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NEAT1-TFE3 and KAT6A-TFE3 renal cell carcinomas, new members of MiT family translocation renal cell carcinoma

Modern Pathology (2019) | Download Citation

Abstract

Microphthalmia-associated transcription factor (MiT) family translocation renal cell carcinoma harbors variable gene fusions involving either TFE3 or TFEB genes. Multiple 5′ fusion partners for TFE3 have been reported, including ASPSCR1, CLTC, DVL2, LUC7L3, KHSRP, PRCC, PARP14, NONO, SFPQ1, MED15, and RBM10. Each of these fusion genes activates TFE3 transcription which can be detected by immunostaining. Using targeted RNA-sequencing, TFE3 fusion gene partners were identified in 5 cases of TFE3 immunohistochemistry positive translocation renal cell carcinoma. Three cases demonstrated known fusions: ASPSCR1-TFE3, MED15-TFE3 and RBM10-TFE3. However, two cases showed unreported NEAT1-TFE3 and KAT6A-TFE3 fusion transcripts. The NEAT1-TFE3 RCC arose in a 59-year-old male; which demonstrated overlapping morphological features seen in NEAT2(MALAT1)-TFEB t(6;11) renal cell carcinoma, including biphasic alveolar/nested tumor cells with eosinophilic cytoplasm. The KAT6A-TFE3 renal cell carcinoma demonstrated typical morphological features of TFE3/Xp11 renal cell carcinoma including papillae, eosinophilic cytoplasm with focal clearing and abundant psammoma bodies. KAT6A gene fusion was reported in some cases of acute myeloid leukemia, which has not been previously reported in solid tumors. This report highlights the genetic complexity of TFE3 translocation renal cell carcinoma; and RNA-sequencing is a powerful approach for elucidating the underlying genetic alterations.

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References

  1. 1.

    Argani P, Cheville J, Ladanyi M. MiT family translocation renal cell carcinoma. In: Moch H, Humphrey PA, Ulbright TM, et al. editors. WHO Classification of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press, 2016. p. 33–34.

  2. 2.

    Argani P, Antonescu CR, Couturier J, et al. PRCC-TFE3 renal carcinomas: morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X;1)(p11.2; q21). Am J Surg Pathol. 2002;26:1553–66.

  3. 3.

    Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001;159:179–92.

  4. 4.

    Argani P, Lui MY, Couturier J, et al. A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2; q23). Oncogene. 2003;22:5374–8.

  5. 5.

    Argani P, Zhang L, Reuter VE, et al. RBM10-TFE3 renal cell carcinoma: a potential diagnostic pitfall due to cryptic intrachromosomal Xp11.2 inversion resulting in false-negative TFE3 FISH. Am J Surg Pathol. 2017;41:655–62.

  6. 6.

    Argani P, Zhong M, Reuter VE, et al. TFE3-fusion variant analysis defines specific clinicopathologic associations among Xp11 translocation cancers. Am J Surg Pathol. 2016;40:723–37.

  7. 7.

    Xia QY, Wang XT, Zhan XM, et al. Xp11 translocation renal cell carcinomas (RCCs) with RBM10-TFE3 gene fusion demonstrating melanotic features and overlapping morphology with t(6;11) RCC: interest and diagnostic pitfall in detecting a paracentric inversion of TFE3. Am J Surg Pathol. 2017;41:663–76.

  8. 8.

    Clark J, Lu YJ, Sidhar SK, et al. Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma. Oncogene. 1997;15:2233–9.

  9. 9.

    Huang W, Goldfischer M, Babyeva S, et al. Identification of a novel PARP14-TFE3 gene fusion from 10-year-old FFPE tissue by RNA-seq. Genes Chromosomes Cancer. 2015;54:500–5.

  10. 10.

    Malouf GG, Monzon FA, Couturier J, et al. Genomic heterogeneity of translocation renal cell carcinoma. Clin Cancer Res. 2013;19:4673–84.

  11. 11.

    Classe M, Malouf GG, Su X, et al. Incidence, clinicopathological features and fusion transcript landscape of translocation renal cell carcinomas. Histopathology. 2017;70:1089–97.

  12. 12.

    Kobos R, Nagai M, Tsuda M, et al. Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein. J Pathol. 2013;229:743–54.

  13. 13.

    Tsuda M, Davis IJ, Argani P, et al. TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res. 2007;67:919–29.

  14. 14.

    Green WM, Yonescu R, Morsberger L, et al. Utilization of a TFE3 break-apart FISH assay in a renal tumor consultation service. Am J Surg Pathol. 2013;37:1150–63.

  15. 15.

    Calio A, Grignon DJ, Stohr BA, et al. Renal cell carcinoma with TFE3 translocation and succinate dehydrogenase B mutation. Mod Pathol. 2017;30:407–15.

  16. 16.

    Argani P, Lal P, Hutchinson B, et al. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol. 2003;27:750–61.

  17. 17.

    Argani P, Ladanyi M. Renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions. In: Eble JN, Sauter G, Epstein JI, et al. editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press, 2004. p. 37–38.

  18. 18.

    Sidhar SK, Clark J, Gill S, et al. The t(X;1)(p11.2; q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Hum Mol Genet. 1996;5:1333–8.

  19. 19.

    Weterman MA, Wilbrink M, Geurts van Kessel A. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11; q21)-positive papillary renal cell carcinomas. Proc Natl Acad Sci USA. 1996;93:15294–8.

  20. 20.

    Calio A, Brunelli M, Segala D, et al. t(6;11) renal cell carcinoma: a study of seven cases including two with aggressive behavior, and utility of CD68 (PG-M1) in the differential diagnosis with pure epithelioid PEComa/epithelioid angiomyolipoma. Mod Pathol. 2018;31:474–87.

  21. 21.

    Argani P, Hawkins A, Griffin CA, et al. A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21.1; q12) chromosome translocation. Am J Pathol. 2001;158:2089–96.

  22. 22.

    Seles M, Hutterer GC, Kiesslich T, et al. Current insights into long non-coding RNAs in renal cell carcinoma. Int J Mol Sci. 2016;17:573.

  23. 23.

    Sunwoo H, Dinger ME, Wilusz JE, et al. MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res. 2009;19:347–59.

  24. 24.

    Yang C, Li Z, Li Y, et al. Long non-coding RNA NEAT1 overexpression is associated with poor prognosis in cancer patients: a systematic review and meta-analysis. Oncotarget. 2017;8:2672–80.

  25. 25.

    Fang J, Qiao F, Tu J, et al. High expression of long non-coding RNA NEAT1 indicates poor prognosis of human cancer. Oncotarget. 2017;8:45918–27.

  26. 26.

    Ning L, Li Z, Wei D, et al. LncRNA, NEAT1 is a prognosis biomarker and regulates cancer progression via epithelial-mesenchymal transition in clear cell renal cell carcinoma. Cancer Biomark. 2017;19:75–83.

  27. 27.

    Jiang L, Shao C, Wu QJ, et al. NEAT1 scaffolds RNA-binding proteins and the microprocessor to globally enhance pri-miRNA processing. Nat Struct Mol Biol. 2017;24:816–24.

  28. 28.

    Davis IJ, Hsi BL, Arroyo JD, et al. Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21; q13) chromosome translocation. Proc Natl Acad Sci USA. 2003;100:6051–6.

  29. 29.

    Zhan HQ, Li ST, Shu Y, et al. Alpha gene upregulates TFEB expression in renal cell carcinoma with t(6;11) translocation, which promotes cell canceration. Int J Oncol. 2018;52:933–44.

  30. 30.

    Borrow J, Stanton VP Jr, Andresen JM, et al. The translocation t(8;16)(p11; p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet. 1996;14:33–41.

  31. 31.

    Roberts I, Fordham NJ, Rao A, et al. Neonatal leukaemia. Br J Haematol. 2018;182:170–84

  32. 32.

    Gervais C, Murati A, Helias C, et al. Acute myeloid leukaemia with 8p11 (MYST3) rearrangement: an integrated cytologic, cytogenetic and molecular study by the groupe francophone de cytogenetique hematologique. Leukemia. 2008;22:1567–75.

  33. 33.

    Camos M, Esteve J, Jares P, et al. Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11; p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression. Cancer Res. 2006;66:6947–54.

  34. 34.

    Coenen EA, Zwaan CM, Reinhardt D, et al. Pediatric acute myeloid leukemia with t(8;16)(p11; p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood. 2013;122:2704–13.

  35. 35.

    Argani P, Aulmann S, Karanjawala Z, et al. Melanotic Xp11 translocation renal cancers: a distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma. Am J Surg Pathol. 2009;33:609–19.

  36. 36.

    Argani P, Hicks J, De Marzo AM, et al. Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am J Surg Pathol. 2010;34:1295–303.

  37. 37.

    Xia QY, Wang Z, Chen N, et al. Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement. Mod Pathol. 2017;30:416–26.

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Acknowledgements

The authors would like to thank Wendy Davis, Magdalena Potoczek and Michele Pizzo for excellent technical support. This work was supported by NCI grant P30 CA006927.

Author information

Affiliations

  1. Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    • Jianming Pei
    • , Jacqueline N. Talarchek
    •  & Joseph R. Testa
  2. Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    • Harry Cooper
    • , Douglas B. Flieder
    • , Tahseen Al-Saleem
    • , Essel Dulaimi
    • , Arthur S. Patchefsky
    •  & Shuanzeng Wei
  3. Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    • Robert G. Uzzo
  4. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    • Robert G. Uzzo
    •  & Joseph R. Testa

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The authors declare that they have no conflict of interest.

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Correspondence to Shuanzeng Wei.

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DOI

https://doi.org/10.1038/s41379-018-0191-7