7620 BIUXX
Authors: Jeong Park Min , Shin Park Seung , Hee Kim Jung , Hun Lee Seung , Min Cho Young , Wan Kim Sang , Soo Shin Chan , Koh Jung-Min 
Published: October 2024

Disclosure: M. Park: None. S. Park: None. J. Kim: None. S. Lee: None. Y. Cho: None. S. Kim: None. C. Shin: None. J. Koh: None.

Background: Pheochromocytoma and paragangliomas (PPGLs) are rare but ﻿has the highest known heritability rate (up to 40%) among all human tumors. Recent advances in genetic testing and an understanding of PPGLs, the “old” genotype-phenotype correlation in these tumors is now being challenged. In this study, we aimed to evaluate the prevalence of germline mutations, and clinical characteristics of patients according to genotype clusters using in a large Korean cohort of PPGL. Materials and Methods: Among 986 patients with PPGL, consecutively enrolled at two tertiary centers from 2000 to 2023, 363 patients underwent genetic testing for germline mutations, including methods such as next-generation sequencing, Sanger sequencing, and multiplex ligation-dependent probe amplification. Anatomical, biochemical, and other clinical information were collected as phenotypic data. We compared the phenotypes based on 1) the presence of mutations and 2) genotype clusters. The genotype clusters were categorized into pseudohypoxia group, further divided into tricarboxylic acid (TCA) cycle (SDHA, SDHB, SDHC, SDHD, and FH) and VHL/EPAS1 (VHL, EPAS1, EGLN1, and PHD1/PHD2), as well as kinase signaling group (RET, NF1, TMEM127, MAX, KIF1B, and MET). Results: Among 363 patients (187 females), 102 (28.1%) PPGL patients harbored a germline mutation. The prevalence of each driver gene mutations was as follows: RET: 26 (7.2%), SDHB: 23 (6.3%), VHL: 22 (6.1%), SDHD: 9 (2.48%), NF: 7 (1.9%), SDHC: 4 (1.10%), FH: 2 (0.55%), EGLN1/2: 2 (0.55%), MAX: 2 (0.55%), KIF1B:1 (0.27%), SDHA: 1 (0.27%). The pseudohypoxia group (n=66) was male-dominant (59.1% vs. 33.3%), and paraganglioma-dominant (59.1% vs. 11.1%) compared to the kinase signaling group (n=36) (all p &lt;0.05). The predominant secretory type was norepinephrine type in the pseudohypoxia group (43.9%) and epinephrine type in the kinase signaling group (66.7%) (p &lt;0.001). The pseudohypoxia group presented a larger tumor size (4.8 vs. 2.5 cm) and metastatic tumors at diagnosis (15.2% vs. 2.7%) than the kinase signaling group (all p &lt;0.05). Metastasis at the diagnosis and during follow-up was detected in 33 (9.1%) of all patients. During the median follow-up duration of 42 months (interquartile range, 18 - 80 months), the kinase signaling group did not develop metastasis. Compared to the wild-type group, the recurrence risk was higher in the pseudohypoxia group (hazard ratio [95% confidence interval] = 3.33 [1.49-7.42], but it was similar in the kinase signaling group. Within the pseudohypoxia group, only the TCA group was at 2.93-fold higher risk of recurrence than wild-type group. Conclusion: ﻿This large Korean cohort study demonstrates that PPGL patients with mutation in the pseudohypoxia group, particularly those in the TCA subcategory had a larger size and a higher recurrence risk than those with mutation in the kinase signaling group or those with wild type.

Presentation: 6/1/2024