Search Results (34)

(1) Background: Sertoli–Leydig cell tumors (SLCTs) are rare ovarian neoplasms that account for less than 0.5% of all ovarian tumors. They usually affect young women and often present with androgenic symptoms. We report a unique case of a 40-year-old woman diagnosed with both SLCT and clear cell papillary renal cell carcinoma (CCP-RCC), a rare tumor association with unclear pathogenesis. (2) Methods: Both tumors were treated surgically. The diagnostic workup included hormonal testing, imaging studies, and extensive genetic testing, including DICER1 mutation analysis and multiplex ligation-dependent probe amplification (MLPA), as well as the examination of a next-generation sequencing (NGS) panel covering ~280 cancer-related genes. (3) Results: Histopathologic examination confirmed a well-differentiated SLCT and CCP-RCC. No pathogenic variants in DICER1 were identified by WES or MLPA. No clinically relevant changes were found in the extended NGS panel either, so a known hereditary predisposition could be ruled out. The synchronous occurrence of both tumors without genomic alterations could indicate a sporadic event or as yet unidentified mechanisms. (4) Conclusions: This case highlights the importance of a multidisciplinary approach in the management of rare tumor compounds. The exclusion of DICER1 mutations and the absence of genetic findings adds new evidence to the limited literature and underscores the importance of long-term surveillance and further research into potential shared oncogenic pathways. Full article

Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a germline VHL variant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INT²GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) programs, we demonstrated that integrating tumor-derived and germline evidence offers a comprehensive approach for the accurate assessment of the germline variants in cancer syndromes. Methods/Results: Here, we present a novel INT²GRATE variant evidence framework (VEF) for evaluating the clinical actionability of the germline variants in VHL syndrome, offering an integrated approach that incorporates both constitutional and tumor data. We analyzed 2672 variants in the VHL gene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, and VHL allelic genetic conditions. The germline INT²GRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INT²GRATE Variant data Portal. Conclusions: This novel and integrated approach to variant assessment and data sharing in hereditary cancer syndromes is essential in the clinical evaluation of genomic variants, advancing precision oncology, and improving patient care. Full article

Molecular testing in renal cell carcinoma (RCC) has allowed for a better understanding of the biology of both sporadic and hereditary diseases, where genetic testing is currently recommended in the guidelines for a select population with risk factors. Historically, screening, surveillance, and management decisions were based solely on clinicopathologic data; however, we now know that molecular profiling can enhance decision making, altering the treatment plan, approach, or selection of systemic therapy and enhancing the delivery of precision oncologic care. Advances and the increasing availability of next-generation sequencing technologies have improved the identification of germline and somatic variants in key RCC-associated genes. Given the molecular heterogeneity of RCC, these modern methods can identify unique genetic events that occur in a single individual, allowing for distinction between a metachronous tumor from metastases. Separate four-tier systems have been proposed to categorize germline and somatic variants according to their clinical significance, which should be highlighted. Additionally, emerging technologies, such as liquid biopsy, show potential for enhancing precision oncology in RCC. With this said, challenges, such as variant interpretation, ethical considerations, and accessibility, persist. This review examines the molecularly defined RCC, genetic testing methodologies currently available, their current clinical applications, limitations, and future directions. Full article

Hereditary papillary renal carcinoma (HPRC) is a rare monogenic hereditary disease in the group of hereditary cancer syndromes. Clinically, HPRC results in the development of multiple papillary renal cell carcinomas of the kidneys in young adults. HPRC is caused by point activating mutations in the MET gene encoding a transmembrane tyrosine kinase receptor. Until now, all detected germline mutations in HPRC patients were missense variants leading to a constitutive activation of the tyrosine kinase domain. We describe, for the first time, unrelated patients with clinical features similar to HPRC and without MET pathogenic missense variants but harboring an extended heterozygous duplication ~101.4 kb in length (chr7:116740252-116841718) in 7q31.2 determined using whole-genome sequencing (WGS). This duplication results in an additional copy of the MET gene fragment, including exons 5-21. The duplicated exons encode most of the receptor domains. According to the American College of Medical Genetics and Genomics (ACMG) criteria, this duplication is classified as variant of uncertain significance (VUS) at present, but it is not excluded that this duplication may represent an activating mutation. Perhaps, further segregation analysis and functional studies will allow us to more accurately resolve the pathogenicity and diagnostic significance of this germline CNV. Full article

von Hippel–Lindau syndrome (VHLS) is a hereditary cancer syndrome with CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, retinal angiomas, and a number of other manifestations. VHLS is caused by a mutation in the VHL gene and is inherited in an autosomal dominant manner. However, some cases of VHLS develop de novo, and among them, there are rare patients with a mosaic form of the disease. Genetic testing in mosaic patients is prone to false-negative results due to the low copy number of a mutant allele in DNA isolated from the blood. We describe a case of molecular genetic diagnostics of VHLS in a 39-year-old patient using various methods, including mutation analysis in asynchronous primary tumors and repeated DNA analysis from blood using NGS with high coverage for the mutant position. As a result, the patient was diagnosed with a mosaic form of VHLS caused by the variant c.481C>T (p.Arg161Ter), the proportion of which in the blood DNA was 2%. We also summarized the literature data on the mosaic form of VHLS: the severity of clinical manifestations, the features of differential diagnostics of VHLS with a negative result of routine molecular genetic VHL testing, and specific options of active surveillance and treatment for mutation carriers. Full article

Percutaneous image-guided ablation (IGA) has emerged as an established alternative to surgical management for small renal masses. This comprehensive review examines traditional and emerging indications, energy sources, techniques, and future developments in IGA for renal cancer treatment. Traditionally, IGA has been indicated for frail or comorbid patients, those with solitary kidneys or chronic kidney disease, and those with histologically proven renal cell carcinomas less than 4 cm in size. Recent evidence supports expanding these indications to include T1b or T2 tumours and hereditary or recurrent renal cell carcinomas. The use of IGA combined with pre-ablation transarterial embolisation is discussed herein. This review then explores traditional energy sources including radiofrequency ablation, cryoablation, and microwave ablation, highlighting their respective advantages and limitations. Emerging technologies such as irreversible electroporation and histotripsy, as promising alternatives, are then presented, highlighting their advantage of being able to treat tumours near critical structures. Future research priorities highlight the need to establish high-quality evidence through innovative trial designs, as well as taking patient-reported outcome measures into account. Health economic considerations are key to ensuring that ablation therapies are cost-effective. The integration of artificial intelligence and radiomics shows vast potential for improving patient selection and treatment outcomes. Additionally, the immunomodulatory effects of ablative therapies suggest possible synergistic benefits when combined with immunotherapy which also require exploration in future research. Technological advancement and research developments will continue to broaden the role of IGA in clinical practice. Full article

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

Introduction: Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information. Methods: Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs. Results: MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney. Conclusions: This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer. Full article

Familial kidney tumors represent a rare variety of hereditary cancer syndromes, although systematic gene sequencing studies revealed that as many as 5% of renal cell carcinomas (RCCs) are associated with germline pathogenic variants (PVs). Most instances of RCC predisposition are attributed to the loss-of-function mutations in tumor suppressor genes, which drive the malignant progression via somatic inactivation of the remaining allele. These syndromes almost always have extrarenal manifestations, for example, von Hippel–Lindau (VHL) disease, fumarate hydratase tumor predisposition syndrome (FHTPS), Birt–Hogg–Dubé (BHD) syndrome, tuberous sclerosis (TS), etc. In contrast to the above conditions, hereditary papillary renal cell carcinoma syndrome (HPRCC) is caused by activating mutations in the MET oncogene and affects only the kidneys. Recent years have been characterized by remarkable progress in the development of targeted therapies for hereditary RCCs. The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs. mTOR downregulation provides significant benefits to patients with tuberous sclerosis. MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations. Full article

Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC. Full article

von Hippel-Lindau (VHL) disease, due to mutations of the tumor suppressor VHL gene, is a rare hereditary syndrome with a high risk of developing clear cell renal cell carcinoma (ccRCC). We asked whether the VHL-C162F mutation interferes with proliferation, migration, healing and forming colony ability by using wild-type VHL (WT VHL) and VHL-C162F reconstituted cells. We then analyzed the in vitro impact of the sunitinib treatment on VHL-C162F cells. We showed that VHL-C162F mutations have no impact on cell morphology, colony formation and migration ability but confer a significant higher healing ability than in WT VHL cells. RNA sequencing analysis revealed that VHL-C162F mutation upregulates genes involved in hypoxia and epithelial mesenchymal transition (EMT) pathways by comparison with VHL WT cells. We next showed a decrease in healing ability in VHL-C162F cells depleting on ZHX2, an oncogenic driver of ccRCC, highlighting the potential involvement of ZHX2 in aggressiveness of the VHL-C162F cells. Moreover, we found that sunitinib treatment inhibits ZHX2 expression and induces a reduced proliferation correlating with downregulation of P-ERK. Sunitinib treatment also conferred a more mesenchymal profile to VHL-C162F cells with significant downregulation of E-cadherin and upregulation of N-cadherin, Slug and AXL. Sunitinib therapy may therefore promote disease progression in VHL-C162F patients. Full article

Subjects with pathogenic (PV) and likely pathogenic (LPV) FLCN variants have an increased risk of manifesting benign and malignant disorders that are related to Birt–Hogg–Dubé syndrome (BHDS): an autosomal dominantly inherited disorder whose severity can vary significantly. Renal cell carcinoma (RCC) development in BHD (Birt–Hogg–Dubé) patients has a very high incidence; thus, identifying this rare syndrome at early stages and preventing metastatic spread is crucial. Over the last decade, the advancement of Next Generation Sequencing (NGS) and the implementation of multigene panels for hereditary cancer syndromes (HCS) have led to a subsequent focus on additional genes and variants, including those of uncertain significance (VUS). Here, we describe a novel FLCN variant observed in a subject manifesting disorders that were suspected to be related to BHDS and with a family history of multiple cancers. Full article

Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes BRCA1 and BRCA2, many other predisposition genes that confer a moderate risk of BC have been identified. Advances in multigene panel testing have allowed the simultaneous sequencing of BRCA1/2 with these genes in a cost-effective way. Germline DNA from 521 cases with BC fulfilling diagnostic criteria for hereditary BC were screened with multigene NGS testing. Pathogenic (PVs) and likely pathogenic (LPVs) variants in moderate penetrance genes were identified in 15 out of 521 patients (2.9%), including 2 missense, 7 non-sense, 1 indel, and 3 splice variants, as well as two different exon deletions, as follows: ATM (n = 4), CHEK2 (n = 5), PALB2 (n = 2), RAD51C (n = 1), and RAD51D (n = 3). Moreover, the segregation analysis of PVs and LPVs into first-degree relatives allowed the detection of CHEK2 variant carriers diagnosed with in situ melanoma and clear cell renal cell carcinoma (ccRCC), respectively. Extended testing beyond BRCA1/2 identified PVs and LPVs in a further 2.9% of BC patients. In conclusion, panel testing yields more accurate genetic information for appropriate counselling, risk management, and preventive options than assessing BRCA1/2 alone. Full article

This study aims to evaluate the safety, efficacy, and renal function preservation of percutaneous cryoablation (PCA) for small renal masses (SRMs) in inherited RCC syndromes. Patients with inherited T1N0M0 RCCs (<7 cm) undergoing PCA from 2015 to 2021 were identified from the European Registry for Renal Cryoablation (EuRECA). The primary outcome was local recurrence-free survival (LRFS). The secondary outcomes included technical success, peri-operative outcomes, and other oncological outcomes estimated using the Kaplan–Meier method. Simple proportions, chi-squared tests, and t-tests were used to analyse the peri-operative outcomes. A total of 68 sessions of PCA were performed in 53 patients with RCC and 85 tumours were followed-up for a mean duration of 30.4 months (SD ± 22.0). The overall technical success rate was 99%. The major post-operative complication rate was 1.7%. In total, 7.4% (2/27) of patients had >25% reduction in renal function. All oncological events were observed in VHL patients. Estimated 5-year LRFS, metastasis-free survival, cancer-specific survival, and overall survival were 96.0% (95% CI 75–99%), 96.4% (95% CI 77–99%), 90.9% (95% CI 51–99%), and 90.9% (95% CI 51–99%), respectively. PCA of RCCs for patients with hereditary RCC SRMs appears to be safe, offers low complication rates, preserves renal function, and achieves good oncological outcomes. Full article