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

PURPOSE

Whether individuals with monoallelic pathogenic variants (PVs) associated with autosomal recessive fumarate hydratase (FH) deficiency are also at risk of autosomal dominant -associated tumors is of paramount clinical importance.

METHODS

A retrospective study of individuals with a PV in the gene identified via multigene panel testing from 2012 to 2019 through a single testing laboratory was performed. Cancer histories of individuals with PVs in ( PV) were compared to those with PVs associated only with autosomal recessive FH deficiency (FH-d PV) and to -negative controls. Cancer histories of individuals with truncating versus nontruncating PV were also compared.

RESULTS

Individuals with 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; < .001) or FH-negative controls (odds ratio, 7.6; 95% CI, 5.2 to 11.2; value < .001). The 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; = .011). Within the PV cohort, there were no differences in the frequency or age at kidney cancer between those with truncating versus nontruncating PV.

CONCLUSION

Unlike 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 -negative controls. These data may inform genetic counseling and risk assessment of individuals with FH-d PV.