Biomedical
Current prospects of hereditary adrenal tumors: towards better clinical management
Peer Reviewed
Abstract
Adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PPGL) are two rare types of adrenal gland malignancies. Regarding hereditary tumors, some patients with ACC are associated with with Li-Fraumeni syndrome (LFS), and those with PPGL with multiple endocrine neoplasia type 2. Recent studies have expanded this spectrum to include other types of hereditary tumors, such as Lynch syndrome or familial adenomatous polyposis. Individuals harboring germline TP53 pathogenic variants that cause LFS have heterogeneous phenotypes depending on the respective variant type. As an example, R337H variant found in Brazilian is known as low penetrant. While 50–80% of pediatric ACC patients harbored a LFS, such a strong causal relationship is not observed in adult patients, which suggests different pathophysiologies between the two populations. As for PPGL, because multiple driver genes, such as succinate dehydrogenase (SDH)-related genes, RET, NF1, and VHL have been identified, universal multi-gene germline panel testing is warranted as a comprehensive and cost-effective approach. PPGL pathogenesis is divided into three molecular pathways (pseudohypoxia, Wnt signaling, and kinase signaling), and this classification is expected to result in personalized medicine based on genomic profiles. It remains unknown whether clinical characteristics differ between cases derived from genetic predisposition syndromes and sporadic cases, or whether the surveillance strategy should be changed depending on the genetic background or whether it should be uniform. Close cooperation among medical genomics experts, endocrinologists, oncologists, and early investigators is indispensable for improving the clinical management for multifaceted ACC and PPGL.
Key Questions
What are the primary hereditary syndromes associated with adrenal tumors?
Hereditary adrenal tumors are primarily associated with syndromes such as Li-Fraumeni syndrome (LFS) for adrenocortical carcinoma (ACC) and multiple endocrine neoplasia type 2 (MEN2) for pheochromocytoma/paraganglioma (PPGL). Recent studies have also linked these tumors to other hereditary conditions like Lynch syndrome and familial adenomatous polyposis.
How do genetic variants influence the development of ACC and PPGL?
Individuals with germline pathogenic variants, such as those in the TP53 gene causing LFS, exhibit varying phenotypes. For instance, the R337H variant found in Brazilian populations is known for its low penetrance. While 50–80% of pediatric ACC patients harbor LFS-related variants, this strong association is less evident in adults, suggesting different pathophysiological mechanisms between age groups.
What is the significance of multi-gene germline panel testing in PPGL?
Given the identification of multiple driver genes in PPGL, including SDH-related genes, RET, NF1, and VHL, comprehensive multi-gene germline panel testing is recommended as a cost-effective approach to understand the genetic underpinnings and guide personalized treatment strategies.
Why is interdisciplinary collaboration important in managing hereditary adrenal tumors?
Effective management of ACC and PPGL requires close cooperation among medical genomics experts, endocrinologists, oncologists, and researchers. Such collaboration is essential to improve clinical outcomes through personalized treatment plans and to advance our understanding of these complex conditions.
