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. 2023 May 10;3(1):e220091.
doi: 10.1530/EO-22-0091. eCollection 2023 Jan 1.

Germline genetic variants in pheochromocytoma/paraganglioma: single-center experience

José V Lima Jr  1   2   3 , Nilza M Scalissi  2 , Kelly C de Oliveira  1 , Susan C Lindsey  1 , Caroline Olivati  3 , Elisa Napolitano Ferreira  3 , Claudio E Kater  1
Affiliations

Germline genetic variants in pheochromocytoma/paraganglioma: single-center experience

José V Lima Jr et al. Endocr Oncol. .

Abstract

Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET (n = 18; 38.3%), VHL (n = 10; 21.3%), SDHB and NF1 (n = 8; 17% each), and MAX, SDHD, TMEM127, and TP53 (n = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.

Keywords: MAX; NF1; RET; SDHB; SDHD; TMEM127; VHL.

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Conflict of interest statement

There is no conflict of interest that could be perceived as prejudicing the impartiality of this research.

Figures

Figure 1
Figure 1
Genetic distribution of 101 PPGL patients (excluding 14 relatives) and 105 PPGL controls according to ACMG criteria.
Figure 2
Figure 2
Distribution of 72 germline variants in 101 PPGL patients (excluding 14 relatives).
See this image and copyright information in PMC

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