Dual-color, Break-apart FISH Assay on Paraffin-embedded Tissues as an Adjunct to Diagnosis of Xp11 Translocation Renal Cell Carcinoma and Alveolar Soft Part Sarcoma

Zhong, Minghao; Angelo, Patricia De; Osborne, Lisa C.; Keane-Tarchichi, Megan; Goldfischer, Michael; Edelmann, Lisa; Yang, Youfeng; Linehan, W. Marston; Merino, María J.; Aisner, Seena C.; Hameed, Meera

doi:10.1097/pas.0b013e3181dd577e

Cited by 107 publications

(79 citation statements)

References 27 publications

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“…As there is evidence of further, as yet unrecognised fusion variants, the direct visualisation of the TFE3 split remains the method with the highest sensitivity for paraffin-embedded, clinical tissue samples. 7,17,21 Of the eight genetically verified Xp11 translocation renal cell carcinomas in both series, seven occurred in adult patients corresponding to an overall frequency of 0.75% Xp11-associated tumours in unselected (adult) cases. The average age of patients with Xp11 translocation renal cell carcinomas was 44 years, the oldest patient 75 years at diagnosis.…”

Section: Discussionmentioning

confidence: 91%

Molecular heterogeneity of TFE3 activation in renal cell carcinomas

et al. 2012

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Renal cell carcinomas associated with Xp11.2 translocations have recently been identified as a distinct biological entity. The translocation results in the fusion of the transcription factor TFE3 to one of several different fusion partners including PRCC, PSF, NONO, ASPL or CTLC with consecutive overexpression of the chimeric protein. As the true frequency of these neoplasms as well as the biological properties of TFE3 activation in renal cell carcinomas are largely unknown, we have examined TFE3 expression as well as the underlying genetic alterations in a large, hospital-based series of renal cell carcinomas with long-term follow-up information. Out of a total of 876 tumours, TFE3 translocations were detected in five cases (0.6%). Three additional cases were identified in a second series of cases comprising of renal cell carcinomas developing in patients before the age of 50. However, using immunohistochemistry, 9% of all renal cell carcinomas showed some degree of TFE3 reactivity. Interestingly, these cases were associated with high nuclear grade, greater tumour extent and metastatic disease as well as an unfavourable patient outcome on uni-and multivariate analysis. Fluorescence in situ hybridisation (FISH) revealed TFE3 amplifications as an additional, novel mechanism leading to increased TFE3 expression levels. In conclusion, our data show that Xp11 translocation renal cell carcinomas are uncommon tumours accounting for o1% of adult renal cell carcinomas and that the diagnosis of Xp11 translocation renal cell carcinomas needs to be verified using molecular techniques. In turn, TFE3 overexpressing tumours show an aggressive behaviour and Xp11 translocation is only one of several possible underlying genomic alterations.

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Section: Discussionmentioning

confidence: 91%

Molecular heterogeneity of TFE3 activation in renal cell carcinomas

et al. 2012

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“…30 Another study did utilize the UOK-109 cell line for validation, although the other controls were not employed. 38 In addition, a recent abstract describes the clinical experience in a renal consultation service with application of a TFE3 break-apart FISH assay to 62 cases with 21 positive results, although details about the probe design, validation, and resulting signal patterns were not included. 32 The current study is therefore, to the best of our knowledge, the first to address the potential for an unbalanced TFE3 rearrangement in a male resulting in only a single signal, which is challenging to distinguish from tissue cut artifact but can be resolved using our reflex ASPSCR1 probe set.…”

Section: Discussionmentioning

confidence: 99%

Molecular cytogenetic analysis for TFE3 rearrangement in Xp11.2 renal cell carcinoma and alveolar soft part sarcoma: validation and clinical experience with 75 cases

et al. 2014

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Renal cell carcinoma with TFE3 rearrangement at Xp11.2 is a distinct subtype manifesting an indolent clinical course in children, with recent reports suggesting a more aggressive entity in adults. This subtype is morphologically heterogeneous and can be misclassified as clear cell or papillary renal cell carcinoma. TFE3 is also rearranged in alveolar soft part sarcoma. To aid in diagnosis, a break-apart strategy fluorescence in situ hybridization (FISH) probe set specific for TFE3 rearrangement and a reflex dual-color, single-fusion strategy probe set involving the most common TFE3 partner gene, ASPSCR1, were validated on formalin-fixed, paraffinembedded tissues from nine alveolar soft part sarcoma, two suspected Xp11.2 renal cell carcinoma, and nine tumors in the differential diagnosis. The impact of tissue cut artifact was reduced through inclusion of a chromosome X centromere control probe. Analysis of the UOK-109 renal carcinoma cell line confirmed the break-apart TFE3 probe set can distinguish the subtle TFE3/NONO fusion-associated inversion of chromosome X. Subsequent extensive clinical experience was gained through analysis of 75 cases with an indication of Xp11.2 renal cell carcinoma (n ¼ 54), alveolar soft part sarcoma (n ¼ 13), perivascular epithelioid cell neoplasms (n ¼ 2), chordoma (n ¼ 1), or unspecified (n ¼ 5). We observed balanced and unbalanced chromosome X;17 translocations in both Xp11.2 renal cell carcinoma and alveolar soft part sarcoma, supporting a preference but not a necessity for the translocation to be balanced in the carcinoma and unbalanced in the sarcoma. We further demonstrate the unbalanced separation is atypical, with TFE3/ASPSCR1 fusion and loss of the derivative X chromosome but also an unanticipated normal X chromosome gain in both males and females. Other diverse sex chromosome copy number combinations were observed. Our TFE3 FISH assay is a useful adjunct to morphologic analysis of such challenging cases and will be applicable to assess the growing spectrum of TFE3-rearranged tumors.

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“…Recently, Zhong et al reported that a dual color, breakapart fluorescence in situ hybridization (FISH) assay is an effective adjunctive method to detect Xp11.2 translocation RCC [13]. We performed this study to evaluate the usefulness of the FISH assay in the diagnosis of Xp11.2 translocation RCC using TFE3 break-apart probes.…”

Section: Introductionmentioning

confidence: 94%

“…Common initial presentations of Xp11.2 translocation RCC are hematuria, abdominal pain, and incidental mass [9][10][11][12][13]. The most characteristic microscopic feature of Xp11.2 translocation RCC is papillary architecture composed of cells with voluminous, clear or eosinophilic cytoplasms, and psammoma bodies [5].…”

Section: Introductionmentioning

confidence: 99%

Usefulness of a break-apart FISH assay in the diagnosis of Xp11.2 translocation renal cell carcinoma

et al. 2011

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Xp11.2 translocation renal cell carcinoma (RCC) is a rare subtype of RCC predominantly reported in young patients. It results from gene fusions between the transcription factor E3 (TFE3) gene, which is located on chromosome Xp11.2, and various fusion partners. Recently, a dual color, break-apart fluorescence in situ hybridization (FISH) assay to detect Xp11.2 translocation was reported. We performed this study to evaluate the usefulness of the FISH assay in the diagnosis of Xp11.2 translocation RCC using a commercially available TFE3 break-apart probe. We immunohistochemically analyzed TFE3 nuclear expression in 809 cases of RCCs using 14 tissue microarray blocks and selected nine cases those showed moderate to strong positive nuclear immunoreactivity for TFE3. The extent of TFE3 nuclear expression was variable. The TFE3 FISH assay was performed in these 9 selected cases and 44 negative control cases. Only four out of nine selected cases showed the TFE3 break-apart signal. TFE3 FISH-positive cases mainly showed diffuse and strong TFE3 immunopositivity, but one case revealed focal and moderate TFE3 staining. On the contrary, TFE3 FISH-negative cases mainly revealed focal and moderate TFE3 immunoreactivity, however, one FISH-negative case revealed diffuse and strong TFE3 nuclear immunopositivity. All negative control cases revealed normal TFE3 FISH results. Our results reveal that TFE3 immunohistochemistry can show false-positive results, and that the TFE3 break-apart FISH assay is a useful complementary method for confirming the diagnosis of Xp11.2 translocation RCC.

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Dual-color, Break-apart FISH Assay on Paraffin-embedded Tissues as an Adjunct to Diagnosis of Xp11 Translocation Renal Cell Carcinoma and Alveolar Soft Part Sarcoma

Cited by 107 publications

References 27 publications

Molecular heterogeneity of TFE3 activation in renal cell carcinomas

Molecular heterogeneity of TFE3 activation in renal cell carcinomas

Molecular cytogenetic analysis for TFE3 rearrangement in Xp11.2 renal cell carcinoma and alveolar soft part sarcoma: validation and clinical experience with 75 cases

Usefulness of a break-apart FISH assay in the diagnosis of Xp11.2 translocation renal cell carcinoma

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