LPCAT1-TERT fusions are uniquely recurrent in epithelioid trophoblastic tumors and positively regulate cell growth

• Published in: PloS one 2021-05, Vol.16 (5), p.e0250518-e0250518
• Main Authors: Oliver, Gavin R, Marcano-Bonilla, Sofia, Quist, Jonathan, Tolosa, Ezequiel J, Iguchi, Eriko, Swanson, Amy A, Hoppman, Nicole L, Schwab, Tanya, Sigafoos, Ashley, Prodduturi, Naresh, Voss, Jesse S, Knight, Shannon M, Zhang, Jin, Fadra, Numrah, Urrutia, Raul, Zimmerman, Michael, Egan, Jan B, Bilyeu, Anthony G, Jen, Jin, Veras, Ema, Al-Safi, Rema'a, Block, Matthew, Kerr, Sarah, Fernandez-Zapico, Martin E, Schoolmeester, John K, Klee, Eric W
• Format: Article
• Language: English
• Subjects: 1-Acylglycerophosphocholine O-Acyltransferase - genetics; 1-Acylglycerophosphocholine O-Acyltransferase - metabolism; Acetyltransferase; Acyltransferase; Adult; Biochemistry; Biology; Biology and Life Sciences; Biomarkers, Tumor - genetics; Cell growth; Cell Proliferation; Chemotherapy; Cytology; Diagnosis; Diseases; Drafting software; Editing; Epithelioid Cells - metabolism; Epithelioid Cells - pathology; Ethical standards; Female; Genetic aspects; Gestational Trophoblastic Disease - etiology; Gestational Trophoblastic Disease - pathology; Health sciences; Histopathology; Humans; Laboratories; Lipids; Medicine; Medicine and Health Sciences; Metastasis; Middle Aged; Molecular biology; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncology; Pathogenesis; Pathology; Precision medicine; Pregnancy; Relapse; Research and analysis methods; Respiratory physiology; Telomerase - genetics; Telomerase - metabolism; Trophoblastic disease; Trophoblastic Neoplasms - genetics; Trophoblastic Neoplasms - metabolism; Trophoblastic Neoplasms - pathology; Trophoblastic tumors; Tumors; Uterine Neoplasms - genetics; Uterine Neoplasms - metabolism; Uterine Neoplasms - pathology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0250518

Gestational trophoblastic disease (GTD) is a heterogeneous group of lesions arising from placental tissue. Epithelioid trophoblastic tumor (ETT), derived from chorionic-type trophoblast, is the rarest form of GTD with only approximately 130 cases described in the literature. Due to its morphologic mimicry of epithelioid smooth muscle tumors and carcinoma, ETT can be misdiagnosed. To date, molecular characterization of ETTs is lacking. Furthermore, ETT is difficult to treat when disease spreads beyond the uterus. Here using RNA-Seq analysis in a cohort of ETTs and other gestational trophoblastic lesions we describe the discovery of LPCAT1-TERT fusion transcripts that occur in ETTs and coincide with underlying genomic deletions. Through cell-growth assays we demonstrate that LPCAT1-TERT fusion proteins can positively modulate cell proliferation and therefore may represent future treatment targets. Furthermore, we demonstrate that TERT upregulation appears to be a characteristic of ETTs, even in the absence of LPCAT1-TERT fusions, and that it appears linked to copy number gains of chromosome 5. No evidence of TERT upregulation was identified in other trophoblastic lesions tested, including placental site trophoblastic tumors and placental site nodules, which are thought to be the benign chorionic-type trophoblast counterpart to ETT. These findings indicate that LPCAT1-TERT fusions and copy-number driven TERT activation may represent novel markers for ETT, with the potential to improve the diagnosis, treatment, and outcome for women with this rare form of GTD.