Molecular Characterization of a Patient's Small Cell Carcinoma of the Ovary of the Hypercalcemic Type

Abstract

Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is a very rare tumor type that mainly affects young women. We report a 21-year old woman with SCCOHT. The patient initially presented with stage T3AN1MX disease and treated with surgery. The patient then received 8 cycles of multi-agent chemotherapy including cisplatin, bleomycin, cyclophosphamide, doxorubicin, and etoposide. Upon relapse, the patient underwent total abdominal hysterectomy, followed by chemotherapy with gemcitabine. The patient subsequently received radiation therapy and chemotherapy with bevacizumab, irinotecan and docetaxel. She passed away approximately 5 months after the second surgery and with her prior permission an immediate autopsy was performed. We examined the gene expression and copy number profiles of the tumor tissue samples obtained from the autopsy and compared them to normal ovary tissues. Our results indicated that although this tumor did not harbor chromosomal abnormalities nor gene copy number changes, there were significant gene expression changes in a number of genes/pathways. More than 5,000 genes showed significant differential expression in the tumor when compared to normal ovary tissue. Pathway enrichment analysis further identified several pathways/processes including the Vitamin D receptor signaling and the hedgehog signaling pathways to be significantly dysregulated. The gene expression profiling also suggests a number of agents such as pazopanib, bortezomib, 5-azacytidine, and PARP inhibitors as treatment options to possibly explore in future trials against this disease.

Ovarian small cell carcinoma of hypercalcemic type – evidence of germline origin and smarca4 gene inactivation. a pilot study

“…They are polyimmunophenotypic, diploid and genetically stable [6,15], affect a young population, are highly aggressive and generally show poor responses to chemotherapy. Hypercalcemia is described in both SCCHT and MRT [11,12,16], and is attributed to ectopic parathormone expression by the tumors [11,17,18]; thus, the difference between them may be rather nosological, although some organ-specific features may be present.…”

“…Despite many years of examination of such tumors, little is known concerning their histogenesis and molecular background [1,[4][5][6]. Identification of the nature and underlying molecular changes may ultimately lead to better therapeutic solutions.…”

Small Cell Carcinoma of the Ovary: A Rare Tumor With a Poor Prognosis

“…27 To date, no studies have investigated the utility of poly ADP ribose polymerase inhibitors, whereas only 2 cases of bevacizumab use have been reported. 26,28 Limitations of the present study include its retrospective nature and the lack of central pathology report; as such, possible tumor misclassifications cannot be excluded. In addition, because of the lack of histopathologic data, we could not discriminate between the hypercalcemic and pulmonary subtypes of small cell carcinoma.…”

“…Molecular characterization can aid in identifying clinical management and identifying molecular targets for targeted agents. 26,27 An ongoing phase 2 trial investigates the utility of tazemetostat, an EZH2 inhibitor. 27 To date, no studies have investigated the utility of poly ADP ribose polymerase inhibitors, whereas only 2 cases of bevacizumab use have been reported.…”

Germline SMARCA4 mutations in patients with ovarian small cell carcinoma of hypercalcemic type

“…Until recently, the SCCHT remained a mystery in terms of histogenesis and molecular background [ 2 , 8 - 10 ]. In year 2013, our research group has described its development in association with an ovarian immature teratoma and brought to light its similarity to atypical teratoid/rhabdoid tumor of the central nervous system (AT/RT).…”