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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 398-400

Novel TBP-RET (TATA.binding protein-rearranged during transfection) fusion in a rare case of Skene gland adenocarcinoma: Sequencing unicorns

1 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology and Medical Oncology, Oregon Health and Science University/Knight Cancer Institute, Portland, OR, USA
2 Department of Pathology, Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
3 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Date of Submission21-May-2021
Date of Decision22-May-2021
Date of Acceptance27-May-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Vivek Subbiah
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_117_21

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How to cite this article:
Thein KZ, Wu J, Subbiah V. Novel TBP-RET (TATA.binding protein-rearranged during transfection) fusion in a rare case of Skene gland adenocarcinoma: Sequencing unicorns. Cancer Res Stat Treat 2021;4:398-400

How to cite this URL:
Thein KZ, Wu J, Subbiah V. Novel TBP-RET (TATA.binding protein-rearranged during transfection) fusion in a rare case of Skene gland adenocarcinoma: Sequencing unicorns. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Aug 19];4:398-400. Available from: https://www.crstonline.com/text.asp?2021/4/2/398/320228

“Now I will believe that there are unicorns.”

–William Shakespeare

Bondili et al. have reported a rare and interesting case of Skene gland adenocarcinoma harboring a novel genetic fusion between the TATA-binding protein (TBP) and rearranged during transfection (RET) genes.[1] Invasive adenocarcinoma of primary periurethral Skene gland origin is an ultra-rare cancer, and the first case was reported by Klotz in 1974. To this date, around 15 cases have been published in the literature. Given the extreme rarity of this entity, management algorithms are case-based with no consensus on the treatment, and the genomic landscape is thus unknown.[2],[3] Lenz et al. reported the first ever case of Skene gland adenocarcinoma in which molecular profiling of the tumor was performed and it was found to harbor a mutation and loss of heterozygosity of the phosphatase and tensin homolog (PTEN).[4] Morphologically, Skene gland adenocarcinoma is the female counterpart of the conventional male prostatic adenocarcinoma (usually Gleason 4 + 4 = 8), albeit the prostate-specific antigen (PSA) positivity and/or prostate markers' immunoreactivity can vary.[2],[3],[4] In the case reported by Bondili et al., although the tumor cells depicted positivity for estrogen and androgen receptors, p16, alpha-methylacyl-CoA racemase (AMACR), CK7, CDX2, and vimentin on immunohistochemistry, other markers such as the paired box gene 8 (PAX8, carcinoembryonic antigen (CEA), p40, and Wilms' tumor protein (WT1) 1 were negative, thus supporting the diagnosis of Skene gland adenocarcinoma. However, other immunohistochemicalHomeobox 1 (NKX3.1), markers such as prostatic-specific acid phosphatase phosphatase (PSAP), PSA, prostein antibody (P501S), and NK3 Homeobox 1 were not analyzed in this case, and the serum PSA level was modest at 0.005 ng/dl. Next-generation sequencing (NGS) analysis of the tumor revealed that it harbored an uncommon TBP-RET gene fusion that encoded a novel TBP-RET fusion protein. When not bound to the DNA, TBP is known to form homodimers that dissociate slowly.[5],[6] Thus, TBP (also called the TFIID), has a critical feature shared by the previously characterized RET fusion partners,[7] that is, it contains a protein dimerization domain that can cause the constitutive activation of the RET kinase. Therefore, the novel TBP-RET fusion could be a potential driver oncogene in this case of Skene gland adenocarcinoma. However, detailed information about the fusion junction has not been reported by the authors.

The functional assessment of the TBP-RET fusion oncogene in the laboratory and its validation as an actionable oncogenic driver in patients are yet to be performed. After the accidental discovery of the RET gene in the human lymphoma DNA more than three decades ago, scientists have been trying to link the RET proto-oncogene to organogenesis and tumorigenesis.[8],[9] Apart from its ligands, the RET proto-oncogene, which encodes a transforming receptor tyrosine kinase, can be activated by either gene fusions or point mutations, which are known to be oncogenic drivers in various malignancies.[10],[11] With the increasing applicability of the NGS technology in clinical practice, an increasing number of novel RET aberrations are being reported. Moreover, the recently developed and highly potent and selective RET inhibitors such as selpercatinib and pralsetinib have further advanced the field of precision therapy for RET-aberrant tumors. RET fusions have been reported to be primary oncogenic drivers in about 2% of the cases of non-small-cell lung cancer and 20% of the cases of papillary thyroid cancer. In addition, RET mutations are oncogenic drivers in around 60% of the cases of sporadic and 90% of the cases of hereditary medullary thyroid cancers.[12],[13] Apart from lung and thyroid cancers, RET fusions occur as oncogenic drivers in <1% of the other malignancies, including breast, pancreatic, colorectal, salivary gland, and ovarian cancers.[11],[14],[15]

The promising results and favorable safety profiles of selpercatinib and pralsetinib, reported in two pivotal multi-center, phase-I/II registrational trials, LIBRETTO-001 and ARROW, respectively, led to the approval of these selective RET inhibitors in patients with RET-altered lung and thyroid cancers in 2020 by the United States Food and Drug Administration.[16],[17],[18] In addition to patients with RET-altered lung and thyroid cancers, the ARROW trial also included 14 patients with RET fusion-positive non-lung and non-thyroid cancers (3 pancreatic, 3 colon, 2 cholangiocarcinoma, and 6 others); the preliminary findings of this trial were reported at the 2021 American Society of Clinical Oncology (ASCO) gastrointestinal cancer symposium.[19] Remarkably, among patients with non-lung/non-thyroid cancers, pralsetinib showed an objective response rate (ORR) of 50%, and a response was observed in all the patients with pancreatic cancer and cholangiocarcinoma. Similarly, data from the LIBRETTO-001 trial on 32 patients with RET fusion-positive non-lung/non-thyroid solid tumors, including 12 different tumor types, were presented at the 2021 American Association for Cancer Research (AACR) annual meeting.[20] The majority (91%) of the patients had received prior systemic therapy. The ORR was reported to be 47% and responses were observed in patients with xanthogranuloma, carcinoid, sarcoma, colon, pancreatic, small intestine, salivary gland, breast, and ovarian cancers.

Even though RET alterations in non-lung/non-thyroid cancers are infrequent, selective RET inhibitors have been shown to confer robust activity against tumors harboring these alterations. Therefore, researchers should remain vigilant when pursuing comprehensive genomic testing to identify these rare alterations. As this is the first case of the novel TBP-RET fusion in a patient with Skene gland adenocarcinoma, it remains to be seen if other patients with Skene gland adenocarcinomas also harbor RET alterations. In addition, the oncogenic potential of the TBP-RET fusion and the clinical utility of RET inhibitors still need to be explored. Nevertheless, this case reiterates the primacy of genomic profiling in rare tumors and that unicorns do exist if we look for them.

Financial support and sponsorship

National Institutes of Health grant R01CA242845 (to V. S. and J. W.), the Oklahoma Tobacco Settlement Endowment Trust (to the Stephenson Cancer Center), the Stephenson Endowed Chair Fund, the Cancer Prevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, 1U01 CA180964, NCATS Grant UL1 TR000371 (Center for Clinical and Translational Sciences), and the MD Anderson Cancer Center Support Grant (P30 CA016672).

Conflicts of interest

Vivek Subbiah reports research funding/Grant support for clinical trials: Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Medimmune, Altum, Dragonfly. Therapeutics, Takeda and National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals; Travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; Consultancy/Advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis. Other: Medscape.

  References Top

Bondili SK, Abraham G, Noronha V, Joshi A, Patil VM, Menon N, et al. Rare case of Skene gland adenocarcinoma with RET-rearrangement. Cancer Res Stat Treat 2021;4:130-5.  Back to cited text no. 1
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Desouki MM, Fadare O. Primary adenocarcinomas of the vulva and related structures: An enigmatic and diverse group of tumors. Semin Diagn Pathol 2021;38:71-84.  Back to cited text no. 2
Kyriazis G, Varughese A, Rodrigues G, Simms M. A rare case of skene's gland adenocarcinoma. Clin Genitourin Cancer 2020;18:e300-2.  Back to cited text no. 3
Lenz J, Michal M, Michal M, Hes O, Konečná P, Lenz D. First molecular genetic characterization of skene's gland adenocarcinoma. Int J Surg Pathol 2021;29:447-53.  Back to cited text no. 4
Coleman RA, Taggart AK, Benjamin LR, Pugh BF. Dimerization of the TATA binding protein. J Biol Chem 1995;270:13842-9.  Back to cited text no. 5
Coleman RA, Pugh BF. Slow dimer dissociation of the TATA binding protein dictates the kinetics of DNA binding. Proc Natl Acad Sci U S A 1997;94:7221-6.  Back to cited text no. 6
Belli C, Anand S, Gainor JF, Penault-Llorca F, Subbiah V, Drilon A, et al. Progresses toward precision medicine in RET-altered solid tumors. Clin Cancer Res 2020;26:6102-11.  Back to cited text no. 7
Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 1985;42:581-8.  Back to cited text no. 8
de Graaff E, Srinivas S, Kilkenny C, D'Agati V, Mankoo BS, Costantini F, et al. Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. Genes Dev 2001;15:2433-44.  Back to cited text no. 9
Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET Aberrations in diverse cancers: Next-generation sequencing of 4,871 patients. Clin Cancer Res 2017;23:1988-97.  Back to cited text no. 10
Liu, X, Hu X, Shen T, Li Q, Mooers BH, Wu J. RET kinase alterations in targeted cancer therapy. Cancer Drug Resist 2020;3:472-81.  Back to cited text no. 11
Subbiah V, Velcheti V, Tuch BB, Ebata K, Busaidy NL, Cabanillas ME, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol 2018;29:1869-76.  Back to cited text no. 12
Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F. State-of-the-Art Strategies for Targeting RET-Dependent Cancers. J Clin Oncol 2020;38:1209-21.  Back to cited text no. 13
Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. Cancer Discov 2020;10:498-505.  Back to cited text no. 14
Subbiah V, Roszik J. Towards precision oncology in RET-aberrant cancers. Cell Cycle 2017;16:813-4.  Back to cited text no. 15
Administration, U.S.F.a.D. FDA Approves Pralsetinib for Lung Cancer with RET Gene Fusions; 2020 September 08. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pralsetinib-lung-cancer-ret-gene-fusions. [Last accessed on 2020 Oct 25].  Back to cited text no. 16
Administration, U.S.F.a.D. FDA Approves Pralsetinib for RET-Altered Thyroid Cancers; 2020 December 01. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-ret-altered-thyroid-cancers. [Last accessed on 2020 Dec 26].  Back to cited text no. 17
U.S. Food and Drug Administration. FDA approves Selpercatinib for Lung and Thyroid Cancers with RET Gene Mutations or Fusions; 2020 May 11. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions. [Last accessed on 2020 Oct 25].  Back to cited text no. 18
Subbiah V, Hu MI, Gainor JF, Mansfield AS, Alonso G, Taylor MH, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion–positive solid tumors. J Clin Oncol 2021;39 Suppl 3:467.  Back to cited text no. 19
Subbiah V, Konda B, Bauer T, McCoach C, Falchook G, Takeda M. CT011 – Efficacy and safety of selpercatinib in RET fusion-positive cancers other than lung or thyroid cancers. In: 2021 American Association for Cancer Research (AACR) Annual Meeting; 2021. Virtual Meeting.  Back to cited text no. 20


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