<p>Ten percent of pancreatic neuroendocrine tumors (pNET) are related to inherited syndromes (<i>MEN1</i>, <i>MEN4</i>, <i>VHL</i>, <i>NF1</i>, and <i>TSC</i>). Growing evidence suggests that clinically sporadic pNETs can also harbor germline pathogenic variants. In this study, we report the prevalence of pathologic/likely pathologic (P/LP) germline variants in a high-risk cohort and an unselected cohort. We collected clinical data of patients with pNETs seen at MD Anderson Cancer Center and Johns Hopkins Hospital. The high-risk cohort included (<i>n</i> = 132) patients seen at MD Anderson Cancer Center who underwent germline testing for high-risk criteria (early onset, personal or family history of cancer, and syndromic features) between 2013 and 2019. The unselected cohort included (<i>n</i> = 106) patients seen at Johns Hopkins Hospital who underwent germline testing following their diagnosis of pNETs between 2020 and 2022. In the high-risk cohort (<i>n</i> = 132), 33% (<i>n</i> = 44) had P/LP variants. The majority of the patients had P/LP variants in <i>MEN1</i> 56% (<i>n</i> = 25), followed by DNA repair pathways 18% (<i>n</i> = 8), and 7% (<i>n</i> = 3) in MSH2 (Lynch syndrome). Patients with P/LP were younger (45 vs. 50 years; <i>P</i> = 0.002). In the unselected cohort (<i>n</i> = 106), 21% (<i>n</i> = 22) had P/LP. The majority were noted in DNA repair pathways 40% (<i>n</i> = 9) and <i>MEN1</i> 36% (<i>n</i> = 8). Multifocal tumors correlated with the presence of P/LP (<i>P</i> = 0.0035). <i>MEN1</i> germline P/LP variants correlated with younger age (40 vs. 56 years; <i>P</i> = 0.0012), presence of multifocal tumors (<i>P</i> < 0.0001), and World Health Organization grade 1 histology (<i>P</i> = 0.0078). P/LP variants are prevalent in patients with clinically sporadic pNET irrespective of high-risk features. The findings support upfront universal germline testing in all patients with pNET.</p><p><b>Prevention Relevance:</b> Here, we present germline data from the largest reported cohort of patients with pNET (<i>n</i> = 238), comprising both a high-risk cohort and an unselected cohort. In both cohorts, we identify a high number of P/LPs, including those in the DNA repair pathway. Our findings support universal germline testing in patients with pNET.</p></div>