Fumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma

Shirin Zavoshi; Eric Lu; Paul C Boutros; Liying Zhang; Avital Harari; Kathryn E Hatchell; Sarah M Nielsen; Edward D Esplin; Karen Ouyang; Keith Nykamp; Blake Wilde; Heather Christofk; Brian Shuch

doi:10.1016/j.urology.2022.11.053

Fumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma

Urology. 2023 Jun:176:106-114. doi: 10.1016/j.urology.2022.11.053. Epub 2023 Feb 10.

Authors

Shirin Zavoshi¹, Eric Lu², Paul C Boutros³, Liying Zhang⁴, Avital Harari⁵, Kathryn E Hatchell⁶, Sarah M Nielsen⁶, Edward D Esplin⁶, Karen Ouyang⁶, Keith Nykamp⁶, Blake Wilde⁷, Heather Christofk⁸, Brian Shuch⁹

Affiliations

¹ Department of Internal Medicine, Ascension St. John Hospital, Detroit, MI; Institute of Urologic Oncology, University of California, Los Angeles, Los Angeles, CA.
² Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA.
³ Institute of Urologic Oncology, University of California, Los Angeles, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA; Departments of Human Genetics and Urology, University of California, Los Angeles, CA.
⁴ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA.
⁵ Division of Endocrine Surgery, Department of Surgery, University of California, Los Angeles, Los Angeles, CA.
⁶ Invitae, San Francisco, CA.
⁷ Department of Biologic Chemistry, University of California, Los Angeles, Los Angeles, CA.
⁸ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA; Department of Biologic Chemistry, University of California, Los Angeles, Los Angeles, CA.
⁹ Institute of Urologic Oncology, University of California, Los Angeles, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA. Electronic address: [email protected].

PMID: 36773955
DOI: 10.1016/j.urology.2022.11.053

Abstract

Objective: To clarify the link between germline variants in fumarate hydratase (FH), hereditary leiomyomatosis and renal cell cancer (HLRCC), and paraganglioma (PGL) and pheochromocytoma (PCC) we utilize a well-annotated hereditary cancer testing database.

Methods: Records of 120,061 patients receiving germline testing were obtained. FH variants were classified into 4 categories: autosomal dominant (AD) HLRCC variants, autosomal recessive (AR) fumarase deficiency (FMRD), variants, previously reported as PGL/PCC FH variants, and variants of unknown significance (VUS) not previously associated with PGL/PCC (NPP-VUS). Rates of PGL/PCC were compared with those with negative genetic testing.

Results: About 1.3% of individuals carried FH variants which were more common among individuals with PGL/PCC compared to those without (3.1% vs 1.3%, P < .0001). PGL/PCC rates were higher among individuals with PGL/PCC FH variants compared to those with negative genetic testing (22.2% vs 0.9%, P < .0001). Neither AD HLRCC variants (0.3% vs 0.9%, P = .35) nor AR FMRD variants (1.4% vs 0.9%, P = .19) carried an increased prevalence of PGL/PCC. An increased prevalence of PGL/PCC was detected in those with NPP-VUS (2.0% vs 0.9%, P = .0023).

Conclusions: Certain FH variants confer an increased risk of PGL/PCC, but not necessarily HLRCC. While universal screening for PGL/PCC among all individuals with FH variants does not appear warranted, it should be considered in select high-risk PGL/PCC FH variants.

MeSH terms

Adrenal Gland Neoplasms* / genetics
Female
Fumarate Hydratase / genetics
Humans
Paraganglioma* / genetics
Pheochromocytoma* / genetics
Skin Neoplasms* / genetics
Uterine Neoplasms*

Substances

Fumarate Hydratase

Supplementary concepts

Fumaric aciduria
Hereditary leiomyomatosis and renal cell cancer