NMRK2 is an efficient diagnostic indicator for Xp11.2 translocation renal cell carcinoma.

Xp11.2 translocation renal cell carcinomas (tRCC) are a rare and highly malignant type of renal cancer, lacking efficient diagnostic indicators and therapeutic targets. Through the analysis of public databases and our cohort, we identified NMRK2 as a potential diagnostic marker for distinguishing Xp11.2 tRCC from kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) due to its specific upregulation in Xp11.2 tRCC tissues. Mechanistically, we discovered that TFE3 fusion protein binds to the promoter of the NMRK2 gene, leading to its upregulation. Importantly, we established RNA- and protein-based diagnostic methods for identifying Xp11.2 tRCC based on NMRK2 expression levels, and the diagnostic performance of our methods was comparable to a dual-color break-apart fluorescence in situ hybridization assay. Moreover, we successfully identified fresh Xp11.2 tRCC tissues after surgical excision using our diagnostic methods and established an immortalized Xp11.2 tRCC cell line for further research purposes. Functional studies revealed that NMRK2 promotes the progression of Xp11.2 tRCC by upregulating the NAD+/NADH ratio, and supplementation with ß-nicotinamide mononucleotide (NMN) or nicotinamide riboside chloride (NR), effectively rescued the phenotypes induced by the knockdown of NMRK2 in Xp11.2 tRCC. Taken together, these data introduce a new diagnostic indicator capable of accurately distinguishing Xp11.2 tRCC and highlight the possibility of developing novel targeted therapeutics. © 2024 The Pathological Society of Great Britain and Ireland.

Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.

Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.

Clinical and pathological heterogeneity of four common fusion subtypes in Xp11.2 translocation renal cell carcinoma.

Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a group of rare and highly heterogeneous renal cell carcinoma (RCC). The translocation involving TFE3 and different fusion partners lead to overexpression of the chimeric protein. The purpose of this study is to explore the clinicopathological features of Xp11.2 tRCC with four common fusion subtypes. Methods: We screened out 40 Xp11.2 tRCC patients from January 2007 to August 2021 in our institution. The diagnosis was initially confirmed by TFE3 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assay and their fusion partners were verified by RNA sequencing. Then the 40 cases were divided into two groups (DBHS family and non-DBHS family group) and a clinical comparison among the four common fusion subtypes was performed. Results: Among the 40 cases, 11 cases with SFPQ-TFE3 gene fusion and 7 cases with NONO-TFE3 gene fusion were classified in DBHS group, the remaining cases with ASPL-TFE3 (11 cases) or PRCC-TFE3 (11 cases) gene fusion were classified in non-DBHS group. Lymph node (LN) metastasis (P=0.027) and distant metastasis (P=0.009) were more common seen in non-DBHS family group than DBHS family group and cases in DBHS family group have better progressive-free survival (PFS) (P=0.02). In addition, ASPL-TFE3 fusion was associated with worse outcome (P=0.03) while NONO-TFE3 fusion (P=0.04) predicted a better prognosis. Conclusions: Different fusion partner genes may play a functional role in various morphology, molecular and biological features of Xp11.2 tRCCs. The impact of fusion partners on clinical characteristics of Xp11.2 tRCCs deserves further exploration.

A case of metastatic Xp11.2 translocation renal cell carcinoma showing a prolonged response to nivolumab as 6th-line treatment.

A female patient with Xp11.2 translocation renal cell carcinoma developed lung metastasis 24 months after partial nephrectomy that was performed at the age of 32. Sunitinib, everolimus, axitinib, temsirolimus and pazopanib were sequentially administered for 55 months and disease progression was observed. Then nivolumab was started as 6th-line treatment. After a transient increase in tumor size, metastatic tumors started to shrink. Eventually, nivolumab provided a partial response with a 35% reduction of tumor size at 50 months and freedom from progression for 60 months. The present case suggests that immune checkpoint inhibitors are effective in selected cases with Xp11.2 translocation renal cell carcinoma.

Case Report: Clinical complete response of advanced renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion by treated by camrelizumab and axitinib: A rare case report.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusions is a rare subtype of renal tumor. This entity predominantly occurs in juveniles, but rarely in adults. Xp11.2 translocation RCC (tRCC) patients with lymph node or organ metastasis are associated with poor prognosis, and the strategy remains controversial. Herein, we presented our experience with the diagnosis and treatment of an adult case of Xp11.2 tRCC. In our clinical practice, a 32-year-old male manifested fever and right flank paroxysmal blunt pain, and computed tomography showed an inhomogeneous mass, 6 cm in diameter, in the right kidney. Then right partial nephrectomy (PN) and renal hilar lymph node dissection by laparoscopic surgery were performed. Pathology revealed that the tumor cells were positive for TFE3 immunohistologically and positive for TFE3 break-apart fluorescence in situ hybridization assay. A splice site mutation c.1544-1G>T of protein tyrosine phosphatase receptor delta (PTPRD) was detected by next-generation sequencing and weak PTPRD expression was confirmed in tumor tissues compared to tumor periphery. This patient was diagnosed with stage III RCC and received immune checkpoint inhibitor (camrelizumab) in combination with tyrosine kinase inhibitor (axitinib) treatment for 1 year. He achieved a clinical complete response with no sign of recurrence or metastasis. PTPRD mutation might be a favorable indicator for Xp11.2 tRCC patients managed by PN and followed by the adjuvant therapy of immune checkpoint inhibitor and tyrosine kinase inhibitor.

Molecular Heterogeneity of Xp11.2 Translocation Renal Cell Carcinoma: The Correlation Between Split Signal Pattern in FISH and Prognosis.

PURPOSE: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a distinct subtype of renal cell carcinoma (RCC) characterized by chromosomal translocations involving TFE3 gene. TFE3 break-apart fluorescence in situ hybridization (FISH) assay is an effective tool to diagnose Xp11.2 tRCC. The aim of this study is to evaluate the correlation between split signal pattern in FISH and the clinicopathological characteristics of Xp11.2 tRCC. PATIENTS AND METHODS: We reviewed 2037 RCC patients who underwent partial nephrectomy or radical nephrectomy from January 2007 to March 2020 in our institution. Forty-nine cases were diagnosed as Xp11.2 tRCC and their split signal patterns were evaluated. X-tile software was used to determine the optimal cut-off value of the percentage of split signal in FISH. Kaplan-Meier analysis and Cox regression analysis were performed to assess the relationship between signal pattern of FISH and the prognosis. RESULTS: Among the 49 patients, 13 patients and 36 patients were classified into high and low split signal group, respectively. Nine cases showed extra amplification signal pattern and 40 cases showed typical translocation signal pattern. Multivariate analysis demonstrated that high percentage of split signal and amplification signal pattern were the independent predictors for progression-free survival (PFS) whereas only pT stage was associated independently with overall survival (OS). CONCLUSION: Xp11.2 tRCC cases with high percentage of split signals or amplification signal pattern may have a worse outcome, and the two indicators need to be highlighted in clinical practice.

[A CASE REPORT OF Xp11.2 TRANSLOCATION RENAL CELL CARTINOMA SUSPECTED RENAL PELVIC CARCINOMA].

The patient was a 33-year-old female who visited the Department of Gastroenterology of this hospital after experiencing lower abdominal pain and nausea. The patient was referred to this department after suspicions of right kidney hemorrhage revealed by non-contrast computed tomography (CT). We also identified hematuria macroscopically, and contrast-enhanced CT scans revealed uneven deep staining in the upper right kidney during the early phase. Furthermore, by the late phase, we identified a 29-mm solid tumor with no staining. There was no clear pseudomembrane and no clear boundary with the kidney parenchyma. Additionally, there was no metastasis to the lymph nodes and other organs. Based on the above findings, we suspected renal parenchymal infiltration of right renal cell carcinoma (RCC) or right renal pelvic carcinoma. Since the patient was young, we considered the risk of the residual tumor and performed total nephroureterectomy and lymph node dissection with an enlarged view. The inside of the resected tumor specimen showed significant necrosis and hematoma spread, which had infiltrated the renal pelvis. Based on the characteristic histological findings and genetic results obtained using the fluorescence in situ hybridization (FISH) approach, we diagnosed the patient with Xp11.2 translocation RCC. No additional treatments were provided after surgery, and even now the patient is being followed-up through outpatient visits, but there has been no recurrence or new metastasis. There have only been a few reported cases of Xp11.2 translocation RCC; therefore, in many cases, treatments and follow-up duration according to the disease stage and disease prognosis have not been determined. In this study, we report a case of Xp11.2 translocation RCC experienced at our hospital, with additional literature considerations.

Translocation Renal Cell Carcinoma in a Child Previously Treated for Infantile Fibrosarcoma.

We report a child who developed a TFE3/Xp11.2 translocation renal cell carcinoma (RCC) when he was 3 years and 3 months old, after previous treatment for infantile fibrosarcoma (IFS). When he was 3 months old, a left axilla mass has been detected, which was tan and solid, was 1.5 cm in greatest dimension, and composed of sheets of spindle cells that was positive for vimentin and fibronectin. Fluorescence in situ hybridization showed positive result in ETV6 gene rearrangements. The final diagnosis was IFS. After surgery and chemotherapy, he remained disease-free until 3 years; later, he was detected to have a tumor in right kidney which measured 2.5 × 2 × 1.5 cm. The tumor comprised clear-cell features that were arranged in papillary and adenoid architecture. The tumor cells were positive for TFE3 and CK. The diagnosis was TFE3/Xp11.2 translocation RCC. Previous research has reported that the radio/chemotherapy for the first tumor might be involved in the pathogenesis of translocation RCC. In our report, this is the first time the IFS is included in the disease spectrum which can cause secondary translocation RCC.

Report of 6 cases of Xp11.2 translocation renal cell carcinoma and literature review / 中华泌尿外科杂志

Objective To explore the clinical and pathological characters of Xp1 1.2 translocation renal cell carcinoma.Method We screened patients of renal cell carcinoma of PUMCH between Jan.2011 and Dec.2015,6 patients with Xp11.2 translocation renal cell carcinoma were found.There were 2 males and 4 females,with average age of 39 (ranging from 16 to 73 years old).Diameter of tumor ranged from 1.9cm to 19.0cm,and 9.6cra in average.Among which,3 cases were detected by routine physical examination,1 by severe anemia (Hb 66g/L),1 by gross hematuria,and 1 by flank discomfort.Before treatment,2 cases had local metastasis (local lymph node,renal pelvis invasion),1 had distant metastasis (pulmonary metastasis).CT examination showed that the tumors had soft tissue density / low density,with significant enhancment or uneven enhancement in enhanced scanning,and were all considered malignancy.6 patients were all treated with surgeries,of which 5 patients received radical nephrectomy,1 patient received nephron sparing surgery.Result Pathologically,most clear cells arranged in a papillary,nest like structure,with psaamoma bodies in them.Immunohistochemical examination showed that all patients were positive for TFE3.AE1/AE3,RCC,Vimentin,CD10,EMA,P504 were positive in different degree.According to pathological result,all 6 patients were proved to be Xp1 1.2 translocation renal cell carcinoma.After surgery,2 patients received immunotherapy,2 received targeted drug therapy,and 1 received local radiotherapy.The follow-up duration ranged from 9 to 56 months (average 37 months).Among which,1 patient died from tumor recurrence and multiple metastasis 22 months after surgery,1 had pulmonary metastasis 12 months after surgery,and the tumor had no significant progress after receiving targeted drug therapy.All the other patients survive without tumor recurrence.Conclusions Xp1 1.2 translocation renal cell carcinoma predominantly occurs in children and adults younger than 40 years.Arterial phase enhancement is slightly lower for Xp1 1.2 translocation renal cell carcinoma in CT scan than that of renal clear cell carcinoma.Histological features and immunohistochemical staining of TFE3 positive expression are important means of diagnosis of this disease.If necessary,gene detection could be done to make better diagnose.Surgery is preferred treatment option.Metastatic leads to poor prognosis,and need to be supplemented by targeted drug therapy.