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Personalized prescription of imatinib in recurrent granulosa cell tumor of the ovary: case report.

ABSTRACT: Ovarian cancer is the fifth leading cause of cancer-related female mortality and the most lethal gynecological cancer. In this report, we present a rare case of recurrent granulosa cell tumor (GCT) of the ovary. We describe the case of a 26-yr-old woman with progressive GCT of the right ovary despite multiple lines of therapy who underwent salvage therapy selection based on a novel bioinformatical decision support tool (Oncobox). This analysis generated a list of potentially actionable compounds, which when used clinically lead to partial response and later long-term stabilization of the patient's disease.

SUBMITTER: Poddubskaya EV

PROVIDER: S-EPMC6549576 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Personalized prescription of imatinib in recurrent granulosa cell tumor of the ovary: case report.

Poddubskaya Elena V EV Baranova Madina P MP Allina Daria O DO Sekacheva Marina I MI Makovskaia Lyudmila A LA Kamashev Dmitriy E DE Suntsova Maria V MV Barbara Viktoria S VS Kochergina-Nikitskaya Irina N IN Aleshin Alexey A AA

Cold Spring Harbor molecular case studies 20190401 2

Ovarian cancer is the fifth leading cause of cancer-related female mortality and the most lethal gynecological cancer. In this report, we present a rare case of recurrent granulosa cell tumor (GCT) of the ovary. We describe the case of a 26-yr-old woman with progressive GCT of the right ovary despite multiple lines of therapy who underwent salvage therapy selection based on a novel bioinformatical decision support tool (Oncobox). This analysis generated a list of potentially actionable compounds ...[more]

PMID: 30655270

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Project description:Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n?=?7), primary aGCTs that subsequently recurred (n?=?9) and their matched recurrences (n?=?9), and aGCT recurrences without matched primary tumors (n?=?10) to targeted massively parallel sequencing of ?410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p?=?0.017). In addition, mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

Project description:BackgroundMost of gastrointestinal stromal tumors (GISTs) are driven by mutations in the KIT/PDGFRA genes and can benefit from TKIs treatment. However, a small subset of GIST (10%-15%) are called "wild-type" GISTs due to the lack of these mutations. Theoretically, they would not benefit from TKIs treatment and may even develop resistance. Therefore, this unexpected response may challenge inherent perceptions. Herein, we present a case of giant wild-type GIST exhibiting an unexpected response to imatinib(IM), followed by laparoscopic surgical resection. Subsequently, potential underlying mechanisms are discussed.Case descriptionThis case describes a 57-year-old man who presented with abdominal pain for two weeks. CT revealed a massive lesion near the splenic hilum along the greater curvature of the stomach, concurrently involving the splenic hilar vessels and surrounding lymph nodes. Ultrasound-guided fine needle aspiration biopsy confirmed it is a mesenchymal spindle cell tumor,GIST. Due to the enormous volume and local invasion, neoadjuvant chemotherapy was initially considered. After 6 months of IM 400 mg/d, CT imaging revealed marked changes in tumor heterogeneity and a significant reduction in volume. Subsequently, laparoscopic surgical resection was performed. Postoperative pathological examination, immunohistochemistry, and genetic testing collectively confirmed it is a wild-type GIST.The patient recovered well and was discharged on the 6th day after surgery, with continued oral IM(400 mg/d) after discharge. No recurrence was observed during follow-up until the publication of this report.ConclusionThis unexpected response suggests that wild-type GISTs may benefit from TKIs treatment, and the potential mechanisms warrant further investigation. Additionally, true wild-type GIST may not be discerned due to current limitations of Next-Generation Sequencing(NGS). Therefore, for advanced/high-risk GIST, additional genetic analysis can be performed after negative NGS results.

Dataset Information

Personalized prescription of imatinib in recurrent granulosa cell tumor of the ovary: case report.

Publications

Personalized prescription of imatinib in recurrent granulosa cell tumor of the ovary: case report.

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