Genetic and Clinical Profiles of Pheochromocytoma and Paraganglioma: A Single Center Study

Abstract

Pheochromocytoma/paraganglioma (PPGL) has a high genetic heterogeneity with 40% germline variants in known pathogenic genes. Data in Chinese on this aspect are scanty. To detect the genetic and clinical profile of Chinese PPGL patients, we examined the variants of 12 known germline pathogenic genes (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127, and KIF1B) by next-generation sequencing and Sanger sequencing in 314 Chinese PPGL subjects. Twenty nine percent of Chinese PPGL patients had germline variants and SDHB was the most frequently mutated (14.6%). The most frequent SDHB variants were in exon 2, exon 7, and IVS 7. Pathogenic variants were more likely to occur in metastatic PPGL patients, paragangliomas, and patients under 30, with the ratio being 50.7% (35/69), 35.9% (56/156), and 49.5% (52/105), respectively. Our cohort included 314 patients from a single setting. The genetic and clinical features of Chinese PPGL patients were unique in some aspects compared to their non-Chinese counterparts. Identification of genotype-phenotype relation can serve as an effective tool for genetic prioritization and clinical decision-making.

Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma

“…The overall frequency of germline variants in our study cohort (32.4%) is consistent with that in the reported European cohorts (27.4-32.9%) [5][6][7] and with recent reports in Asians (32.6-34.1%) [22,23,31]. The prevalence of variants in AS presentations vary widely (11.0-36.6%) [6,11,12,18,[21][22][23] depending on the definition of "sporadic" and the number of genes investigated.…”

“…This study suggested that the genetic background of PPGL and the associated genotype-phenotype relationship established in Caucasian populations may not apply to Asian populations. It is also worth noting that in the few cohort studies of PPGL in Asia [21][22][23], the profiles of the most common mutated gene and the recurring SDHB variants vary widely by ethnicity even within Asia. In several case reports and case series from Japan, characteristic variants with PPGL have been reported [24][25][26][27][28]; however, there are no comprehensive national studies.…”

Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma

“…Pheochromocytoma associated with a pathogenic variant occurs at a younger age than pheochromocytoma cases without any mutation ( 8 ). Although there is no clear age limit, having been diagnosed younger than 30–45 may indicate the presence of a mutation.…”

Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas

“…In the recent years, molecular pathogenesis of this group of lesions has advanced significantly. Almost 40% of PPGLs patients carry germline mutations in a growing list of genes including SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, MAX, TEMEM127, FH, NF1, and KIF1B [ 3 , 4 ]. Besides, genes such as EGLN1, EGLN2, MDH2, SLC25A11, MERTK , DLST , and KMT2D are also shown to be related to PPGLs [ 5 – 10 ].…”

“…Recently, whole exome sequencing (WES) technology has been employed to detect germline variations of 121 patients who did not have mutations on definite pathogenic genes. In our previous report, the use of next-generation sequencing (NGS) covering SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, MAX, TEMEM127, FH, NF1, and KIF1B was analyzed in the cohort with 314 PPGL patients [ 3 ]. Among them, four patients showed CHEK2 gene heterozygous mutations.…”