TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion and several somatic copy number alterations, including the loss of 22q, are associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibit low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis reveals five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which show association with fusion patterns and prognosis. In line with the aggressive nature, the high angiogenesis/stroma/proliferation cluster exclusively consists of tumors with ASPSCR1-TFE3 fusion. Here, we describe the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.

Purpose: Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC. Experimental Design: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded. Results: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade–based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03). Conclusions: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer that has no standard treatment for advanced disease. We described comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion, certain fusion isoforms and high somatic copy number alteration burdens were associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibited low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis revealed five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which showed association with fusion patterns and prognosis. Specifically, the high angiogenesis/stroma/proliferation cluster exclusively consisted of tumors with ASPSCR1-TFE3 fusion, which was likely to benefit from combination of immune checkpoint and anti-angiogenesis inhibitors. Our findings reveal the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.

Diffuse midline glioma, H3 K27M-mutant (H3 K27Mmt DMG), is a rare and highly aggressive tumor that is more common in children than in adults. Few studies have compared the differences between pediatric and adult patients with this rare tumor. We here report our retrospective study of 94 adult and 70 pediatric cases of diffuse midline glioma. Surgical tumor samples were analyzed by routine histopathology and immunohistochemistry for H3 K27M, IDH1 R132H, ATRX, p53, OLIG2, glial fibrillary acidic protein, and Ki-67; Sanger sequencing for hot mutation spots in genes including H3F3A, HIST1H3B, IDH1, IDH2, TERT, and BRAF; and methylation-specific polymerase chain reaction for O 6 -methylguanine DNA methyltransferase promoter methylation. The most frequent anatomic locations in adult and pediatric patients were the thalamus and brainstem, respectively. Molecular profiling revealed higher frequencies of ATRX loss and H3.3 mutation in adult than in pediatric H3 K27M-mt DMGs. TERT promoter mutations and O 6methylguanine DNA methyltransferase promoter methylation were not detected in pediatric patients but were present in a few adult patients. During the follow-up period, 93/122 patients (70.1%) died from the disease, with a median survival time of 10.5 months (range: 1 to 104 mo). Kaplan-Meier analyses demonstrated that the prognosis was better for adult patients than the pediatric cohort (P = 0.0003). Multivariate analyses indicated that patient age, primary tumor size, status of ATRX expression, and Ki-67 index were independent prognosticators. The present study showed that there were differences between adult and pediatric H3 K27M-mt DMGs in terms of the anatomic location of tumor, molecular changes, and prognosis.

AimsXp11 translocation renal cell carcinoma (RCC) is a distinctive subtype of RCC with TFE3 (Transcription Factor Binding to IGHM Enhancer 3) gene rearrangement. The gross features in most Xp11 translocation RCCs closely resemble clear cell RCCs. In this study, we report six cases of Xp11 translocation RCCs with a unique multicystic architecture, reminiscent of multilocular cystic renal cell neoplasm of low malignant potential (MCRN-LMP).Methods and resultsMicroscopically, the renal mass was well circumscribed with multilocular cystic architecture. The cyst walls and septa were mostly lined by a single layer of cells with clear cytoplasm and low-grade nuclei, reminiscent of MCRN-LMP. Psammoma bodies were detected in four cases. One particular patient was misdiagnosed with benign cysts in local hospitals and led to second operation. Tumour cells were settled according to the track of the first surgical procedure. TFE3 fluorescence in situ hybridization (FISH) assay confirmed the diagnosis of Xp11 translocation RCCs. FISH and RNA sequencing analyses confirmed MED15-TFE3 gene fusion in all six cases. Respective patients were alive, without any recent evidence of disease recurrence and/or metastasis.ConclusionsHere, we introduce a relatively inertia-variant of Xp11 translocation RCC which mimics MCRN-LMP. The distinctive morphological condition is linked to MED15-TFE3 gene fusion. In fact, renal neoplasms with morphological features of MCRN-LMP, especially those containing psammoma bodies, should be routinely evaluated for evidence of TFE3 gene rearrangements.

Glioma is the most common intracranial malignant tumor, with poor prognosis. The new World Health Organization (WHO) integrated classification (2016) for diffuse glioma is mainly based on the status of the isocitrate dehydrogenase (IDH) gene (IDH) mutation and 1p/19q codeletion, with diffuse glioma separated into three distinct molecular categories: chromosome 1p/19q codeletion/IDH mutant, 1p/19q intact /IDH mutant, and IDH wild-type. Gliomas harboring 1p/19q codeletion but without IDH mutation are rare and cannot be classified according to the new revision of the WHO classification. Here we report three high-grade gliomas with this atypical molecular phenotype, and describe their histological and immunohistochemical features, the status of mutations in TERT promopter, H3F3A, HIST1H3B, and BRAF, as well as MGMT promoter methylation, and prognosis. Considering morphology, molecular parameters, and patients prognosis, we found that high-grade gliomas harboring 1p/19q codeletion but without IDH mutation were not typical glioblastoma multiforme (GBM) but were more likely to be GBM than anaplastic oligodendroglioma.

CDK12 (Cyclin-Dependent Kinase 12)-mutated prostate cancer patients often respond badly to current therapies. Immunotherapy and platinum-based chemotherapy are recommended based on the molecular features of CDK12 -mutated tumors, but the reported patient outcomes are still unsatisfying. Here we report a prostate cancer patient with CDK12 somatic mutation who received multiple therapy options, including platinum-based chemotherapy and immunotherapy. His sequential circulating tumor DNA (ctDNA) -based liquid biopsy tests showed that his original CDK12 mutation fell undetectable twice. This phenomenon was observed only when he was responding well to platinum-based chemotherapy. His responses to immunotherapy were not satisfying. This case indicates that platinum-based chemotherapy can be a good option for treating patients with CDK12 mutation. More importantly, dynamic ctDNA-based liquid biopsies to monitor patients’ CDK12 mutation status are critical in evaluating patients’ response and tolerance during platinum-based chemotherapy, therefore may lead to a better overall prognosis. In conclusion, CDK12 -mutated prostate cancer patients are likely to benefit from platinum-based chemotherapy, especially with the help of dynamic ctDNA-based liquid biopsies to monitor their CDK12 mutation status.

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