Dataset Information

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.

ABSTRACT:

Purpose

Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma-pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols.

Methods

A multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing.

Results

Two hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n?=?188/263, 72%), followed by SDHD (n?=?35/263, 13%) and SDHC (n?=?28/263, 11%). SDHx-related tumors were found in 17% (n?=?45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n?=?39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n?=?14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n?=?12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n?=?75/491) of imaging screens.

Conclusion

Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.

SUBMITTER: Greenberg SE

PROVIDER: S-EPMC7710583 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.

Greenberg Samantha E SE Jacobs Michelle F MF Wachtel Heather H Anson Amanda A Buchmann Luke L Cohen Debbie L DL Bonanni Maria M Bennett Bonita B Naumer Anne A Schaefer Amanda M AM Kohlmann Wendy W Nathanson Katherine L KL Else Tobias T Fishbein Lauren L

Genetics in medicine : official journal of the American College of Medical Genetics 20200803 12

<h4>Purpose</h4>Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma-pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols.<h4>Methods</h4>A multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and ...[more]

PMID: 32741965

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Project description:BackgroundPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.MethodsMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.ResultsComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.ConclusionsThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

Dataset Information

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.

Purpose

Methods

Results

Conclusion

Publications

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.

Similar Datasets

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