Ung thư biểu mô tế bào thận có đột biến TFE3/Xp11.2 báo cáo một trường hợp ở trẻ em và đối chiếu y văn

TÓM TẮT Ung thư biểu mô tế bào thận (UTBM) - Renal cell carcinoma là khối u ác tính hiếm gặp, chỉ chiếm 2 - 6% các khối u thận ác tính ở trẻ em. UTBM tế bào thận có đột biến TFE3 trên nhiễm sắc thể Xp11.2 (TFE3/ Xp11.2) là một dưới nhóm của UTBM tế bào thận, thường có tiên lượng nặng hơn các nhóm khác của UTBM tế bào thận. Chúng tôi thông báo một trẻ 10 tuổi vào viện vì đau bụng và phát hiện khối u thận trái. Sau khi phẫu thuật cắt u được làm xét nghiệm mô bệnh học, nhuộm hóa mô miễn dịch TFE3(+), CD10(+), CK7(-) chẩn đoán: UTBM tế bào thận có đột biến TFE3/Xp11.2. Bệnh nhân ổn định, ra viện sau 2 tuần. Tái khám sau hai tháng không phát hiện u tái phát hay di căn. ABSTRACT RENAL CELL CARCINOMA ASSOCIATED WITH XP11.2 TRANSLOCATION FACTORE3 GENE FUSION: A CHILD CASE REPORT AND LITERATURE REVIEW Renal cell carcinoma is a rare malignancy, accounting for only 2 - 6% of renal malignancies in children. Renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion is a subgroup of renal cell carcinoma, often with a more severe prognosis than other groups of renal cell carcinoma. We report on a 10 - year - old child was admitted to the hospital because of abdominal painand a left kidney tumor. After tumor resection, histopathological examination, immunohistochemical staining was positive for TFE3, CD10, negative for CK7, diagnosis renal cell carcinoma associated with Xp11.2 translocation factor E3 gene fusion. Two weeks after surgery, the patient was stable and discharged from the hospital. Re - examination after two months did not detect tumor recurrence or metastasis. Key word: Renal cell carcinoma, TFE3, Xp11.2 translocation.

Xp11.2 Translocation Renal Cell Carcinoma With TFE3 Rearrangement: Distinct Morphological Features and Prognosis With Different Fusion Partners

BackgroundRenal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion is a rare and new subtype of RCC and was classified by the WHO in 2004. Since then, multiple 5′ fusion partners for TFE3 have been reported; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11.2 RCCs has not been well defined.MethodsFour Xp11.2 translocation RCCs were identified by morphological, immunostaining, and fluorescence in situ hybridization (FISH) assays from 200 patients who attended Guangdong General Hospital between January 2017 and January 2020. All these four cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners. The clinicopathologic features, including clinical manifestations, pathological findings, treatment strategies, clinical outcomes, and follow-up information on Xp11.2 translocation RCCs, were recorded and evaluated.ResultsThese four cases affected one male and three females. The median age was 13 years at the time of diagnosis (range = 4–20 years). All the examined tumors were unilateral and unifocal. The largest diameter of these tumors ranged from 2.0 to 10.0 cm, and the average was 5.55 cm. Regional lymph node or distant metastasis developed in two patients. Three cases demonstrated known fusions: ASPCR1–TFE3 (two cases) and PRCC–TFE3 (one case). However, one case showed an unreported VCP–TFE3 fusion gene in Xp11.2 translocation RCCs. Immunohistochemistry results revealed tumor cells diffusely positive for TFE3, but have no consistency in other markers. Moreover, there were different clinical prognoses among the different variant TFE3 rearrangements; RCC patients with VCP–TFE3 translocation had worse prognosis compared to those with other fusion types. Follow-up were available for all the patients and ranged from 3 to 36 months. Three patients were without evidence of disease progression, while that with VCP–TFE3 fusion died of the disease 3 months after the diagnosis.ConclusionIn conclusion, our data expand the list of TFE3 gene fusion partners and the clinicopathologic features of Xp11.2 RCCs with specific TFE3 gene fusions. We identified a novel VCP–TFE3 fusion in Xp11.2 translocation RCCs for the first time, which has unique morphology and worse prognosis than those with other variant TFE3 rearrangements. Integration of morphological, immunohistochemical, and molecular methods is often necessary for the precise diagnosis and optimal clinical management of malignant tumors.

Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma

Background Xp11.2 translocation renal cell carcinoma (tRCC) is defined by translocation of the transcription factor E3 (TFE3) gene located on chromosome Xp11.2. Due to the high incidence in women, 17β-estradiol (E2) may be a factor influencing TFE3 breaks, and the topoisomerase II (TOP2) poison is considered one of the important risk factors in mediating DNA breaks. In this study, we investigated the potential pathogenesis of Xp11.2 tRCC using the renal epithelial cell line HK-2. Methods Immunofluorescence assay was performed to analyze DNA breaks by quantifying phosphorylation of H2AX (γH2AX), and the micronuclei (MN) assay was designed for monitoring chromosome breaks. The chromatin immunoprecipitation (CHIP) was used to detect whether proteins bound to specific DNA site, and the co-immunoprecipitation (Co-IP) was used to confirm whether proteins bound to other proteins. In some experiments, siRNA and shRNA were transfected to knockdown target genes. Results Our results demonstrated that DNA double-strand breaks were mediated by TOP2β in HK-2 cells, and this process could be amplified through estrogen receptor α (ERα)-dependent pathway induced by E2. After performing translocation site analysis using target region sequencing data in two Xp11.2 tRCC cell lines and ten Xp11.2 tRCC patients, we confirmed that TOP2β and ERα could both bind to TFE3 translocation sites directly to mediate DNA breaks in a E2-dependent manner. However, TOP2β and ERα were not observed to have direct interaction, indicating that their collaborative may be implemented in other ways. Besides, TFE3 was found to be upregulated through NRF1 with increasing E2 concentration, which could increase the risk of TFE3 breaks. Conclusion Our results indicate that E2 amplifies TOP2β-mediated TFE3 breaks by ERα-dependent pathway, and E2 upregulates TFE3 by NRF1 to increase the risk of TFE3 breaks. This suggests that E2 is an important pathogenic factor for Xp11.2 tRCC pathogenesis.

Long survival of a young patient with Xp11.2 translocation metastatic clear cell renal carcinoma: case report and review of the literature

Introduction: Xp11.2 translocation is a rare subtype of renal cell carcinoma (RCC), identified as a single entity only from 2004 by World Health Organization (WHO). These tumors involve pediatric age group and rarely patients over 40 years old. Children show indolent disease; adult population has invasive tumor at diagnosis with rapid progression. Case report: We describe a case report of a young woman affected by metastatic clear cell renal carcinoma with Xp11.2 translocation. She achieved a longer stable disease (SD) to first line treatment with atezolizumab plus bevacizumab, obtaining a progression free survival (PFS) of 21 months. After she received cabozantinib, sunitinib and then sorafenib. Conclusions: The patient had an overall survival (OS) of 51 months, which is much higher than that reported in literature data. Unfortunately, the biology of Xp11.2 translocation RCC and its therapeutic management are still unclear.

Xp11.2 Translocation Renal Cell Carcinoma: Clinical Characteristics and Potential Prognostic Predictors

Background. Xp11.2 translocation renal cell carcinoma, a rare malignancy, has a higher prevalence in children than in adults. It is relatively indolent in children but manifests with an aggressive course in adults. Clinical characteristics and prognostic studies for adult patients are scarce due to its rarity. Methods. This retrospective single-center study consecutively enrolled 24 newly diagnosed Xp11.2 translocation RCC adult patients. Clinical presentations were recorded, and baseline laboratory results and follow-up data were collected. Possible risk factors for progression-free survival and overall survival were first scanned with chi-square tests and t -tests to compare patients who suffered from progression or death with who did not. Multivariate Cox regression was further utilized to identify independent risk factors. Results. Twenty-four adult patients (median age 32, range 16-73), with a male-to-female ratio of 1 : 1, was included from April 2010 to March 2020. After follow-up for 35.7 months (+/- months), seven patients died. With univariate analysis, higher C-reactive protein-to-albumin (CRP/Alb) ratio ( p = 0.028 ), higher baseline fibrinogen ( p = 0.006 ), and presence of distant metastasis ( p = 0.007 ) were associated with progression of the disease; higher preoperative fibrinogen ( p = 0.014 ) and distant metastasis ( p = 0.020 ) were associated with death. With multivariate Cox regression, only baseline fibrinogen level ( p = 0.001 ) was identified as an independent risk factor for progression-free survival; meanwhile, fibrinogen level ( p = 0.048 ) and distant metastasis ( p = 0.043 ) were identified as independent risk factors for survival. Conclusions. Overall, relatively high CRP/Alb ratios, fibrinogen, and distant metastasis were associated with a poor prognosis of Xp11.2 tRCC adult patients; among them, only baseline fibrinogen levels independently predicted the progression of Xp11.2 tRCC; thus, it may help to identify patients with worse progression or death risk.

Estradiol Increases Risk of Topoisomerase Ⅱβ-Mediated DNA Strand Breaks to Initiate Xp11.2 Translocation Renal Cell Carcinoma

Background: Xp11.2 translocation renal cell carcinoma (tRCC) is defined by translocation of the transcription factor E3 (TFE3) gene located on chromosome Xp11.2. Due to the high incidence in women, 17β-estradiol (E2) may be a factor influencing TFE3 breaks, and the topoisomerase Ⅱ (TOP2) poison is considered one of the important risk factors in mediating DNA breaks. In this study, we investigated the potential pathogenesis of Xp11.2 tRCC using the renal epithelial cell line HK-2.Methods: Immunofluorescence assay was performed to analyze DNA breaks by quantifying phosphorylation of H2AX (γH2AX), and the micronuclei (MN) assay was designed for monitoring chromosome breaks. The chromatin immunoprecipitation (CHIP) was used to detect whether proteins bound to specific DNA site, and the co-immunoprecipitation (Co-IP) was used to confirm whether proteins bound to other proteins. In some experiments, siRNA and shRNA were transfected to knockdown target genes.Results: Our results demonstrated that DNA double-strand breaks were mediated by TOP2β in HK-2 cells, and this process could be amplified through estrogen receptor α (ERα)-dependent pathway induced by E2. After performing translocation site analysis using target region sequencing data in two Xp11.2 tRCC cell lines and ten Xp11.2 tRCC patients, we confirmed that TOP2β and ERα could both bind to TFE3 translocation sites directly to mediate DNA breaks in a E2-dependent manner. However, TOP2β and ERα were not observed to have direct interaction, indicating that their collaborative may be implemented in other ways. Besides, TFE3 was found to be upregulated through NRF1 with increasing E2 concentration, which could increase the risk of TFE3 breaks.Conclusion: Our results indicate that E2 amplifies TOP2β-mediated TFE3 breaks by ERα-dependent pathway, and E2 upregulates TFE3 by NRF1 to increase the risk of TFE3 breaks. This suggests that E2 is an important pathogenic factor for Xp11.2 tRCC pathogenesis.

Adult Xp11.2 translocation renal cell carcinoma managed effectively with pazopanib

Xp11.2 translocation renal cell carcinoma (TRCC) is a rare and aggressive variant of renal cell carcinoma (RCC) when presenting in adults. We report a case of a man in his early 40s who was diagnosed with stage III Xp11.2 TRCC and underwent radical nephrectomy. Seven months following the surgery, an adrenal nodule and bilateral pulmonary nodules were discovered. He underwent cryoablation of the adrenal nodule and systemic treatment with daily pazopanib. He displayed stable disease for approximately 6 years. Following this period, multiple hospitalisations interrupted daily pazopanib therapy resulting in progression of disease. His regimen was then changed to ipilimumab and nivolumab, followed by current daily therapy with axitinib. The patient now shows stable disease in his 10th year after diagnosis. This case study demonstrates the efficacy of pazopanib for metastatic Xp11.2 TRCC and warrants further investigation to supplement the guidelines regarding the use of targeted therapy for TRCC.

Clinicopathologic features of Xp11.2 translocation renal cell carcinoma and its response to target therapy.

e16559 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a unique RCC subtype with high malignant potential and poor prognosis, its natural course and response to systemic therapy are not fully understood. We analyzed the clinic features of this distinct entity and the benefit of systemic therapy in these patients. Methods: Between May 2006 and December 2019, 1113 consecutive patients diagnosed with RCC from Peking university cancer hospital (Beijing, China) were reviewed, data of the clinical characteristics and outcome of patients with metastatic Xp11.2 RCC were retrospectively collected. Tumor response to systemic therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results: Metastatic Xp11.2 translocation RCC was found in 41 cases. The median PFS and Median OS was 6.3 months (4.4 - 8.8) and 17.3 months (12.4 - 21.8) for the whole cohort, respectively. First-line treatment mainly included sunitinib (n = 12), sorafenib (n = 13), axitinib (n = 6), and pazopanib (n = 4), and the median PFS of these regimens was 5.4 months, 5.1 months, 9.4 months, 8.3 months, respectively. Twenty-three patients received subsequent therapies, the median PFS and the median OS was 4.3 months and 12 months for the second-line therapy(n = 21), 4.3 months and 14.1 months for the third-line therapy(n = 11), 2.4 months and 9.6 months for the fourth-line therapy(n = 6). Conclusions: Metastatic Xp11.2 translocation RCC is an aggressive disease. Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) agents appeared to demonstrate some efficacy, the combination of VEGFR-TKI and immune checkpoint inhibitor (ICI) might be a useful tool for the treatment of metastatic Xp11.2 translocation RCC.

Factors Associated with Survival From Xp11.2 Translocation Renal Cell Carcinoma Diagnosis—A Systematic Review and Pooled Analysis

Purpose: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a rare subtype of renal cell carcinoma (RCC), characterized by translocations of Xp11.2 breakpoints, involving of the transcription factor three gene (TFE3). The aim of our study was to comprehensively characterize the clinical characteristics and outcomes, and to identify risk factors associated with OS and PFS in Xp11.2 tRCC patients.Methods: Literature search on Xp11.2 tRCC was performed using databases such as pubmed EMBASE and Web of Science. Studies were eligible if outcomes data (OS and/or PFS) were reported for patients with a histopathologically confirmed Xp11.2 tRCC. PFS and OS were evaluated using the univariable and multivariable Cox regression model.Results: There were 80 eligible publications, contributing 415 patients. In multivariable analyses, the T stage at presentation was significantly associated with PFS (HR: 3.87; 95% CI: 1.70 to 8.84; p = 0.001). The median time of PFS was 72 months. In the multivariable analyses, age at diagnosis (HR: 2.16; 95% CI: 1.03 to 4.50; p = 0.041), T stage at presentation (HR: 4.44; 95% CI: 2.16 to 9.09; p < 0.001) and metastasis status at presentation (HR: 2.67; 95% CI: 1.12 to 6.41; p = 0.027) were all associated with OS, with a median follow-up time of 198 months.Conclusion: T stage at presentation is the only factor that is associated with both PFS and OS in patients with Xp11.2 tRCC. Also, patients over 45 or with metastases are more likely to have poorer OS.

Low expression of TRAF3IP2-AS1 promotes progression of NONO-TFE3 translocation renal cell carcinoma by stimulating N6-methyladenosine of PARP1 mRNA and downregulating PTEN

Background NONO-TFE3 translocation renal cell carcinoma (NONO-TFE3 tRCC) is one subtype of RCCs associated with Xp11.2 translocation/TFE3 gene fusions RCC (Xp11.2 tRCCs). Long non-coding RNA (lncRNA) has attracted great attention in cancer research. The function and mechanisms of TRAF3IP2 antisense RNA 1 (TRAF3IP2-AS1), a natural antisense lncRNA, in NONO-TFE3 tRCC remain poorly understood. Methods FISH and qRT-PCR were undertaken to study the expression, localization and clinical significance of TRAF3IP2-AS1 in Xp11.2 tRCC tissues and cells. The functions of TRAF3IP2-AS1 in tRCC were investigated by proliferation analysis, EdU staining, colony and sphere formation assay, Transwell assay and apoptosis analysis. The regulatory mechanisms among TRAF3IP2-AS1, PARP1, PTEN and miR-200a-3p/153-3p/141-3p were investigated by luciferase assay, RNA immunoprecipitation, Western blot and immunohistochemistry. Results The expression of TRAF3IP2-AS1 was suppressed by NONO-TFE3 fusion in NONO-TFE3 tRCC tissues and cells. Overexpression of TRAF3IP2-AS1 inhibited the proliferation, migration and invasion of UOK109 cells which were derived from cancer tissue of patient with NONO-TFE3 tRCC. Mechanistic studies revealed that TRAF3IP2-AS1 accelerated the decay of PARP1 mRNA by direct binding and recruitment of N6-methyladenosie methyltransferase complex. Meanwhile, TRAF3IP2-AS1 competitively bound to miR-200a-3p/153-3p/141-3p and prevented those from decreasing the level of PTEN. Conclusions TRAF3IP2-AS1 functions as a tumor suppressor in NONO-TFE3 tRCC progression and may serve as a novel target for NONO-TFE3 tRCC therapy. TRAF3IP2-AS1 expression has the potential to serve as a novel diagnostic and prognostic biomarker for NONO-TFE3 tRCC detection.