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Sino-European Differences in the Genetic Landscape and Clinical Presentation of Pheochromocytoma and Paraganglioma


Abstract

CONTEXT

Pheochromocytomas and paragangliomas (PPGLs) are characterized by distinct genotype-phenotype relationships according to studies largely restricted to Caucasian populations.

OBJECTIVE

To assess for possible differences in genetic landscapes and genotype-phenotype relationships of PPGLs in Chinese versus European populations.

DESIGN

Cross-sectional study.

SETTING

2 tertiary-care centers in China and 9 in Europe.

PARTICIPANTS

Patients with pathologically confirmed diagnosis of PPGL, including 719 Chinese and 919 Europeans.

MAIN OUTCOME MEASURES

Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Frequencies of mutations were examined according to tumor location and catecholamine biochemical phenotypes.

RESULTS

Among all patients, higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. Among patients with apparently sporadic PPGLs, the most frequently mutated genes in Chinese were HRAS (16.5% [13.6-19.3] vs 9.8% [7.6-12.1]) and FGFR1 (9.8% [7.6-12.1] vs 2.2% [1.1-3.3]), whereas among Europeans the most frequently mutated genes were NF1 (15.9% [13.2-18.6] vs 6.6% [4.7-8.5]) and SDHx (10.7% [8.4-13.0] vs 4.2% [2.6-5.7]). Among Europeans, almost all paragangliomas lacked appreciable production of epinephrine and identified gene mutations were largely restricted to those leading to stabilization of hypoxia inducible factors. In contrast, among Chinese there was a larger proportion of epinephrine-producing paragangliomas, mostly due to HRAS and FGFR1 mutations.

CONCLUSIONS

This study establishes Sino-European differences in the genetic landscape and presentation of PPGLs, including ethnic differences in genotype-phenotype relationships indicating a paradigm shift in our understanding of the biology of these tumors.

Abstract

CONTEXT

Pheochromocytomas and paragangliomas (PPGLs) are characterized by distinct genotype-phenotype relationships according to studies largely restricted to Caucasian populations.

OBJECTIVE

To assess for possible differences in genetic landscapes and genotype-phenotype relationships of PPGLs in Chinese versus European populations.

DESIGN

Cross-sectional study.

SETTING

2 tertiary-care centers in China and 9 in Europe.

PARTICIPANTS

Patients with pathologically confirmed diagnosis of PPGL, including 719 Chinese and 919 Europeans.

MAIN OUTCOME MEASURES

Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Frequencies of mutations were examined according to tumor location and catecholamine biochemical phenotypes.

RESULTS

Among all patients, higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. Among patients with apparently sporadic PPGLs, the most frequently mutated genes in Chinese were HRAS (16.5% [13.6-19.3] vs 9.8% [7.6-12.1]) and FGFR1 (9.8% [7.6-12.1] vs 2.2% [1.1-3.3]), whereas among Europeans the most frequently mutated genes were NF1 (15.9% [13.2-18.6] vs 6.6% [4.7-8.5]) and SDHx (10.7% [8.4-13.0] vs 4.2% [2.6-5.7]). Among Europeans, almost all paragangliomas lacked appreciable production of epinephrine and identified gene mutations were largely restricted to those leading to stabilization of hypoxia inducible factors. In contrast, among Chinese there was a larger proportion of epinephrine-producing paragangliomas, mostly due to HRAS and FGFR1 mutations.

CONCLUSIONS

This study establishes Sino-European differences in the genetic landscape and presentation of PPGLs, including ethnic differences in genotype-phenotype relationships indicating a paradigm shift in our understanding of the biology of these tumors.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Endocrinology, Diabetes and Metabolism
Life Sciences > Biochemistry
Life Sciences > Endocrinology
Life Sciences > Clinical Biochemistry
Health Sciences > Biochemistry (medical)
Language:English
Date:1 October 2020
Deposited On:16 Feb 2021 10:40
Last Modified:17 Feb 2021 21:00
Publisher:Oxford University Press
ISSN:0021-972X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1210/clinem/dgaa502
PubMed ID:32750708

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