Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

Duffy, Karen; Al‐Saleem, Tahseen; Karbowniczek, Magdalena; Ewalt, David H.; Prowse, Amanda; Henske, Elizabeth P.

doi:10.1038/modpathol.3880517

Cited by 21 publications

(13 citation statements)

References 49 publications

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“…This suggests that VHL and tuberin inhibit HIF through distinct cellular pathways: VHL by mediating HIF1 degradation, and tuberin by inhibiting HIF1 synthesis via mTOR. This is consistent with our finding that clear cell carcinomas in TSC patients lack VHL gene mutations [43], suggesting that mutations in TSC1 or TSC2 lead to clear cell carcinomas via a VHLindependent mechanism. …”

Section: The Future Of Tsc Therapysupporting

confidence: 91%

Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond

Henske

2005

Pediatr Nephrol

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The renal manifestations of tuberous sclerosis complex (TSC) are remarkably diverse, including polycystic kidney disease, oncocytomas, renal cell carcinomas, and both benign and malignant angiomyolipomas. All of these occur in children as well as adults with TSC. Benign angiomyolipomas, which can cause spontaneous life-threatening hemorrhage, are by far the most prevalent and the greatest source of morbidity. What is particularly unusual about TSC, setting it apart from virtually all other inherited forms of renal disease, is the abnormalities of both mesenchymal cells (angiomyolipomas) and epithelial cells (cysts, oncocytomas, and carcinomas). Recently, the TSC1/TSC2 protein complex was shown to inhibit the kinase mTOR (mammalian target of rapamycin). This places TSC1/TSC2 at center stage in signaling pathways that regulate cell growth. Furthermore, recent advances in TSC1/TSC2 signaling open the door for targeted therapy for TSC patients. Here, we will address the genetic, cellular and biochemical mechanisms that may contribute to the unusually broad spectrum of renal disease in cells with TSC1 or TSC2 mutations, and consider how the TSC signaling pathways may be linked to other renal diseases such as polycystic kidney disease and renal cell carcinoma.

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Section: The Future Of Tsc Therapysupporting

confidence: 91%

Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond

Henske

2005

Pediatr Nephrol

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“…Recently, mutational analysis of the VHL gene in two clear cell renal cell carcinomas from tuberous sclerosis complex patients did not reveal any VHL mutations or LOH at 3p. 13 In accordance, neither of the two renal cell carcinomas in our young patients group demonstrated LOH of the VHL gene region or TFE3 expression, suggesting a separate genetic pathway in renal cell carcinoma associated with tuberous sclerosis.…”

Section: Discussionsupporting

confidence: 73%

“…Six of these tumors were classified as translocation carcinomas and were among the 8 tumors that showed the typical translocation carcinoma morphology with ample, distinctly voluminous, soap bubble-like cytoplasm (case nos. 7,9,10,[12][13][14] (Figs. 1C, 3C).…”

Section: Immunohistochemical Findingsmentioning

confidence: 99%

Morphologic and Molecular Characterization of Renal Cell Carcinoma in Children and Young Adults

Bruder¹,

Passera²,

Harms³

et al. 2004

American Journal of Surgical Pathology

244

193

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A new WHO classification of renal cell carcinoma has been introduced in 2004. This classification includes the recently described renal cell carcinomas with the ASPL-TFE3 gene fusion and carcinomas with a PRCC-TFE3 gene fusion. Collectively, these tumors have been termed Xp11.2 or TFE3 translocation carcinomas, which primarily occur in children and young adults. To further study the characteristics of renal cell carcinoma in young patients and to determine their genetic background, 41 renal cell carcinomas of patients younger than 22 years were morphologically and genetically characterized. Loss of heterozygosity analysis of the von Hippel-Lindau gene region and screening for VHL gene mutations by direct sequencing were performed in 20 tumors. TFE3 protein overexpression, which correlates with the presence of a TFE3 gene fusion, was assessed by immunohistochemistry. Applying the new WHO classification for renal cell carcinoma, there were 6 clear cell (15%), 9 papillary (22%), 2 chromophobe, and 2 collecting duct carcinomas. Eight carcinomas showed translocation carcinoma morphology (20%). One carcinoma occurred 4 years after a neuroblastoma. Thirteen tumors could not be assigned to types specified by the new WHO classification: 10 were grouped as unclassified (24%), including a unique renal cell carcinoma with prominently vacuolated cytoplasm and WT1 expression. Three carcinomas occurred in combination with nephroblastoma. Molecular analysis revealed deletions at 3p25-26 in one translocation carcinoma, one chromophobe renal cell carcinoma, and one papillary renal cell carcinoma. There were no VHL mutations. Nuclear TFE3 overexpression was detected in 6 renal cell carcinomas, all of which showed areas with voluminous cytoplasm and foci of papillary architecture, consistent with a translocation carcinoma phenotype. The large proportion of TFE3 "translocation" carcinomas and "unclassified" carcinomas in the first two decades of life demonstrates that renal cell carcinomas in young patients contain genetically and phenotypically distinct tumors with further potential for novel renal cell carcinoma subtypes. The far lower frequency of clear cell carcinomas and VHL alterations compared with adults suggests that renal cell carcinomas in young patients have a unique genetic background.

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“…Furthermore, the immunophenotype of TSC-associated RCC has not been studied using modern antibody repertoires. (5, 11-13) Few RCCs in TSC patients have been reported to have co-expression of renal tubular and melanocytic markers such as HMB-45, and unlikely represented Xp11 translocation RCC, which further added to the tumor heterogeneity identified in these patients(5, 14). Absence of von Hippel-Lindau ( VHL ) gene mutation and loss of heterozygosity (LOH) was reported in 6 clear cell TSC-associated RCCs (13), in contrast to cytogenetic findings in sporadic RCC of the general non-TSC population, suggesting that clear cell TSC-associated RCC develops independently of canonical pathways.…”

Section: Introductionmentioning

confidence: 99%

Renal Cell Carcinoma in Tuberous Sclerosis Complex

Yang

Cornejo²,

Sadow³

et al. 2014

American Journal of Surgical Pathology

215

193

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Renal cell carcinoma (RCC) occurs in 2-4% of patients with tuberous sclerosis complex (TSC). Previous reports have noted a variety of histologic appearances in these cancers, but the full spectrum of morphologic and molecular features has not been fully elucidated. We encountered 46 renal epithelial neoplasms from 19 TSC patients and analyzed their clinical, pathological and molecular features, enabling separation of these 46 tumors into three groups. The largest subset of tumors (n=24) had a distinct morphological, immunological and molecular profile, including prominent papillary architecture and uniformly deficient SDHB expression prompting the novel term “TSC-associated papillary RCC.” The second group (n=15) was morphologically similar to a hybrid oncocytic/chromophobe tumor (HOCT) while the last 7 renal epithelial neoplasms of group 3 remained unclassifiable. The TSC-associated papillary RCCs (PRCC) had prominent papillary architecture lined by clear cells with delicate eosinophilic cytoplasmic thread-like strands that occasionally appeared more prominent and aggregated to form eosinophilic globules. All 24 (100%) of these tumors were the International Society of Urological Pathology (ISUP) nucleolar grade 2 or 3 with mostly basally located nuclei. Tumor cells from 17 of 24 TSC-associated PRCC showed strong, diffuse labeling for CA-IX (100%), CK7 (94%), vimentin (88%), CD10 (83%), and were uniformly negative for succinate dehydrogenase subunit B (SDHB), TFE3 and AMACR. Gains of chromosomes 7 and 17 were found in 2 tumors, whereas chromosome 3p deletion and TFE3 translocations were not detected. In this study, we reported a sizable cohort of renal tumors seen in TSC and were able to identify them as different morphotypes which may help to expand the morphologic spectrum of TSC-associated RCC.

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Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

Cited by 21 publications

References 49 publications

Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond

Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond

Morphologic and Molecular Characterization of Renal Cell Carcinoma in Children and Young Adults

Renal Cell Carcinoma in Tuberous Sclerosis Complex

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