Wang Han, Rehim Shamsnur, Wang Hongjing
Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
Hum Genomics. 2025 Jul 21;19(1):83. doi: 10.1186/s40246-025-00797-8.
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 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 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 variants in the development of HLRCC-associated RCC, providing a basis for future clinical risk stratification and personalized surveillance strategies.
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 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).
Individuals harboring pathogenic or likely pathogenic 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, < 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, < 0.05), while the association was not statistically significant in European cohorts (OR = 1.11, 95% CI: 0.57 to 2.17, > 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, < 0.05), while no significant association was observed in phenotype-first cohorts (OR = 1.34, 95% CI: 0.81 to 2.22, > 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.
This meta-analysis suggests that individuals harboring pathogenic or likely pathogenic 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 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.
The online version contains supplementary material available at 10.1186/s40246-025-00797-8.
富马酸水合酶（FH）是三羧酸（TCA）循环中的一种关键线粒体酶，催化富马酸可逆水合生成苹果酸，从而促进有氧ATP生成并维持代谢稳态。该基因的种系致病性或可能致病性变异与遗传性平滑肌瘤病和肾细胞癌（HLRCC）密切相关，HLRCC是一种罕见的遗传性癌症综合征，其特征为皮肤和/或子宫平滑肌瘤以及肾细胞癌（RCC）风险显著增加。这些变异涵盖了广泛的基因改变，包括错义、无义、移码、剪接位点变异以及大片段基因组缺失。然而，特定致病性变异亚型与发生HLRCC相关RCC风险之间的关系仍不清楚。因此，本研究系统回顾了现有文献并进行荟萃分析，以初步探索不同功能亚型变异在HLRCC相关RCC发生中的潜在作用，为未来临床风险分层和个性化监测策略提供依据。
我们系统检索了4个主要电子数据库——PubMed/MEDLINE、Embase、Scopus和Web of Science——以查找相关研究。为评估致病性或可能致病性变异亚型（错义变异与功能丧失（LOF）变异）与HLRCC相关RCC风险之间的关联，我们基于未调整的比值比（OR）进行了固定效应荟萃分析。此外，还按地理区域（北美和欧洲）、组织学亚型（特别是II型乳头状RCC（II型PRCC））、肿瘤特征（如远处转移和临床分期）以及研究设计（变异/基因优先与表型优先）进行了探索性亚组分析。这些分层旨在评估临床或方法学特征是否可能调节观察到的关联，并为未来基于假设的研究提供背景信息。所有统计检验均为双侧检验，使用标准指标评估异质性。效应估计值以OR及其相应的95%置信区间（CI）表示。
与携带错义变异的个体相比，携带致病性或可能致病性LOF变异的个体发生HLRCC相关RCC的风险显著更高（OR = 1.75，95% CI：1.28至2.38，P < 0.001）。按地理区域进行的亚组分析显示，北美队列中存在显著关联（OR = 1.64，95% CI：1.11至2.43，P < 0.05），而欧洲队列中的关联无统计学意义（OR = 1.11，95% CI：0.57至2.17，P > 0.05）。按研究设计分层进一步显示，变异优先或基因优先队列中的关联更强（OR = 1.62，95% CI：1.03至2.55，P < 0.05），而表型优先队列中未观察到显著关联（OR = 1.34，95% CI：0.81至2.22，P > 0.05）。在诊断为HLRCC相关RCC的患者中，携带LOF变异的患者在诊断时更可能表现为晚期疾病。相比之下，携带错义变异的患者更常与II型PRCC相关，且远处转移倾向更高。
该荟萃分析表明，与携带错义变异的个体相比，携带致病性或可能致病性LOF变异的个体发生HLRCC相关RCC的风险可能高出约1.75倍。虽然合并效应具有统计学意义，但亚组分析揭示了区域和确定相关的差异，表明潜在的异质性。这些发现强调了变异亚型作为个性化风险评估生物标志物的潜在效用。有必要进行进一步的前瞻性研究以验证这些关联，并指导遗传性肾癌综合征的监测策略。
在线版本包含可在10.1186/s40246 - 025 - 00797 - 8获取的补充材料。
