Characterization of hereditary tumor risk in individuals with SDHA germline variants.

Abstract

10610 Background: Paragangliomas (PGLs) are rare neuroendocrine tumors with a high degree of heritability; up to 30% of individuals diagnosed with a PGL are estimated to have a germline pathogenic variant (GPV) related to hereditary PGL risk. GPVs in the SDHA gene have been associated with a PGL and gastrointestinal stromal tumor (GIST) risk lower than that of other hereditary PGL predisposition genes (van der Tuin et al . 2018). However, data about penetrance, tumor characteristics, and other aspects of SDHA carriers is limited. Further characterization of SDHA GPV is important to better understand tumor risks and develop SDHA -specific screening recommendations. Methods: Participants were identified from the Family Cancer Assessment Clinic at the University of Utah Huntsman Cancer Institute and had an SDHA pathogenic/likely pathogenic variant. Cancer diagnoses and diagnostic modalities were confirmed by medical records. Results: Out of 93 identified SDHA + individuals, 14 (15%) had a personal history of an SDHA -associated tumor (10 PGL and 4 GIST). None of these individuals also had a known family history of an SDHA -associated tumor. Average age at diagnosis was 37 (range = 17-69) with two diagnoses under age 18. There were no cases of multiple PGL/GIST in a single individual. Head and neck PGLs were the most common SDHA -associated tumor (7/14, 50%). They appeared to have lower malignancy risk (0/7, 0%) compared to extra-adrenal PGL (3/3, 100%) and GIST diagnoses (3/4, 75%). Secreting PGLs were rare (1/10, 10%). SDHB immunohistochemistry staining was completed for 8/14 PGL/GIST and was deficient in 5/8 (63%). Fifty-four (58%) SDHA + individuals were seen by HCI’s hereditary paraganglioma clinic and 39 (42%) had undergone some type of high-risk PGL screening as of January 2025. The most common reasons for not undergoing screening or being seen by the clinic included age <10 years old or >70 (8/93), deceased status (4/93), and current active cancer treatment (16/93). Fifty-eight of 93 (63%) SDHA variants were an incidental finding or a known familial variant without a family history of PGL/GIST. Zero (0/79) asymptomatic individuals have had a documented PGL/GIST diagnosis after SDHA + genetic testing. Conclusions: As work continues to develop gene-specific hereditary PGL screening recommendations, our analysis adds to the body of research affirming lower penetrance of SDHA variants compared to other hereditary PGL genes. Additionally, the lack of individuals with a personal and family history of SDHA -associated tumors or with multiple tumors indicates that a more nuanced approach to screening recommendations in this patient population is likely warranted. However, the younger age of onset and increased malignancy risk seen in the affected individuals in our study compared to sporadic PGL indicates that in certain contexts, such as in an individual diagnosed with a PGL/GIST, an SDHA GPV could impact surgical and treatment decisions.