RESUMEN
BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.
Asunto(s)
Síndrome de Birt-Hogg-Dubé , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Birt-Hogg-Dubé/complicaciones , Carcinogénesis , ARN , Factores de Transcripción ForkheadRESUMEN
The patient was a 70-year-old man who underwent transurethral resection of a bladder tumor. The pathological diagnosis was urothelial carcinoma (UC) with sarcomatoid variant, â§pT2. After neoadjuvant chemotherapy using gemcitabine and cisplatin (GC), radical cystectomy was performed. The histopathological diagnosis was no tumor remnant (ypT0ypN0). Seven months later, the patient underwent an emergency partial ileectomy for ileal occlusion, after sudden complaints of vomiting and abdominal pain and fullness. Postoperatively, two cycles of adjuvant GC chemotherapy were administered. Approximately 10 months after ileal metastasis, a mesenteric tumor appeared. After seven cycles of methotrexate/epirubicin/nedaplatin and 32 cycles of pembrolizumab therapy, the mesentery was resected. The pathological diagnosis was UC with sarcomatoid variant. No recurrence was noted for 2 years after resection of the mesentery.
Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Masculino , Humanos , Anciano , Neoplasias de la Vejiga Urinaria/cirugía , Íleon , Terapia Neoadyuvante , Quimioterapia AdyuvanteRESUMEN
Malignant peritoneal mesothelioma is generally characterized by chief complaints such as abdominal mass and abdominal pain. We report a case of malignant peritoneal mesothelioma diagnosed as an inguinal mass. A 69-year-old man was referred to our hospital complaining of abdominal distension and swelling in the right inguinal region. Abdominal/pelvic contrast-enhanced computed tomography revealed a 22 cm tumor from the right inguinal canal to the peritoneal cavity and a large amount of ascites. Because imaging analyses revealed no metastasis, we planned tumor resection. We resected the tumor with the peritoneum and right testis and sampled some nodules in the mesentery. Histopathological examination of the tumor led to the diagnosis of epithelial malignant mesothelioma. Adhering to chemotherapy guidelines for pleural malignant mesothelioma, six courses of pemetrexed and cisplatin combination chemotherapy were performed. He is alive with no evidence of new local tumor or nodules in the mesentery 1 year postoperatively.
Asunto(s)
Mesotelioma Maligno , Mesotelioma , Neoplasias Peritoneales , Anciano , Cisplatino , Humanos , Masculino , Mesotelioma/diagnóstico por imagen , Mesotelioma/tratamiento farmacológico , Pemetrexed , Neoplasias Peritoneales/diagnóstico por imagenRESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase gene (FH). Individuals with FH mutations are at risk of developing renal cell carcinoma (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is as yet no standardized therapy for advanced HLRCC-RCC. We report an aggressive RCC case in a 49-year-old man. Nine weeks after undergoing a total nephroureterectomy of the right kidney, he had a metastasectomy at port site. Within 14 weeks of the initial surgery, multiple recurrent tumors developed in the right retroperitoneal space. The pathological diagnosis was FH-deficient RCC. Genetic testing identified a heterozygous germline mutation of FH (c.641_642delTA), which confirmed the diagnosis of HLRCC-RCC. He received combination therapy with the immune checkpoint inhibitors (ICIs) nivolumab and ipilimumab as the first-line therapy. After 31 weeks of ICI treatment, a complete response was achieved. The disease-free condition has been prolonged for 24 months since the initial surgical treatment. This is the first case report of successful treatment of HLRCC-RCC with nivolumab plus ipilimumab. This combination immunotherapy is expected to be an effective approach to treat patients with advanced-stage HLRCC-RCC.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/terapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/uso terapéutico , Leiomiomatosis/terapia , Síndromes Neoplásicos Hereditarios/terapia , Nivolumab/uso terapéutico , Neoplasias Cutáneas/terapia , Neoplasias Uterinas/terapia , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/genética , Mutación de Línea Germinal , Humanos , Leiomiomatosis/diagnóstico por imagen , Leiomiomatosis/genética , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/diagnóstico por imagen , Síndromes Neoplásicos Hereditarios/genética , Linaje , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/genética , Tomografía Computarizada por Rayos X , Neoplasias Uterinas/diagnóstico por imagen , Neoplasias Uterinas/genéticaRESUMEN
AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies. METHODS: Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours. RESULTS: All patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence. CONCLUSIONS: HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.
Asunto(s)
Leiomiomatosis/genética , Leiomiomatosis/patología , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Adulto , Pueblo Asiatico , Variaciones en el Número de Copia de ADN , Femenino , Fumarato Hidratasa/genética , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: TRIM21 is an E3 ubiquitin ligase for interferon regulatory factors (IRFs) that are involved in innate and acquired immunity. Here, we evaluated the role of TRIM21 in the interferon (IFN) signature of systemic lupus erythematosus (SLE). METHODS: Twenty SLE patients and 24 healthy controls were enrolled in this study. We analyzed mRNA expression of TRIM21, type I IFN, and IFN-inducible genes in peripheral blood mononuclear cell (PBMC). The protein levels of IRFs were assessed by Western blotting in PBMCs cultured with or without MG-132. RESULTS: The expression of TRIM21 mRNA and protein was significantly higher in SLE PBMCs as compared to healthy controls. There was a correlation between TRIM21 mRNA expression and SLE activities. In contrast to a negative correlation between mRNA expression level of TRIM21 and those of type I IFNs in healthy controls, we found a positive correlation between them in anti-TRIM21 antibody-positive SLE patients. Neither positive nor negative correlation was observed in the autoantibody-negative SLE patients. Western-blotting analysis revealed impaired ubiquitin-dependent proteasomal degradation of IRFs in SLE PBMCs. CONCLUSION: Our study showed ubiquitin-dependent proteasomal degradation of IRFs was impaired in anti-TRIM21 antibody-dependent and -independent fashions, leading to amplification of IFN signature in SLE.
Asunto(s)
Factores Reguladores del Interferón/genética , Lupus Eritematoso Sistémico , Ribonucleoproteínas/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Femenino , Expresión Génica , Humanos , Interferón-alfa/genética , Interferón gamma/metabolismo , Leucocitos Mononucleares/inmunología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Gravedad del Paciente , ARN Mensajero/genéticaRESUMEN
Hereditary renal cell carcinomas (RCCs) are life-threatening disorders not only for the patients but also for their relatives. Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). The protein product, FLCN, functions as a tumor suppressor, and the affected patients have high risks of developing multiple RCCs. The carcinogenic mechanisms stemming from FLCN dysfunction have been investigated using rodent models and human RCC tissues. However, very limited information has been available about in vitro signaling of human renal cells with genetically mutant FLCN. Herein, we established a new cell line, BHD-F59RSVT, from a BHD patient's chromophobe RCC by transfecting SV40 large T antigen. We investigated FLCN mutations, chromosome profiles, and cytopathologic characteristics of the cell line. BHD-F59RSVT reflected the patient's FLCN germline mutation, a 3-nt deletion in exon 13 (c.1528_1530delGAG). Neither somatic mutation nor loss of heterozygosity of FLCN was detectable. Chromosome 17p11.2 of the FLCN proximal region demonstrated a trimodal pattern. Genome-wide chromosomal analysis revealed a loss of chromosome 16 and mosaic segmental gains in chromosome 7. BHD-F59RSVT cells were positive when immunostained for cytokeratin 7, supporting their origin from distal convoluted tubules. Western blotting analysis demonstrated severely suppressed FLCN expression at the protein level. The collective findings indicate that the established cell line will be suitable for functional analysis of the typical phenotype of BHD-associated RCC with suppressed FLCN expression.
Asunto(s)
Síndrome de Birt-Hogg-Dubé/genética , Carcinoma de Células Renales/genética , Mutación de Línea Germinal , Neoplasias Renales/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , Síndrome de Birt-Hogg-Dubé/complicaciones , Carcinoma de Células Renales/complicaciones , Carcinoma de Células Renales/patología , Línea Celular Transformada , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN/métodos , Salud de la Familia , Femenino , Humanos , Neoplasias Renales/complicaciones , Neoplasias Renales/patología , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Linaje , Proteínas Proto-Oncogénicas/metabolismo , Cariotipificación Espectral/métodos , Células Tumorales Cultivadas , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Birt-Hogg-Dubé syndrome (BHD) is a familial disorder associated with a germline mutation of FLCN that is a tumor suppressor gene. Patients with BHD have high risks for developing multiple renal cell carcinomas (RCCs). The frequent histological types are hybrid oncocytic/chromophobe tumors (HOCTs) and chromophobe RCCs. The morphology of HOCTs could alert pathologists to the possibility of BHD. On the other hand, chromophobe RCCs occurring in BHD patients demonstrate positive immunostaining for cytokeratin-7, CD82, and Ksp-cadherin similar to their sporadic counterparts. Highly reliable markers for BHD-associated chromophobe RCCs have not been identified. In the present study, we analyzed the state of chromosome 17 in 18 renal tumors composed of 8 chromophobe RCCs, 7 HOCTs, and 3 papillary RCCs obtained from BHD patients using fluorescent and chromogenic in situ hybridization probes for the centromeric region of chromosome 17 long arm. All chromophobe RCCs and HOCTs were disomic except for 1 chromophobe RCC that showed monosomy. On the other hand, 12 of 14 sporadic chromophobe RCCs were monosomic (P = .0008). The state of chromosomes 2 and 6 were also statistically different (P = .0074 and P = .0007, respectively). Three BHD-associated papillary RCCs demonstrated either trisomy (n = 2) or disomy (n = 1). Three of 5 sporadic papillary RCCs showed trisomy. The results indicate that fluorescent and chromogenic in situ hybridization of the centromeric region of chromosome 17 long arm should be a potent useful marker for chromophobe RCCs in patients who have not been diagnosed with BHD and thereby help to determine whether the cases should be considered for genetic testing.
Asunto(s)
Biomarcadores de Tumor/genética , Síndrome de Birt-Hogg-Dubé/genética , Carcinoma de Células Renales/genética , Cromosomas Humanos Par 17 , Hibridación Fluorescente in Situ , Neoplasias Renales/genética , Anciano , Biomarcadores de Tumor/análisis , Síndrome de Birt-Hogg-Dubé/diagnóstico , Cadherinas/análisis , Carcinoma de Células Renales/química , Carcinoma de Células Renales/diagnóstico , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Proteína Kangai-1/análisis , Queratina-7/análisis , Neoplasias Renales/química , Neoplasias Renales/diagnóstico , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas/genética , Trisomía , Proteínas Supresoras de Tumor/genéticaRESUMEN
Birt-Hogg-Dubé syndrome is an inherited disorder caused by germline mutations of the folliculin gene (FLCN). The affected patients are prone to developing renal cell carcinomas (RCCs). Most mutant FLCN-associated RCCs (mFLCN-RCCs) are histologically chromophobe RCCs and hybrid oncocytic/chromophobe tumors. It is incompletely understood whether mFLCN-RCCs have different chromosomal abnormalities compared with their sporadic histological counterparts. Herein, we describe somatic mutations of FLCN and DNA-copy number abnormalities using a high-density, whole-genome, single-nucleotide polymorphism array. The histological types included chromophobe RCC (n = 12), hybrid oncocytic/chromophobe tumor (n = 5), and clear-cell RCC (n = 2). Of 19 tumors, 8 had pathological somatic mutations of FLCN. Among 11 mFLCN-RCCs investigated by single-nucleotide polymorphism array, 8 showed balanced genomic profiles, 2 had gains in chromosome 3q, and 1 had gains in chromosomes 1q and 7. All had copious numbers of loss of heterozygosity in a wide range of chromosomes. The common loss-of-heterozygosity regions were chromosomes 3p24, 8q11, 16q11, Xp22-21, Xp11, Xq11, Xq13, and Xq23. Most of the loss of heterozygosity was because of uniparental disomy. Common uniparental disomy patterns in chromophobe RCCs and hybrid oncocytic/chromophobe tumors indicated that these types were relatively similar in cytogenetic events. Two clear-cell RCCs also shared several uniparental disomy regions with chromophobe RCCs and hybrid oncocytic/chromophobe tumors. mFLCN-RCCs may have common therapeutic targets among different histological types.
Asunto(s)
Síndrome de Birt-Hogg-Dubé/genética , Carcinoma de Células Renales/genética , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Neoplasias Renales/genética , Disomía Uniparental/genética , Adulto , Anciano , Síndrome de Birt-Hogg-Dubé/complicaciones , Carcinoma de Células Renales/etiología , Cromosomas Humanos , Femenino , Pruebas Genéticas/métodos , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys. We found that absolute Fnip2 mRNA copy number was low relative to Fnip1 in organs that showed phenotypes under Fnip1 deficiency but was comparable to Fnip1 mRNA copy number in mouse kidney. Strikingly, kidney-targeted Fnip1/Fnip2 double inactivation produced enlarged polycystic kidneys, as was previously reported in Flcn-deficient kidneys. Kidney-specific Flcn inactivation did not further augment kidney size or cystic histology of Fnip1/Fnip2 double-deficient kidneys, suggesting pathways dysregulated in Flcn-deficient kidneys and Fnip1/Fnip2 double-deficient kidneys are convergent. Heterozygous Fnip1/homozygous Fnip2 double-knockout mice developed kidney cancer at 24 mo of age, analogous to the heterozygous Flcn knockout mouse model, further supporting the concept that Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn and that kidney tumorigenesis in human Birt-Hogg-Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Our findings uncover important roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Portadoras/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Alelos , Animales , Proteínas Reguladoras de la Apoptosis/genética , Síndrome de Birt-Hogg-Dubé/genética , Proteínas Portadoras/genética , Modelos Animales de Enfermedad , Femenino , Riñón/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Enfermedades Renales Poliquísticas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder associated with a germline mutation of folliculin (FLCN). The affected families are at a high risk for developing multiple renal cell carcinomas (RCC). Little is known about the immunostaining patterns of mutant FLCN-associated RCCs. We investigated 32 RCCs obtained from 17 BHD patients. The studied tumors included chromophobe RCCs (n = 15), hybrid oncocytic/chromophobe tumors (HOCT) (n = 14) and clear cell RCCs (n = 3). Almost all chromophobe RCCs and HOCTs revealed positive staining for S100A1, Ksp-cadherin and CD82. They stained either focally or diffusely for CK7, and were negative for CA-IX. All clear cell RCCs were positively stained for CA-IX and negative for CK7. These data confirmed that mutant FLCN-associated oncocytic and clear cell RCCs exhibited generally similar immunostaining patterns compared to their sporadic counterparts. Frequent positive staining for S100A1, Ksp-cadherin and CD82 in chromophobe RCCs and HOCTs indicated that these two types were relatively similar rather than distinctively different in their patterns of immunoreactivity. Characteristic peri-nuclear halos and polygonal cells with clear cytoplasm, which often misleads pathologists into the diagnosis of clear cell RCC, should be carefully examined using an immunohistochemical panel including CA-IX, Ksp-cadherin, CD82 and CK7.