Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma

Clark, Jeremy; Lu, Yue; Sidhar, SK; Parker, Craig J.; Gill, S; Smedley, Damian; Hamoudi, Rifat; Linehan, W. Marston; Shipley, Janet; Cooper, CS

doi:10.1038/sj.onc.1201394

Cited by 299 publications

(236 citation statements)

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“…Importantly, the validation included examination of break-apart TFE3 on the UOK-109 renal carcinoma cell line, confirming detection by both metaphase and interphase FISH of the recurrent but very subtle inversion near the centromere of chromosome X, which creates TFE3/NONO fusion. 21 Neither the ability to identify this subtle inversion nor use of an X centromere control probe and ASPSCR1 reflex probe set were described in a previous publication of a TFE3 break-apart probe set. 30 Another study did utilize the UOK-109 cell line for validation, although the other controls were not employed.…”

Section: Discussionmentioning

confidence: 99%

“…5,16 The TFE3/ASPSCR1 involves fusion of either exon 3 or 4 of TFE3 to ASPSCR1, which replaces the N-terminus of TFE3 but retains the DNA-binding region, activation domain, and nuclear localization signal. 17 Other known partners of TFE3 include PRCC, [18][19][20] PSF, 21 NONO, 21 or CLTC 22 resulting from t(X;1)(p11.2;q21), t(X;1)(p11.2;p34), inv(X) (p11.2q12), or t(X;17)(p11.2;q23), respectively. Each of these rearrangements provides a more robust promoter for TFE3 causing overexpression of the chimeric fusion product and a subset are known to have a stronger capacity for transactivation of other genes.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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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“…TFE3 was the first family member to be identified as a fusion oncogene (Sidhar et al 1996;Weterman et al 1996;Clark et al 1997). A significant fraction of pediatric papillary renal cell carcinomas (now termed "translocation-associated" renal cell carcinomas) was seen to harbor translocations that fused the TFE3 to a variety of alternative 5Ј partner genes.…”

Section: Mitf As An Oncogenementioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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“…2 At present, five different translocations involving the Xp11.2 chromosomal region have been characterised, resulting in the fusion of the TFE3 (transcription factor binding to IGHM enhancer 3) to PRCC (t(X;1)(p11;q21)), PSF (t(X;1) (p11;p34)), NONO (inv(X)(p11;q12)), ASPL (t(X;17)(p11;q25)) or CLTC (t(X;17)(p11;q23)). [3][4][5][6] In addition, another, at present unknown fusion partner of the TFE3 has recently been located on chromosome 19q13. 1.…”

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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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Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma

Cited by 299 publications

References 24 publications

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

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

Malignant melanoma: genetics and therapeutics in the genomic era

Molecular heterogeneity of TFE3 activation in renal cell carcinomas

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