Search Results (10)

Fumarate hydratase (FH) deficiency is a rare, yet impactful metabolic disorder caused by mutations in the FH gene, affecting the Krebs cycle, leading to the accumulation of fumarate and pseudohypoxic states. This metabolic shift promotes cell signaling alterations that can drive tumorigenesis, as heterozygous germline mutations in the FH gene, resulting in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. FH-deficient uterine leiomyomas show peculiar histological features that may lead to misdiagnosis STUMP (smooth muscle tumor of uncertain malignant potential) and uLMS (uterine leiomyosarcoma). Definitive diagnosis involves clinical evaluation, imaging, and histopathological examination, with immunohistochemistry for FH protein being a key diagnostic tool. Management of FH-deficient leiomyomas may involve conventional treatments like surgery and hormonal therapy but also requires careful monitoring and genetic counseling for associated malignancies. High-intensity focused ultrasound (HIFU) has emerged as a promising treatment option for fibroids, although long-term efficacy remains a concern also because of its inability to obtain tissue for a pathological diagnosis. Fumarate hydratase deficiency (FHD) represents a significant challenge in gynecologic oncology due to its association with an increased risk of hereditary leiomyomatosis and renal cell carcinoma. Nevertheless, to the best of our knowledge, there is a lack of studies demonstrating the potential role of FH deficiency in increased risk of leiomyosarcomatosus transformation. Early detection, genetic screening, and personalized treatment approaches are critical for improving patient outcomes. The aim of this review is to develop a narrative overview of the implications of FHD in gynecological diseases and its correlation with cancer risk. For the first time, this review offers an overview of the necessity for studies to address the possible correlation between FH deficiency and the risk of developing leiomyosarcoma, focusing on new perspectives that can be explored in the field of better FH deficiency knowledge and cancer risk. Full article

Renal cell carcinoma (RCC) comprises various histologically distinct subtypes, each characterized by specific genetic alterations, necessitating individualized management and treatment strategies for each subtype. An exhaustive search of the PubMed database was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on molecular mechanisms of kidney cancer. On the other hand, all non-original articles and articles published in any language other than English were excluded. Hereditary kidney cancer represents 5–8% of all kidney cancer cases and is associated with syndromes such as von Hippel–Lindau syndrome, Birt–Hogg–Dubè syndrome, succinate dehydrogenase-deficient renal cell cancer syndrome, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, fumarate hydratase deficiency syndrome, BAP1 tumor predisposition syndrome, and other uncommon hereditary cancer syndromes. These conditions are characterized by distinct genetic mutations and related extra-renal symptoms. The majority of renal cell carcinoma predispositions stem from loss-of-function mutations in tumor suppressor genes. These mutations promote malignant advancement through the somatic inactivation of the remaining allele. This review aims to elucidate the main molecular mechanisms underlying the pathophysiology of major syndromes associated with renal cell carcinoma. By providing a comprehensive overview, it aims to facilitate early diagnosis and to highlight the principal therapeutic options available. Full article

Background and Objectives: Mutations in succinate dehydrogenase (SDH) and fumarate hydratase (FH) give rise to various familial cancer syndromes, with these alterations being characteristic of certain types of histomorphologically specific leiomyomas that hold significant predictive value. Materials and Methods: This study presents two cases of uterine leiomyomas exhibiting rare histomorphological and genetic characteristics, which are crucial for prognosis and further treatment. Results: Distinct histopathological features such as marked nuclear atypia, intracellular eosinophilic globules, and abnormal intratumoral vessels raise suspicion for specific leiomyoma subtypes, which carry predictive significance for additional hereditary cancer syndromes. Immunohistochemical analysis confirmed FH/SDH deficiency in both patients, who underwent careful follow-up. Conclusions: This study describes two cases involving unusual leiomyomas, the histopathological characteristics of which may easily go unrecognized. These features hold predictive significance because their specific mutations point to additional hereditary cancer syndromes, highlighting the need for further examinations. Full article

Uterine leiomyomas (ULs) are the most common benign tumor of the uterus. They can be associated with symptoms including abnormal uterine bleeding, pelvic pain, urinary frequency, and pregnancy complications. Despite the high prevalence of UL, its underlying pathophysiology mechanisms have historically been poorly understood. Several mechanisms of pathogenesis have been suggested, implicating various genes, growth factors, cytokines, chemokines, and microRNA aberrations. The purpose of this study is to summarize the current research on the relationship of genetics with UL. Specifically, we performed a literature review of published studies to identify how genetic aberrations drive pathophysiology, epidemiology, and therapeutic approaches of UL. With regards to pathophysiology, research has identified MED12 mutations, HMGA2 overexpression, fumarate hydratase deficiency, and cytogenetic abnormalities as contributors to the development of UL. Additionally, epigenetic modifications, such as histone acetylation and DNA methylation, have been identified as contributing to UL tumorigenesis. Specifically, UL stem cells have been found to contain a unique DNA methylation pattern compared to more differentiated UL cells, suggesting that DNA methylation has a role in tumorigenesis. On a population level, genome-wide association studies (GWASs) and epidemiologic analyses have identified 23 genetic loci associated with younger age at menarche and UL growth. Additionally, various GWASs have investigated genetic loci as potential drivers of racial disparities in UL incidence. For example, decreased expression of Cytohesin 4 in African Americans has been associated with increased UL risk. Recent studies have investigated various therapeutic options, including ten-eleven translocation proteins mediating DNA methylation, adenovirus vectors for drug delivery, and “suicide gene therapy” to induce apoptosis. Overall, improved understanding of the genetic and epigenetic drivers of UL on an individual and population level can propel the discovery of novel therapeutic options. Full article

Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect. Full article

Uterine leiomyomas or uterine fibroids are the most common benign soft tissue tumor in reproductive-aged women. Fumarate hydratase deficient (FH-d) uterine fibroids are a rare subtype that is diagnosed only on pathologic evaluation. FH-d uterine fibroids may be the first indicator of hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Therefore, identifying and understanding the clinical implication and diagnosis of FH-d uterine fibroids is critical for early diagnosis of HLRCC. This case series investigates the uncommon yet significant condition of FH-d uterine fibroids. We examined the clinical manifestation, diagnostic imaging, and histopathological characteristics of FH-d uterine fibroids in five cases identified at our institution over the last ten years. All diagnoses were confirmed by pathologic evaluation after surgical treatment. Gynecologists and pathologists play a critical role in the early diagnosis of FH-d uterine fibroids and must recognize the relevant clinical and pathologic findings that raise suspicion about this diagnosis. The detection of these cases is largely dependent on the pathologist’s ability to recognize unique histopathologic features. Once these characteristics are identified, it should prompt a referral to a gynecologist to consider conducting germline genetic testing. The management of FH-d uterine fibroids necessitates a multidisciplinary approach, including proper genetic screening and regular surveillance, especially for renal tumors. Full article

Leiomyomas are smooth muscle-derived benign neoplasms that can affect all organs, most frequently in the uterus. Fumarate hydratase gene (FH) mutation is characterised by an autosomal dominant disease with increased occurrence of renal tumours, but also by cutaneous (CLs) and uterine leiomyomas (ULs). So far, an increased occurrence of skin tumours in non-mutated patients with ULs has not been verified. To this aim, a case-group of women who were FH non-mutated patients surgically treated for ULs (n = 34) was compared with a control-group (n = 37) of consecutive age-matched healthy women. The occurrence of skin neoplasms, including CLs and dermatofibromas (DFs), was evaluated. Moreover, the microscopic features of FH non-mutated skin tumours were compared with those of an age-matched population group (n = 70) who presented, in their clinical history, only one type of skin tumour and no ULs. Immunohistochemical and in vitro studies analysed TGFβ and vitamin D receptor expression. FH non-mutated patients with ULs displayed a higher occurrence of CLs and DFs (p < 0.03 and p < 0.001), but not of other types of skin tumours. Immunohistochemistry revealed a lower vitamin D receptor (VDR) expression in CLs and DFs from the ULs group compared with those from the population group (p < 0.01), but a similar distribution of TGFβ-receptors and SMAD3. In vitro studies documented that TGFβ-1 treatment and vitamin D3 have opposite effects on α-SMA, TGFβR2 and VDR expression on dermal fibroblast and leiomyoma cell cultures. This unreported increased occurrence of CLs and DFs in FH non-mutated patients with symptomatic ULs with vitamin D deficiency suggests a potential pathogenetic role of vitamin D bioavailability also for CLs and DFs. Full article

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient’s family was advised to undergo genetic counseling to consider additional RCC screening. Full article

Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)—an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed. Full article

Paragangliomas and pheochromocytomas are rare neuroendocrine tumours with a very strong genetic component. It is estimated that around 40% of all cases are caused by a germline mutation in one of the 13 predisposing genes identified so far. Half of these inherited cases are intriguingly caused by mutations in genes encoding tricarboxylic acid enzymes, namely SDHA, SDHB, SDHC, SDHD, and SDHAF2 genes, encoding succinate dehydrogenase and its assembly protein, FH encoding fumarate hydratase, and MDH2 encoding malate dehydrogenase. These mutations may also predispose to other type of cancers, such as renal cancer, leiomyomas, or gastro-intestinal stromal tumours. SDH, which is also the complex II of the oxidative respiratory chain, was the first mitochondrial enzyme to be identified having tumour suppressor functions, demonstrating that 80 years after his initial proposal, Otto Warburg may have actually been right when he hypothesized that low mitochondrial respiration was the origin of cancer. This review reports the current view on how such metabolic deficiencies may lead to cancer predisposition and shows that the recent data may lead to the development of innovative therapeutic strategies and establish precision medicine approaches for the management of patients affected by these rare diseases. Full article