Fumarate hydratase variant prevalence and manifestations among individuals receiving germline testing.

Abstract

BACKGROUND:

Germline variants in fumarate hydratase (FH) are associated with autosomal dominant (AD) hereditary leiomyomatosis and renal cell cancer (HLRCC) and autosomal recessive (AR) fumarase deficiency (FMRD). The prevalence and cancer penetrance across different FH variants remain unclear.

METHODS:

A database containing 120,061 records from individuals undergoing cancer germline testing was obtained. FH variants were classified into 3 categories: AD HLRCC variants, AR FMRD variants, and variants of unknown significance (VUSs). Individuals with variants from these categories were compared with those with negative genetic testing.

RESULTS:

FH variants were detected in 1.3% of individuals (AD HLRCC, 0.3%; AR FMRD, 0.4%; VUS, 0.6%). The rate of AD HLRCC variants discovered among reportedly asymptomatic individuals without a clear indication for HLRCC testing was 1 in 2668 (0.04%). In comparison with those with negative genetic testing, the renal cell carcinoma (RCC) prevalence was elevated with AD HLRCC variants (17.0% vs 4.5%; P < .01) and VUSs (6.4% vs 4.5%; P = .02) but not with AR FMRD variants.

CONCLUSIONS:

The prevalence of HLRCC discovered incidentally on germline testing is similar to recent population carrier estimates, and this suggests that this is a relatively common cancer syndrome. Compared with those with negative genetic testing, those with VUSs had an elevated risk of RCC, whereas those with AR FMRD variants did not.

• Authors: Eric Lu, Kathryn E Hatchell, Sarah M Nielsen, Edward D Esplin, Karen Ouyang, Keith Nykamp, Shirin Zavoshi, Shantao Li, Liying Zhang, Blake R Wilde, Heather R Christofk, Paul C Boutros, Brian Shuch
• Journal: Cancer (Cancer) Vol. 128 Issue 4 Pg. 675-684 (02 15 2022) ISSN: 1097-0142 [Electronic] United States
• PMID: 34724198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Cancer Society.

Chemical References

• Fumarate Hydratase

Topics

• Carcinoma, Renal Cell (epidemiology, genetics)
• Female
• Fumarate Hydratase (genetics)
• Germ Cells
• Germ-Line Mutation
• Humans
• Kidney Neoplasms (epidemiology, genetics)
• Leiomyomatosis (epidemiology, genetics, pathology)
• Neoplastic Syndromes, Hereditary (epidemiology, genetics, pathology)
• Prevalence
• Skin Neoplasms (epidemiology, genetics, pathology)
• Uterine Neoplasms (epidemiology, genetics, pathology)