Association between fumarate hydratase variant subtypes and the risk of HLRCC-associated renal cell carcinoma: systematic review and meta-analysis

Abstract

Background: Fumarate hydratase (FH) is a key mitochondrial enzyme in the tricarboxylic acid (TCA) cycle, catalyzing the reversible hydration of fumarate to malate, thereby facilitating aerobic ATP production and maintaining metabolic homeostasis. Germline pathogenic or likely pathogenic variants in the FH gene are strongly linked to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a rare hereditary cancer syndrome characterized by cutaneous and/or uterine leiomyomas and a markedly increased risk of renal cell carcinoma (RCC). These variants span a wide spectrum of genetic alterations, including missense, nonsense, frameshift, splice-site variants, as well as large genomic deletions. However, the relationship between specific pathogenic FH variant subtypes and the risk of developing HLRCC-associated RCC remains unclear. Therefore, this study systematically reviewed the existing literatures and conducted a meta-analysis to preliminarily explore the potential role of different functional subtypes of FH variants in the development of HLRCC-associated RCC, providing a basis for future clinical risk stratification and personalized surveillance strategies.

Methods: We systematically searched 4 major electronic databases—PubMed/MEDLINE, Embase, Scopus, and Web of Science—for relevant studies. To evaluate the association between pathogenic or likely pathogenic FH variant subtypes (Missense vs. Loss-of-Function (LOF)) and the risk of HLRCC-associated RCC, we performed a fixed-effects meta-analysis based on unadjusted odds ratios (ORs). In addition, exploratory subgroup analyses were performed by geographic region (North America and Europe), histological subtype (particularly type II papillary RCC (Type II PRCC)), tumor characteristics (such as distant metastasis and clinical stage), and study design (variant/gene-first vs. phenotype-first). These stratifications were intended to assess whether clinical or methodological features might modulate the observed associations and to provide context for future hypothesis-driven research. All statistical tests were two-sided, and heterogeneity was assessed using standard metrics. Effect estimates are reported as ORs with corresponding 95% confidence intervals (CIs).

Results: Individuals harboring pathogenic or likely pathogenic FH LOF variants exhibited a significantly higher risk of developing HLRCC-associated RCC compared to those harboring missense variants (OR = 1.75, 95% CI: 1.28 to 2.38, p < 0.001). Subgroup analysis by geographic region showed a significant association in North American cohorts (OR = 1.64, 95% CI: 1.11 to 2.43, p < 0.05), while the association was not statistically significant in European cohorts (OR = 1.11, 95% CI: 0.57 to 2.17, p > 0.05). Stratification by study design further revealed a stronger association in variant-first or gene-first cohorts (OR = 1.62, 95% CI: 1.03 to 2.55, p < 0.05), while no significant association was observed in phenotype-first cohorts (OR = 1.34, 95% CI: 0.81 to 2.22, p > 0.05). Among patients diagnosed with HLRCC-associated RCC, those with LOF variants were more likely to present with advanced-stage disease at diagnosis. In contrast, patients with missense variants were more frequently associated with Type II PRCC and exhibited a higher propensity for distant metastasis.

Conclusion: This meta-analysis suggests that individuals harboring pathogenic or likely pathogenic FH LOF variants may have an approximately 1.75-fold higher risk of developing HLRCC-associated RCC compared to those with missense variants. While the pooled effect was statistically significant, subgroup analyses revealed regional and ascertainment-related differences, indicating potential underlying heterogeneity. These findings underscore the potential utility of FH variant subtypes as biomarkers for individualized risk assessment. Further prospective studies are warranted to validate these associations and guide surveillance strategies in hereditary renal cancer syndromes.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40246-025-00797-8.

Fig. 1

Preferred reporting items for PRISMA flow diagram

Fig. 2

Forest plot of the association between individuals with FH LOF variants and those with missense variants in relation to the risk of HLRCC-associated RCC (unadjusted ORs). The squares represent the risk estimates for individual studies; horizontal lines indicate the 95% CIs; the diamonds represent the pooled estimate with corresponding 95% CI. A fixed-effect model was used, and all statistical tests were two-sided. Heterogeneity test: χ² = 6.15, df = 12 (P = 0.91); I² = 0.0%

Fig. 3

Forest plots of the association between individuals with FH LOF variants and those with missense variants in relation to the risk of HLRCC-associated RCC in different geographic regions, presented as unadjusted ORs: (a) North America; (b) Europe. Squares represent the risk estimates for individual studies, and horizontal lines indicate the corresponding 95% CIs. Diamonds represent the pooled ORs with their 95% CIs. A fixed-effect model was applied, and all statistical tests were two-sided. Heterogeneity tests: (a) χ² = 3.94, df = 7 (P = 0.79); I² = 0.0%. (b) χ² = 1.22, df = 4 (P = 0.87); I² = 0.0%

Fig. 4

Forest plots of unadjusted ORs comparing FH LOF and missense variants in HLRCC-associated RCC, stratified by study design: (a) Phenotype-first studies; (b) Variant-/gene-first studies. Squares represent the effect estimates from individual studies, with horizontal lines indicating the 95% CIs. Diamonds indicate the pooled estimates and corresponding 95% CIs. A fixed-effect model was applied, and all statistical tests were two-sided. Heterogeneity tests: (a) χ²=4.06, df = 8 (P = 0.85); I² = 0.0%. (b) χ²=1.77, df = 3 (P = 0.62); I²=0.0%

Fig. 5

Forest plots illustrating the association between FH LOF variants and missense variants among patients with HLRCC-associated RCC, presented as unadjusted ORs, for the following outcomes: (a) Risk of type II papillary RCC; (b) Risk of distant metastasis; (c) Risk of advanced-stage disease. Squares represent the effect estimates from individual studies, with horizontal lines indicating the 95% CIs. Diamonds indicate the pooled estimates and corresponding 95% CIs. A fixed-effect model was applied, and all statistical tests were two-sided. Heterogeneity tests: (a) χ² =5.74, df = 7 (P = 0.57); I²=0.0%. (b) χ²=0.45, df = 2 (P = 0.80); I²=0.0%. (c) χ²=2.03, df = 2 (P = 0.36); I²=1.0%

Fig. 6

(a) Funnel plot of the standard error versus the log-transformed odds ratio for the overall meta-analysis assessing the association between FH LOF and missense variants with HLRCC-associated RCC. (b) Funnel plot after applying the trim-and-fill method to assess potential publication bias