Asunto(s)
Carcinoma de Células Renales , Fumarato Hidratasa , Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Uterinas , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/patología , Femenino , Fumarato Hidratasa/deficiencia , Fumarato Hidratasa/genética , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/enzimología , Neoplasias Renales/patología , Leiomiomatosis/diagnóstico , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/patología , Pronóstico , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patologíaRESUMEN
Fumarate hydratase (FH), encoded by the FH gene, is an enzyme which catalyses the conversion of fumarate to L-malate as part of the tricarboxylic acid cycle. Biallelic germline mutations in FH result in fumaric aciduria, a metabolic disorder resulting in severe neurological and developmental abnormalities. Heterozygous germline mutations in FH result in hereditary leiomyomatosis and renal cell carcinoma, a cancer predisposition syndrome. FH deficiency has multiple oncogenic mechanisms including through promotion of aerobic glycolysis, induction of pseudohypoxia, post-translational protein modification and impairment of DNA damage repair by homologous recombination. FH-deficient neoplasms can present with characteristic morphological features that raise suspicion for FH alterations and also frequently demonstrate loss of FH immunoreactivity and intracellular accumulation of 2-succinocysteine, also detected by immunohistochemistry.
Asunto(s)
Fumarato Hidratasa/deficiencia , Fumarato Hidratasa/metabolismo , Errores Innatos del Metabolismo/enzimología , Hipotonía Muscular/enzimología , Neoplasias/enzimología , Trastornos Psicomotores/enzimología , Animales , Fumarato Hidratasa/genética , Regulación Enzimológica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Leiomiomatosis/enzimología , Leiomiomatosis/genética , Leiomiomatosis/patología , Errores Innatos del Metabolismo/genética , Hipotonía Muscular/genética , Mutación , Neoplasias/genética , Neoplasias/patología , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Fenotipo , Trastornos Psicomotores/genética , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
Asunto(s)
Carcinoma de Células Renales/genética , Ciclo del Ácido Cítrico , Daño del ADN , ADN Mitocondrial/metabolismo , Fumarato Hidratasa/genética , Neoplasias Renales/genética , Leiomiomatosis/enzimología , Síndromes Neoplásicos Hereditarios/enzimología , Neoplasias Cutáneas/enzimología , Neoplasias Uterinas/enzimología , Adulto , Anciano , Carcinoma de Células Renales/etiología , Carcinoma de Células Renales/metabolismo , Reparación del ADN , Replicación del ADN , Femenino , Fumarato Hidratasa/deficiencia , Perfilación de la Expresión Génica , Humanos , Neoplasias Renales/etiología , Neoplasias Renales/metabolismo , Leiomiomatosis/complicaciones , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación , Síndromes Neoplásicos Hereditarios/complicaciones , Neoplasias Cutáneas/complicaciones , Neoplasias Uterinas/complicaciones , Adulto JovenRESUMEN
AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. METHODS AND RESULTS: We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. CONCLUSION: Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.
Asunto(s)
Fumarato Hidratasa/genética , Leiomioma/genética , Leiomiomatosis/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Cutáneas/genética , Neoplasias Uterinas/genética , Adolescente , Adulto , Análisis Mutacional de ADN , Femenino , Fumarato Hidratasa/metabolismo , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Leiomioma/enzimología , Leiomioma/patología , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Mutación , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/patología , Prevalencia , Estudios Retrospectivos , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Análisis de Matrices Tisulares , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patología , Adulto JovenRESUMEN
Pathology-based screening of uterine smooth muscle tumors (uSMT) for morphology suggestive of fumarate hydratase deficiency (FH-d morphology) has been proposed as a method to identify women at increased risk for hereditary leiomyomatosis renal cell carcinoma (HLRCC) syndrome. For 5 years our clinical diagnostic practice has evaluated all women with any type of uSMT for FH-d morphology (defined, at low magnification, as staghorn shaped blood vessels and alveolar pattern edema and, at high magnification, as tumor macronucleoli surrounded by a halo and cytoplasmic eosinophilic globules) and, when present, used the pathology report to advise genetic counseling to further evaluate for HLRCC syndrome. We now report the results of this prospective screening strategy, with emphasis on the incidence and clinicopathologic features of FH-d morphology in uSMT, the rate of patient uptake of referral to genetic counseling, and the results of genetic testing for FH germline mutation. Among 2060 women with a uSMT, FH-d morphology was reported in 1.4% (30 women). Ten women elected to undergo FH genetic testing and 6 of 10 (60%) had a FH germline mutation: 5 were pathogenic mutations and 1 was a mutation variant of unknown significance. Therefore, the screening program led to a confirmed genetic diagnosis of HLRCC syndrome in 0.24% of all women with any type of uSMT. The women with a pathogenic mutation were ages 24 to 40 years. Although the majority of leiomyoma with bizarre nuclei exhibited FH-d morphology, the uSMT were conventional leiomyomas with FH-d morphology in 2 of 5 women found to have a pathogenic FH germline mutation. Relying on an abnormal FH immunostain result to trigger genetic counseling referral would have resulted in 2 of 5 (40%) cases with pathogenic FH germline mutation but normal FH immunoexpression going undetected, both of which were missense type mutations. There was no difference in the incidence of pathogenic FH germline mutation between FH-d morphology uSMT with an abnormal versus a normal FH immunostain result. Overall, this study demonstrates that prospective morphology-based screening, integrated with referral for genetic counseling, can result in the diagnosis of HLRCC syndrome in otherwise unselected women with uSMT. We conclude that this strategy should be incorporated in the routine pathologic examination of all uterine smooth muscle tumors.
Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Fumarato Hidratasa/genética , Asesoramiento Genético , Mutación de Línea Germinal , Leiomiomatosis/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Cutáneas/genética , Neoplasias Uterinas/genética , Adulto , Anciano , Biopsia , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Leiomiomatosis/terapia , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/patología , Síndromes Neoplásicos Hereditarios/terapia , Aceptación de la Atención de Salud , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Derivación y Consulta , San Francisco , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Factores de Tiempo , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapia , Adulto JovenRESUMEN
BACKGROUND: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is rare and highly aggressive and is believed to arise mostly in the setting of hereditary leiomyomatosis-RCC syndrome with a germline mutation of FH. Because of the aggressiveness of these tumors and a frequent lack of ascertainable family history, these tumors may first present as metastases and be sampled by cytology. The cytologic findings of FH-deficient RCC have not previously been reported. METHODS: Cytologic and limited biopsy samples from patients with FH-deficient RCC were reviewed retrospectively. RESULTS: In total, 24 cytologic and limited biopsy samples from 19 patients (6 women and 13 men; age range, 22-69 years) who had FH-deficient RCC and metastasis at presentation were evaluated. These included 21 cytology samples ranging from malignant effusions (n = 7) to metastases (n = 11), to samples of primary kidney tumors (n = 3). The samples exhibited cells, often in clusters and abortive papillae, with voluminous, finely vacuolated cytoplasm and large, pleomorphic nuclei with prominent, viral inclusion-like nucleoli. A distinctive finding of peripheral cytoplasmic clearing frequently was apparent, and intranuclear cytoplasmic pseudoinclusions were less frequent. Of 7 cell block and biopsy samples, several of which represented sampling from the same patient, all demonstrated tissue fragments that had discernable morphologic patterns associated with FH-deficient RCC, including tubulocystic and intracystic papillary growth. CONCLUSIONS: Features characteristic and suggestive of FH-deficient RCC may be identified in cytologic and small biopsy samples. Although the current samples were identified retrospectively in well characterized cases of FH-deficient RCC, the authors argue that, with appropriate clinical correlation, these features are sufficiently distinctive to trigger recognition and confirmatory workup.
Asunto(s)
Carcinoma de Células Renales/genética , Fumarato Hidratasa/genética , Mutación de Línea Germinal , Neoplasias Renales/genética , Riñón/metabolismo , Adulto , Anciano , Biopsia , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/patología , Femenino , Fumarato Hidratasa/deficiencia , Predisposición Genética a la Enfermedad/genética , Humanos , Riñón/enzimología , Riñón/patología , Neoplasias Renales/enzimología , Neoplasias Renales/patología , Leiomiomatosis/enzimología , Leiomiomatosis/genética , Leiomiomatosis/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by inactivation of the Krebs cycle enzyme fumarate hydratase (FH). HLRCC patients are at high risk of developing kidney cancer of type 2 papillary morphology that is refractory to current radiotherapy, immunotherapy and chemotherapy. Hence, an effective therapy for this deadly form of cancer is urgently needed. Here, we show that FH inactivation (FH-/- ) proves synthetic lethal with inducers of ferroptosis, an iron-dependent and nonapoptotic form of cell death. Specifically, we identified gene signatures for compound sensitivities based on drug responses for 9 different drug classes against the NCI-60 cell lines. These signatures predicted that ferroptosis inducers would be selectively toxic to FH-/- cell line UOK262. Preferential cell death against UOK262-FH-/- was confirmed with 4 different ferroptosis inducers. Mechanistically, the FH-/- sensitivity to ferroptosis is attributed to dysfunctional GPX4, the primary cellular defender against ferroptosis. We identified that C93 of GPX4 is readily post-translationally modified by fumarates that accumulate in conditions of FH-/- , and that C93 modification represses GPX4 activity. Induction of ferroptosis in FH-inactivated tumors represents an opportunity for synthetic lethality in cancer.
Asunto(s)
Fumarato Hidratasa/fisiología , Leiomiomatosis/enzimología , Síndromes Neoplásicos Hereditarios/enzimología , Neoplasias Cutáneas/enzimología , Neoplasias Uterinas/enzimología , Línea Celular Tumoral , Activación Enzimática , Glutatión Peroxidasa/fisiología , Humanos , Leiomiomatosis/patología , Síndromes Neoplásicos Hereditarios/patología , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Uterinas/patologíaRESUMEN
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by germline mutations in the FH gene, and is associated with increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma (HLRCC-associated RCC). Absent immunohistochemical expression of fumarate hydratase (FH) has previously been used to diagnose HLRCC-associated RCC, but immunohistochemical staining of leiomyomas is not standard practice. We performed immunohistochemistry (IHC) on whole sections from consecutive cutaneous leiomyomas from our archives to evaluate for both FH and succinate dehydrogenase B expression, in addition to clinicopathologic data collection and review of all hematoxylin and eosin-stained slides for blinded morphologic evaluation of features reported to be seen in HLRCC-associated uterine leiomyomas. Ninety-six cutaneous leiomyomas from 87 patients were identified; 12 of these specimens were from 7 patients with documented HLRCC. FH expression by IHC was absent in 9 specimens and retained in 85 specimens; 2 cases were equivocal with minimal FH expression. Seven of the 9 absent expression specimens were from patients with HLRCC, as were both of the equivocal specimens. The overall sensitivity and specificity of absent FH expression in leiomyomas for detection of patients with HLRCC were 70.0% and 97.6%, respectively. Inclusion of cases classified as equivocal increased sensitivity to 75.0%. Succinate dehydrogenase B expression was retained in 95 specimens and equivocal in 1 specimen. None of the evaluated morphologic features showed any association with leiomyomas in HLRCC. Loss of FH immunohistochemical expression in cutaneous leiomyomas is a sensitive and specific marker for detection of HLRCC, thus suggesting a role for prospective FH IHC in patients with these tumors to screen for HLRCC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Fumarato Hidratasa/metabolismo , Leiomiomatosis/diagnóstico , Síndromes Neoplásicos Hereditarios/diagnóstico , Neoplasias Cutáneas/diagnóstico , Succinato Deshidrogenasa/metabolismo , Neoplasias Uterinas/diagnóstico , Adolescente , Adulto , Bases de Datos Factuales , Femenino , Humanos , Inmunohistoquímica , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Masculino , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/patología , Sensibilidad y Especificidad , Método Simple Ciego , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patologíaRESUMEN
Germ line mutations of the gene encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) cause a hereditary cancer syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC-associated tumors harbor biallelic FH inactivation that results in the accumulation of the TCA cycle metabolite fumarate. Although it is known that fumarate accumulation can alter cellular signaling, if and how fumarate confers a growth advantage remain unclear. Here we show that fumarate accumulation confers a chronic proliferative signal by disrupting cellular iron signaling. Specifically, fumarate covalently modifies cysteine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA translation. Simultaneously, fumarate increases ferritin gene transcription by activating the NRF2 (nuclear factor [erythroid-derived 2]-like 2) transcription factor. In turn, increased ferritin protein levels promote the expression of the promitotic transcription factor FOXM1 (Forkhead box protein M1). Consistently, clinical HLRCC tissues showed increased expression levels of both FOXM1 and its proliferation-associated target genes. This finding demonstrates how FH inactivation can endow cells with a growth advantage.
Asunto(s)
Carcinoma de Células Renales/patología , Ferritinas/genética , Fumarato Hidratasa/metabolismo , Fumaratos/farmacología , Neoplasias Renales/patología , Leiomiomatosis/patología , Biosíntesis de Proteínas/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Secuencia de Aminoácidos , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteína Forkhead Box M1/metabolismo , Humanos , Espacio Intracelular/metabolismo , Proteína 2 Reguladora de Hierro/química , Proteína 2 Reguladora de Hierro/metabolismo , Neoplasias Renales/enzimología , Neoplasias Renales/genética , Leiomiomatosis/enzimología , Leiomiomatosis/genética , Modelos Biológicos , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Ácido Succínico/metabolismoRESUMEN
We report the case of a 56 year-old male with an atypical leiomyoma in the context of a cutaneous leiomyomatosis and a family history of uterine leiomyomatosis. The genetic study revealed a mutation in the gene for the enzyme fumarate hydratase, but he has not had any renal malignancy so far. Atypical leiomyoma is a rare tumor that usually presents as a single lesion and is exceptional in patients with cutaneous leiomyomatosis. The relation between fumarate hydratase enzyme mutations with multiple leiomyomas, uterine leiomyomatosis and an increased risk of developing kidney cancer is widely known. However, the role of these mutations in the development of atypical leiomyomas is still impossible to clarify given the few cases reported in the literature.
Asunto(s)
Fumarato Hidratasa/genética , Leiomiomatosis/genética , Mutación , Neoplasias Cutáneas/genética , Humanos , Leiomioma/enzimología , Leiomioma/genética , Leiomioma/patología , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patologíaRESUMEN
AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is an autosomal dominant disorder caused by heterozygotic germline mutations in fumarate hydratase (FH) with incomplete penetrance, and clinically challenging to diagnose. Immunohistochemical stainings may favor an earlier diagnosis. METHODS AND RESULTS: The authors have tested 31 smooth muscle neoplasms. Ten of the 13 lesions from patients with HLRCC syndrome showed negative FH staining. Most sporadic piloleiomyomas presented strongly positive FH staining although 5 cases were negative. Sensitivity of FH staining in our series is 83.3% but specificity is 75%. Anti-S-(2-succino)-cysteine (2SC) showed the opposite intensity staining pattern and showed great correlation with anti-FH (rho spearman = -0.797). Anti-2SC staining increased the diagnostic accuracy in 19% of the cases. LIMITATIONS: The main limitation of this study is the lack additional clinical data to further classify the cases as the case inclusion was histopathological. CONCLUSIONS: Negative FH staining could indicate a high risk of HLRCC but it could also suggest the presence of a syndrome in up to 25% of sporadic cases. Thus, when there is a doubtful case, anti-2SC may be added to exclude the syndrome if a negative staining is found.
Asunto(s)
Biomarcadores de Tumor/análisis , Cisteína/análogos & derivados , Fumarato Hidratasa/análisis , Inmunohistoquímica , Leiomiomatosis/enzimología , Procesamiento Proteico-Postraduccional , Neoplasias Cutáneas/enzimología , Neoplasias Uterinas/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Cisteína/análisis , Análisis Mutacional de ADN , Regulación hacia Abajo , Detección Precoz del Cáncer , Femenino , Fumarato Hidratasa/genética , Humanos , Leiomiomatosis/genética , Leiomiomatosis/patología , Masculino , Persona de Mediana Edad , Mutación , Síndromes Neoplásicos Hereditarios , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
Se presenta un varón de 56 años con un leiomioma atípico en el contexto de una leiomiomatosis cutánea, con antecedentes familiares de miomatosis uterina y con estudio genético que revela una mutación en el gen de la enzima fumarato hidratasa, sin que hasta el momento presente ningún tipo de neoplasia maligna renal. El leiomioma atípico es un tumor poco frecuente, que usualmente ocurre de forma aislada, siendo excepcional la presentación en pacientes con leiomiomatosis cutánea. Es ampliamente conocida la relación de la mutación de la enzima fumarato hidratasa con leiomiomas mútiples, miomas uterinos y el mayor riesgo de desarrollar cáncer renal; sin embargo, el papel de esta mutación en el desarrollo de leiomiomas atípicos es por hoy imposible de esclarecer debido a los escasos casos recogidos en la literatura.
We report the case of a 56 year-old male with an atypical leiomyoma in the context of a cutaneous leiomyomatosis and a family history of uterine leiomyomatosis. The genetic study revealed a mutation in the gene for the enzyme fumarate hydratase, but he has not had any renal malignancy so far. Atypical leiomyoma is a rare tumor that usually presents as a single lesion and is exceptional in patients with cutaneous leiomyomatosis. The relation between fumarate hydratase enzyme mutations with multiple leiomyomas, uterine leiomyomatosis and an increased risk of developing kidney cancer is widely known. However, the role of these mutations in the development of atypical leiomyomas is still impossible to clarify given the few cases reported in the literature.
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/genética , Leiomiomatosis/genética , Fumarato Hidratasa/genética , Mutación , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Leiomioma/enzimología , Leiomioma/genética , Leiomioma/patologíaRESUMEN
Cutaneous leiomyoma is a benign skin tumor that originates from the smooth muscle, such as the arrector pili muscle of the hair follicles. Familial cases with multiple cutaneous leiomyomas exist, which typically show an autosomal dominant inheritance trait. Most patients with the disease are known to carry heterozygous germ line mutations in the fumarate hydratase (FH) gene and can be complicated by tumors in internal organs, especially uterine leiomyoma and renal cell cancer in high frequency. In this study, we identified a Japanese male patient with multiple cutaneous leiomyomas and found a novel heterozygous splice site mutation, c.738 + 2T>A, in the FH gene of the patient, which was unexpectedly inherited from his unaffected father. Further analysis demonstrated loss of heterozygosity in the tumor tissue, which resulted in a hemizygote state of the mutant allele. Expression studies with the tumor tissue showed that the mutation led to skipping of exon 5 at mRNA levels, which was predicted to cause an in-frame deletion of FH protein (p.Ser186_Gln246del). The protein structure analysis strongly suggested that the deletion would severely disrupt the conformation of the FH protein including the substrate-binding domain, and thus would severely affect the expression and the function. Our findings further disclose the molecular basis of multiple cutaneous leiomyomas and also provide precious information to the mutation carriers in the family for an early diagnosis of renal cell cancer in the future.
Asunto(s)
Fumarato Hidratasa/genética , Leiomiomatosis/enzimología , Leiomiomatosis/genética , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Fumarato Hidratasa/química , Humanos , Pérdida de Heterocigocidad , Masculino , Modelos Moleculares , Mutación , Conformación Proteica , Sitios de Empalme de ARN , Adulto JovenRESUMEN
OBJECTIVE: To describe a novel mutation in the fumarate hydratase (FH) gene in a family with atypical uterine leiomyomas. DESIGN: Case report and review of the literature. SETTING: Academic community hospital. PATIENT(S): Three sisters who presented as nulligravidas aged 27-30 years with large atypical uterine leiomyomas. INTERVENTION(S): Abdominal myomectomy, robotic myomectomy, hysterectomy, gene sequencing. MAIN OUTCOME MEASURE(S): Identification of a family with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome and a novel mutation in the FH gene. RESULT(S): Two of the three sisters tested positive for a novel FH mutation p.Leu99Glufsx6. The eldest sister was clinically diagnosed with HLRCC. The patients' father also carries the same mutation in the FH gene. The patients and their father are now undergoing yearly screening for renal cancer. CONCLUSION(S): Patients with HLRCC are at risk for developing renal cancer as well as losing their fertility via early hysterectomy. Physicians must be aware of this condition and refer at-risk individuals for genetic testing.
Asunto(s)
Biomarcadores de Tumor/genética , Fumarato Hidratasa/genética , Leiomioma/genética , Leiomiomatosis/genética , Mutación , Neoplasias Cutáneas/genética , Neoplasias Uterinas/genética , Adulto , Biopsia , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Histerectomía , Leiomioma/enzimología , Leiomioma/patología , Leiomioma/cirugía , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Leiomiomatosis/cirugía , Imagen por Resonancia Magnética , Masculino , Síndromes Neoplásicos Hereditarios , Linaje , Fenotipo , Procedimientos Quirúrgicos Robotizados , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Carga Tumoral , Miomectomía Uterina/métodos , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugíaRESUMEN
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Fumarato Hidratasa/deficiencia , Leiomiomatosis/enzimología , Neoplasias Cutáneas/enzimología , Neoplasias Uterinas/enzimología , Adulto , Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Femenino , Fumarato Hidratasa/genética , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Leiomiomatosis/genética , Leiomiomatosis/patología , Leiomiomatosis/cirugía , Persona de Mediana Edad , Mutación , Síndromes Neoplásicos Hereditarios , Fenotipo , Pronóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Síndrome , Análisis de Matrices Tisulares , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugíaRESUMEN
Reed syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma caused by mutations in the fumarate hydratase gene. Dermatologic evaluation is often the first or only opportunity to discover the diagnosis of Reed syndrome in affected patients, which may prove to be life-saving. We present a 40-year-old woman with history of large uterine leiomyomas who presented with a two-year history of a pruritic papular eruption on the left neck refractory to topical corticosteroids. After histopathologic examination and genetic work-up, the patient was found to have a novel mutation in the fumarate hydratase gene and was subsequently diagnosed with Reed syndrome.
Asunto(s)
ADN de Neoplasias/genética , Fumarato Hidratasa/genética , Leiomiomatosis/genética , Mutación , Neoplasias Cutáneas/genética , Neoplasias Uterinas/genética , Adulto , Biopsia , Análisis Mutacional de ADN , Femenino , Fumarato Hidratasa/metabolismo , Humanos , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patologíaRESUMEN
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant syndrome that results from mutations in the fumarate hydratase (FH) gene. Patients with HLRCC are at risk for smooth muscle tumors of the uterus and skin as well as renal tumors. The renal cell carcinomas associated with HLRCC are usually high stage at presentation, aggressive, and have poor clinical outcomes. Therefore these patients and family members would benefit from early identification and appropriate surveillance. In small studies, HLRCC-associated uterine leiomyomas have been noted to display characteristic morphologic features including eosinophilic cytoplasmic inclusions, prominent eosinophilic nucleoli, and perinucleolar halos. Limited data suggest that positive staining for 2-succinocysteine (2SC) and loss of staining for FH by immunohistochemistry (IHC) can help with identification of HLRCC. The aim of this study was to evaluate the ability of morphology and IHC for FH and 2SC to help identify HLRCC in young patients with uterine smooth muscle tumors. We identified 194 evaluable uterine leiomyomas from women less than 40 years of age. We found FH gene aberrations by mutation analysis in 5 cases, a 2.6% incidence. Of these 5 cases, 4 displayed the characteristic morphologic features outlined above, whereas 1 did not. All 5 tumors with FH gene abnormalities showed positive staining for 2SC, whereas no FH gene aberrations were found in the 2SC-negative cases. Loss of FH staining was seen in 2 of the 5 cases, 1 with frameshift mutation and the other with homozygous deletion, whereas the remaining 3 cases with missense FH gene mutations were FH positive. Our study shows that morphologic features can be helpful for detection of HLRCC in uterine leiomyomas, although they may not be present in every case. IHC for 2SC and FH can be helpful: presence of positive staining for 2SC is sensitive and specific for detection of FH gene aberrations, whereas loss of staining for FH is specific but not sufficiently sensitive, as cases with missense mutations in the FH gene can show retained staining.
Asunto(s)
Biomarcadores de Tumor , Cisteína/análogos & derivados , Análisis Mutacional de ADN , Fumarato Hidratasa , Inmunohistoquímica , Leiomiomatosis/diagnóstico , Mutación , Neoplasias Cutáneas/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Factores de Edad , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biopsia , Cisteína/análisis , Femenino , Fumarato Hidratasa/análisis , Fumarato Hidratasa/genética , Predisposición Genética a la Enfermedad , Humanos , Leiomiomatosis/química , Leiomiomatosis/enzimología , Leiomiomatosis/genética , Leiomiomatosis/patología , Síndromes Neoplásicos Hereditarios , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Neoplasias Cutáneas/química , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Uterinas/química , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Adulto JovenAsunto(s)
Antiinflamatorios/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Fumarato Hidratasa/genética , Leiomiomatosis/enzimología , Mutación Puntual/genética , Neoplasias Cutáneas/enzimología , Neoplasias Uterinas/enzimología , Femenino , Humanos , Leiomiomatosis/tratamiento farmacológico , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios , Reacción en Cadena de la Polimerasa , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológicoAsunto(s)
Leiomiomatosis/diagnóstico , Neoplasias Cutáneas/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Femenino , Fumarato Hidratasa/genética , Humanos , Neoplasias Renales/enzimología , Neoplasias Renales/genética , Leiomiomatosis/enzimología , Leiomiomatosis/genética , Leiomiomatosis/patología , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.