Melanotic PEComa of the Sinonasal Mucosa With NONO-TFE3 Fusion

McGregor, Stephanie M.; Alikhan, Mir; John, Rahel A.; Kotler, Howard S.; Bridge, Julia A.; Mujacic, Ibro; Kadri, Sabah; Segal, Jeremy P.; Krausz, Thomas

doi:10.1097/pas.0000000000000778

Cited by 29 publications

(18 citation statements)

References 19 publications

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“…The other examined cells did not meet the break-apart cutoff values, but several cells displayed one co-localization signal and one small separation of the 5 0 TFE3 and 3 0 TFE3 probes ( Figure 2B). Similar subtle break-apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12,13,14].…”

Section: Tfe3 Activation In a Tsc1-altered Malignant Pecomasupporting

confidence: 72%

TFE3 activation in a TSC1‐altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms

Schmiester

Dolnik

Kornak

et al. 2020

The Journal of Pathology CR

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Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.

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Section: Tfe3 Activation In a Tsc1-altered Malignant Pecomasupporting

confidence: 72%

TFE3 activation in a TSC1‐altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms

Schmiester

Dolnik

Kornak

et al. 2020

The Journal of Pathology CR

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“…In addition to the characteristics of nucleic acid binding, NONO can also interact with the terminal end region of the RNA polymerase II subunit to participate in pre-mRNA synthesis and treatment [102]. NONO expression is abnormal in prostate cancer, colorectal cancer, breast cancer and melanoma, which indicates that NONO may cause tumors [103][104][105][106]. In addition, at the transcription level, upstream-of-N-Ras (UNR) also plays an important role.…”

Section: Transcriptional Regulation-mediated Rbp Disordersmentioning

confidence: 99%

RNA-binding proteins in tumor progression

et al. 2020

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RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.

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“…Additionally, we present here a rare TFE3-translocated PEComa with a NONO-TFE3 fusion. To date, this specific fusion has been described in fewer than 20 renal cell carcinomas, a Xp11 neoplasm of the prostate, one melanotic PEComa of the orbita, and the only other published melanotic PEComa of the sinonasal mucosa apart from this case [4,18,28,30]. Interestingly, three of the extrarenal cases including ours are located in the sinonasal/orbital region, suggesting that this anatomical region might be typical for this molecularly distinct and rare subtype.…”

Section: Molecular Backgroundmentioning

confidence: 61%