Molecular Profiling of Benign Metastasizing Leiomyoma of the Uterus Revealing Unique Novel Therapeutic Targets

Abstract

Extra-uterine manifestations of benign uterine leiomyoma (fibroids) are rare. Benign metastasizing leiomyoma (BML) comprises an uncommon variant characterized by metastatic lung nodules. The pathologic characteristics for BML are well known in the literature; however, the underlying biology and molecular mechanisms remain poorly understood. We present a case of a 43-year-old woman who presented to the hospital complaining of dyspnea and lower extremity edema. Medical history includes a previous hysterectomy for leiomyomata two years prior. A reduced ejection fraction and right atrium globular filling defect are seen on transthoracic echo (TTE). CT scans of the chest, abdomen, and pelvis reported pelvic mass with an extensive inferior vena cava (IVC) thrombus extending into the right atrium, which was subsequently completely resected. Subsequent histopathology for the thrombus reported intravascular leiomyomatosis (IVL) and pelvic mass reported benign leiomyoma. Two years later, the symptoms recurred, and a chest CT revealed new pulmonary nodules. Subsequent pathology from a biopsy of these nodules was consistent with BML with ER+/PR+ on immunohistochemical staining. Genetic testing showed amplification of JUN, cyclin-dependent kinase 4 (CDK4), and MCL1, and loss of SUFU, AT-rich interaction domain 1A (AR1D1A), RB transcriptional corepressor 1 (RB1), and hepatocyte nuclear factor 1-alpha (HNF1A). The patient deemed to be a poor surgical candidate, and, therefore, she was started on hormonal treatment with leuprolide and letrozole. The disease remained stable upon follow-up at 48 months. Here, we report novel genomic profiling findings for the first time in a patient with a newly diagnosed BML. These findings may suggest molecular evidence that IVL may not be as benign as previously thought. Our study further highlights the value of genetic profiling in the understanding of this tumor's behavior and identification of new patient-specific therapeutic targets.

Update on clinical characteristics and molecular insights for uterine intravenous leiomyomatosis (Review)

“…The unique alterations in IVL, including distinct MED12 mutations, downregulated expression levels of the angiogenesis-related gene CXCL8 and elevated expression levels of the HOXA13 gene and anti-apoptosis-related genes, are the focus for exploring the molecular mechanism of IVL progression. These studies have revealed that the unique molecular profile of IVL partially overlaps with uterine leiomyoma and uterine leiomyosarcoma, similar to their intermediate clinical behavior (4,16,19,22,23). Future work investigating these DEGs will provide further insight into the possible pathogenesis of IVL.…”

“…Typically, IVL is diagnosed in women of reproductive-age with a history of uterine leiomyomas, and it is considered to be one of the more unusual extrauterine leiomyomas. Other similar unique growth patterns are found in benign metastasizing leiomyoma (BML), leiomyomatosis peritonealis disseminata, parasitic leiomyoma and retroperitoneal growth (4). Due to the lack of obvious symptoms in the early stages and no effective diagnostic approach, it is usually challenging to make a diagnosis prior to surgery.…”

Estrogen Regulates the Expression and Localization of YAP in the Uterus of Mice

“…YAP and phospho-YAP protein levels were significantly reduced by siYAP treatment. Next, we evaluated the expression levels of target factors known to be expressed in reproductive organs including ADAMTS1 [ 10 , 11 ], AMOT [ 2 , 12 ], AMOTL1 [ 13 ], ANKRD1 [ 14 , 15 ], CTNNA1 , MCL1 [ 16 ], AREG , and AXL [ 17 ]. qRT-PCR analysis revealed that YAP knockdown decreased the expression of ADAMTS1 , AMOT , AMOTL1 , ANKRD1 , CTNNA1 , and MCL1 but significantly increased the expression of AREG and AXL ( Figure 5 B).…”

“…Connective tissue growth factor (CTGF) and cysteine-rich angiogenesis inducer 61 (CYR61) are well-characterized factors that regulate various cellular processes such as proliferation and migration [ 6 , 7 , 8 , 9 ]. YAP is also involved in gene expression of numerous other factors including ADAM metallopeptidase with thrombospondin type 1 motif 1 ( ADAMTS1 ) [ 10 , 11 ], angiomotin ( AMOT ) [ 2 , 12 ], angiomotin like 1 ( AMOTL1 ) [ 13 ], ankyrin repeat domain 1 ( ANKRD1 ) [ 14 , 15 ], catenin alpha 1 ( CTNNA1 ), MCL1 apoptosis regulator, BCL2 family member ( MCL1 ) [ 16 ], amphiregulin ( AREG ), and AXL receptor tyrosine kinase ( AXL ) [ 17 ].…”

Hippo Signaling in the Endometrium

“…As YAP does not contain a DNA-binding domain, it binds to a transcription factor of the TEAD family, such as TEAD1-4, and induces the expression of target genes such as CTGF and CYR61 [ 83 ] that promote cell growth, proliferation, cell migration, and survival [ 35 , 84 , 85 , 86 , 87 ]. Other YAP target genes included AMOT, AMOTL1, AMOTL2 [ 88 , 89 ], CTNNA1 [ 90 ], CTNNB1 [ 91 , 92 , 93 ], ADAMTS1 [ 94 , 95 ], ANKRD1 [ 96 , 97 ], AXL [ 98 ], MCL1 [ 99 ], and THBS1 [ 100 ].…”