Abstract 3132: Tumorigenesis of MEN2 pheochromocytoma

Abstract

Abstract Backgrounds: Pheochromocytomas are catecholamine-secreting neuroendocrine tumors, which occur sporadically or as part of inherited syndromes, such as multiple endocrine neoplasia type2 (MEN2), caused by deleterious mutations within the RET protooncogene. Although the RET mutation is implicated in the development of MEN2-associated pheochromocytoma, there is a long (typically 40 years) latency period before the disease onset, suggesting the need of the acquisition of secondary hits. However, little is known about such secondary alterations involved in the pathogenesis of MEN2. In this study, we compared genetic profiles of MEN2 pheochromocytoma and its precursor lesion, adrenal medullary hyperplasia (AMH). Materials and methods: Samples were collected from surgical specimens in 6 MEN2 pheochromocytoma cases, including a MEN2B case with RET p.M918T and 5 MEN2A cases with RET p.C634F, p.C634F, p.C634Y, p.E768D and p.C620S, and 1 AMH case with MEN2A carrying RET p.C634Y. Spatially separated samples were collected from a tumor slice (“tumor parts”). Multiple microscale sampling was also performed from apparently normal adrenal medulla (“non-tumor parts”). Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. Result: Regarding “tumor parts”, a total of 20 samples from 6 MEN2 pheochromocytomas was analyzed. The number of somatic mutations per sample was ranging from 2 to 10. No somatic mutations commonly implicated in sporadic pheochromocytomas were detected. In a case with MEN2B, 1p, 3q and 21q losses were shared across all 3 samples, while 11p and 11q losses and 5p, 5q, 12p, 12q and 15q gains were private, suggesting that 1p, 3q and 21q losses occurred early in the tumorigenesis. In 5 MEN2A cases, 1p (80%), 3q (100%), 21q (60%) and 22q (60%) losses were frequently shared across all samples in each case. As for “non-tumor parts”, a total of 12 samples from 2 MEN2 pheochromocytoma cases and 1 AMH case were analyzed. The number of somatic mutations per sample ranged from 0 to 15. In 2 MEN2 pheochromocytoma cases, no somatic mutations were shared across the samples or no CNAs were detected, while 12 mutations were shared in two samples derived from an AMH case. Interestingly, these samples harbored 17p loss alone, while 1p, 3q, 21q or 22q losses were not found. Conclusion and perspective: MEN2 pheochromocytoma and AMH had different genetic characteristics, where 1p, 3q, 21q and 22q losses could have a role in early tumorigenesis. Further studies involving an increasing number of patients with MEN2 pheochromocytoma and AMH are warranted. Citation Format: Tatsuki Ogasawara, Yoichi Fujii, Nobuyuki Kakiuchi, Yusuke Shiozawa, Hiromichi Suzuki, Ryuichi Sakamoto, Yusaku Yoshida, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa. Tumorigenesis of MEN2 pheochromocytoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3132.