Prostatic carcinoma with neuroendocrine differentiation harboring the EWSR1-FEV fusion transcript in a man with the WRN G327X germline mutation: A new variant of prostatic carcinoma or a member of the Ewing sarcoma family of tumors?

Febres‐Aldana, Christopher A.; Krishnamurthy, Kritika; Delgado, Ruben; Kochiyil, Jyotsna; Poppiti, Robert; Medina, Ana Maria

doi:10.1016/j.prp.2019.152758

Cited by 5 publications

(5 citation statements)

References 26 publications

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“…Although we were able to generate EWSR1 breakpoints at high frequencies in a prostate cancer cell line, EWSR1 rearrangements are not common in prostate cancer. A recent study did find a EWSR1/FEV fusion in a prostate tumor from a single patient, but it is unclear whether this tumor should be categorized as prostate adenocarcinoma or Ewing's sarcoma (Febres-Aldana et al, 2020). Our data indicate that high levels of AR in the cell are necessary for AR binding and function within the EWSR1 gene.…”

Section: Discussionmentioning

confidence: 49%

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

Nicholas

Hollenhorst

2020

Preprint

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Ewing's sarcoma is most prevalent in adolescent males and is almost always the result of a chromosomal rearrangement that creases a fusion gene with EWSR1 as the 5' fusion partner.Why EWSR1 is more commonly rearranged than other, similar genes and why Ewing's sarcoma is predisposed to adolescent males is not known. We found that in prostate cancer, androgen signaling upregulated a 5' EWSR1 isoform by promoting usage of an intronic polyadenylation site proximal to the Ewing's sarcoma breakpoint hotspot. An intronic Androgen Receptor (AR) binding site was necessary for this upregulation. Strikingly, androgen signaling drove high levels of breakpoint formation in EWSR1. Androgen signaling also promoted R-loop formation and Rloops were necessary for breakpoint formation. These data suggest that aberrant androgen signaling leads to R-loop-mediated DNA damage at the EWSR1 breakpoint hotspot and subsequent misrepair could promote EWSR1 gene fusions in Ewing's sarcoma.

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Section: Discussionmentioning

confidence: 49%

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

Nicholas

Hollenhorst

2020

Preprint

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“…While some RFP have been previously reported in the literature, many RFP had not been previously reported ( Table S2). The RFPs identified included additional members of the ETS ( ETS1, ETV1, ETV4 [ 29 , 30 ], FEV [31] , [32] , [33] ) and CREB ( CREB3L2 [ 34 , 35 ], CREB3L3 [ 36 , 37 ], CREB3L4 ) TF families ( Table 2 ). The remaining RFPs were classified as other transcription factors (Other (TF) – Rare; n = 53) and non-transcription factors (Other (non-TF) – Rare; n = 49).…”

Section: Resultsmentioning

confidence: 99%

Gene partners of the EWSR1 fusion may represent molecularly distinct entities

Walker,

Jin,

Millis

et al. 2023

Translational Oncology

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“…Our search of the PubMed database using the keywords "neuroendocrine prostate cancer," "BRCA2 mutation," and "Case" yielded 13 case reports. [10][11][12][13][14][15][16][17][18][19][20][21][22] Of these, 5 cases from 4 articles involved individuals who had no prior history of cancer and were administered olaparib (Table 1). [12,15,21,22] In terms of age and initial PSA levels, the patient was younger and had a significantly higher PSA value than did the other cases presented in the Table 1.…”

Section: Discussion and Literature Reviewmentioning

confidence: 99%

Brain metastasis in a patient with BRCA2-mutated treatment-related neuroendocrine prostate carcinoma and long-term response to radiotherapy and Olaparib: A case report and literature review

Uehara,

Obinata,

Hashimoto

et al. 2024

Medicine

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Background: A new subtype of prostate cancer called treatment-related neuroendocrine prostate carcinoma (t-NEPC) was added to the revised World Health Organization classification of prostate cancer in 2022. t-NEPC cases are increasing, and there is no established standard treatment. Methods: A 49-year-old male patient was referred to our department for dysuria. A rectal examination and a prostate biopsy revealed stony hardness and prostate adenocarcinoma, respectively. Imaging studies confirmed the presence of multiple bone and lymph node metastases. The patient was started on upfront treatment with androgen deprivation therapy and an androgen receptor signaling inhibitor, which resulted in a significant (>90%) decrease in prostate-specific antigen (PSA) levels. The patient experienced postrenal failure 6 months later, attributable to local disease progression. Concurrently, there was an elevation in neuron-specific enolase (NSE) levels and an enlargement of pelvic lymph node metastases, without PSA progression. Results: Biopsy specimen for cancer genome profiling revealed deletion of BRCA 2 and PTEN, AR amplification, and the presence of the TMPRSS2-ERG fusion gene. Based on increased NSE and BRCA2 mutations, a diagnosis of t-NEPC with BRCA2 mutation was eventually made. The patient received docetaxel chemotherapy and pelvic radiotherapy. Subsequently, he was treated with olaparib. His NSE levels decreased, and he achieved a complete response (CR). However, 18 months following the olaparib administration, brain metastases appeared despite the absence of pelvic tumor relapse, and the patient’s PSA levels remained low. Consequently, the patient underwent resection of the brain metastases using gamma knife and whole-brain radiotherapy but died approximately 3 months later. Conclusion subsections: Platinum-based chemotherapy is often administered for the treatment of t-NEPC, but there are few reports on the effectiveness of olaparib in patients with BRCA2 mutations. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.

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Prostatic carcinoma with neuroendocrine differentiation harboring the EWSR1-FEV fusion transcript in a man with the WRN G327X germline mutation: A new variant of prostatic carcinoma or a member of the Ewing sarcoma family of tumors?

Cited by 5 publications

References 26 publications

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

Gene partners of the EWSR1 fusion may represent molecularly distinct entities

Brain metastasis in a patient with BRCA2-mutated treatment-related neuroendocrine prostate carcinoma and long-term response to radiotherapy and Olaparib: A case report and literature review

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