Different Fumarate Hydratase Gene Variants Are Associated With Distinct Cancer Phenotypes.

Abstract

Whether individuals with monoallelic <i>FH</i> pathogenic variants (PVs) associated with autosomal recessive fumarate hydratase (FH) deficiency are also at risk of autosomal dominant <i>FH</i>-associated tumors is of paramount clinical importance. A retrospective study of individuals with a PV in the <i>FH</i> gene identified via multigene panel testing from 2012 to 2019 through a single testing laboratory was performed. Cancer histories of individuals with PVs in <i>FH</i> (<i>FH</i> PV) were compared to those with PVs associated only with autosomal recessive FH deficiency (FH-d PV) and to <i>FH</i>-negative controls. Cancer histories of individuals with truncating versus nontruncating <i>FH</i> PV were also compared. Individuals with <i>FH</i> PV were more likely to have kidney cancer than those with FH-d PV (odds ratio, 9.0; 95% CI, 4.4 to 20.0; <i>P</i> < .001) or FH-negative controls (odds ratio, 7.6; 95% CI, 5.2 to 11.2; <i>P</i> value < .001). The <i>FH</i> PV cohort had kidney cancer at a significantly younger age (median age: 35.0 years; interquartile range, 26.0-45.0 years) than the FH-d PV cohort (median age: 44.5 years; interquartile range, 43.5-53.5 years; <i>P</i> = .011). Within the <i>FH</i> PV cohort, there were no differences in the frequency or age at kidney cancer between those with truncating versus nontruncating PV. Unlike <i>FH</i> PV, FH-d PV are not associated with kidney cancers at early ages of onset. The FH-d PV cohort had a cancer phenotype that resembled <i>FH</i>-negative controls. These data may inform genetic counseling and risk assessment of individuals with FH-d PV.