Renal cell carcinoma risk among individuals heterozygous for fumarate hydratase variants: further insights into genotype-phenotype correlations

BACKGROUND: FH-tumor predisposition syndrome (FH-TPS) is an autosomal dominant cancer predisposition syndrome caused by the fumarate hydratase (FH) gene. FH was initially shown to cause hereditary leiomyomatosis and renal cell cancer (HLRCC), historically called Reed syndrome. More recently, certain germline FH variants have been linked to pheochromocytoma (PHEO) risk in individuals without features of HLRCC. Diagnosis of these apparently non-overlapping conditions, FH-TPS-PHEO and FH-TPS-HLRCC, has increased through application of broad hereditary cancer gene panels. Early HLRCC studies suggested high lifetime RCC risk; however, emerging data suggests RCC risk in FH-TPS-HLRCC is lower than previous estimates. METHODS: Individuals with likely pathogenic or pathogenic (LPV/PV) FH variants were identified in a large, ethnically diverse health system. Heterozygotes were classified as FH-TPS-PHEO, FH-TPS-HLRCC, or FH-ARC (autosomal recessive carrier for congenital fumarate hydratase deficiency without FH-TPS risk) based on variant phenotype-genotype prediction. Groups were evaluated for demographics, FH testing indications, FH-TPS-HLRCC related clinical features, and RCC. Cumulative RCC incidence was estimated via Aalen-Johansen estimator. RESULTS: Among 279 individuals with LPV/PV in FH, 4 had FH-TPS-PHEO, 111 FH-TPS-HLRCC, and 164 FH-ARC. The FH-TPS-HLRCC and FH-ARC groups were approximately two-thirds female. FH-ARC was less ethnically diverse due to a common variant in Northern Europeans (c.1431_1433dup). One-third of FH-TPS-HLRCC individuals underwent testing for cancer-related indications unrelated to FH-TPS-HLRCC, and nearly 75% of these were women who had uterine leiomyomata suggestive of FH-TPS-HLRCC. One-quarter of FH-TPS-HLRCC individuals were diagnosed via cascade testing, 40% of whom had clinical features of FH-TPS-HLRCC. RCC occurred in nine patients (5 FH-TPS-HLRCC, 3 FH-ARC, 1 FH-TPS-PHEO). All RCCs in FH-TPS-HLRCC were FH-deficient and occurred at earlier average age than the sporadic RCC in other groups. Cumulative RCC incidence by age 70 was 7.3% (95% CI 2.1-15.3%) in FH-TPS-HLRCC and 2.6% (95% CI 0.0-7.1%) in FH-ARC. RCC risk before age 25 in FH-TPS-HLRCC was negligible. CONCLUSIONS: FH-TPS-HLRCC is underdiagnosed and RCC risk is lower than earlier HLRCC estimates. Many individuals are identified through broad hereditary cancer gene panel testing and exhibit less obvious manifestations such as uterine leiomyomata. Adult RCC surveillance is warranted in FH-TPS-HLRCC, but the need for pediatric screening merits further study.