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.
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.
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.
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.
Cancer. 2021 Nov 01 [Epub ahead of print]
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
Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, California., Invitae, San Francisco, California., Institute of Urologic Oncology, University of California Los Angeles, Los Angeles, California., Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut., Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California., Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California., Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.