Background: Struma Ovarii (SO) is a rare ovarian teratoma characterized by the presence of thyroid tissue in >50% of the tumor. The majority of SO are benign; however, malignant transformation occurs in up to 5% of the cases. The molecular foundations of benign and malignant SO are grossly unknown. Therefore, the goal of this study was to perform the first comprehensive genomic and transcriptomic analysis of the benign and malignant SO. Material and Method: We performed whole-exome sequencing (WES) and targeted RNA-sequencing (seq) on the DNA and RNA extracted from formalin-fixed paraffin-embedded SO tumor tissue samples. WES library was prepared using Agilent’s SureSelect XT HS2 kit, with 4 samples failing the quality assessment (QA). Variants were called from GATK processed WES data and annotated using VEP (with ClinVar and COSMIC databases). The targeted RNA-Seq library was prepared using the TruSight RNA Pan-Cancer Panel kit covering 1385 cancer genes, with all samples passing QA. The clinical characteristics of the study cohort were summarized by percentages for categorical variables and medians with 25-75% interquartile ranges for continuous variables. Results: The study included 31 tissue samples - 21 benign and 10 malignant, including 6 cases of papillary thyroid cancer (PTC), 3 of follicular variant of PTC, and 1 of follicular thyroid cancer. Patients with benign SO were characterized by the median age at diagnosis of 39 years [33-54], tumor size of 3.1 cm [2.5-5.8], while the patients with malignant SO presented at age of 45 [28-54], tumor size of 6 cm [0.85-14] and metastatic disease in 30% (3/10) - 2 patients with peritoneal metastases and 1 patient with pelvic lymph node metastases. The E1A Binding Protein P300, EP300 (6/27), and Isocitrate dehydrogenase, IDH2 (5/27) were the topmost mutated genes in the SO samples. Malignant SO samples were characterized with the presence of pathogenic variants of KRAS (pQ61L and pG12V), NRAS (pQ61R), TP53 (splice site) mutations, and Nuclear Receptor Binding SET Domain Protein 1 (NSD1) fusion as the most common molecular drivers. Among benign SO samples, the most common driver was Thyroglobulin (TG) fusion with either Guanine Nucleotide binding protein (GNAS) or Rac Family Small GTPase 1 (RAC1). Differential expression analysis showed that the member of tumor suppressor family - tumor protein 63 (TP63) was the most downregulated (Log2FC = -3), while Double-sex and Mab-3 Related Transcription Factor 1 (DMRT1), implicated in the development of germ cell tumors, was the most upregulated gene in malignant SO samples over benign (Log2FC = 2.1; padj<0.05). Conclusions: In contrast to cancer arising from the thyroid gland, characterized by BRAFV600E as the most common mutation, malignant SO belongs to RAS-like tumors. The downregulation of tumor suppressors and upregulation of DMRT1 might be implicated in the malignant transformation of SO. Citation Format: Shilpa Thakur, Darryl Nousome, Kshama Aswath, Stephanie Cardenas, Sonam Kumari, Ruth Adewale, Maria Merino, Esra Dikoglu, Padmasree Veeraraghavan, Sriram Gubbi, Joanna Klubo-Gwiezdzinska. Genomic and transcriptomic characterization of benign and malignant struma ovarii [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 769.
Background: Next generation sequencing has led to the categorization of thyroid cancer (TC) based on the molecular and transcriptomic profile into the BRAF-like and RAS-like tumors. The BRAF-RAS score (BRS) has been developed to quantify the extent to which the gene expression profile resembles either the BRAFV600E- or RAS-mutant profiles and is utilized as a continuous measure from -1 to +1, respectively. Oncogene-driven signaling pathways have an impact on the intracellular metabolism– glycolysis and oxidative phosphorylation (OXPHOS). There are limited data on the genotype-metabolic phenotype correlation in TC cells. Therefore, the goal of this study was to perform a comprehensive analysis of the association between the BRS and TC cell metabolism. Methods: We analyzed the mRNA expression of key enzymes involved in glycolysis (lactate dehydrogenase LDHA) and OXPHOS (ATP synthase) in 496 BRAF-like and RAS-like human TC tissue samples based on The Cancer Genome Atlas. We performed an in vitro study using 8 TC cell lines– 4 BRAF-like with BRS between -1 and 0, and 4 RAS-like with BRS between 0 and +1. OXPHOS was determined by measuring oxygen consumption rate (OCR) of each cell line using Seahorse XF Cell Mito Stress Test Kit, while Seahorse XF Glycolysis Stress Test Kit was used to measure the extracellular acidification rate (ECAR) due to anaerobic glycolysis The association between the OCR, ECAR and BRS was tested using the Pearson correlation coefficient (r). Student T-test was used to compare the continuous variables between the groups with a p-value of ≤ 0.05 as statistically significant. Results:RAS-like tumors were associated with higher mRNA expression of the OXPHOS marker ATP synthase than BRAF-like lesions, as evidenced by a moderate positive correlation (r = 0.5) between ATP synthase expression and BRS. BRAF-like tumors were characterized by a relatively higher mRNA expression of a glycolytic enzyme LDHA, as documented by a moderate negative correlation (r = -0.6) between LDHA expression and BRS. Consistently, functional in vitro studies revealed that RAS-like cell lines had a higher OXPHOS compared with BRAF-like cell lines (maximum OCR: 2538.4±1601.3 vs 548.5±276.5, p=0.049, respectively). The glycolysis rate was comparable between RAS-like and BRAF-like cell lines (maximum ECAR: 1290.4±520.5 vs 2399.9±1413.1, p=0.19, respectively). There was a strong positive correlation between the BRS and OCR (r=0.78) and a low to negligible negative correlation between BRS and ECAR (r=-0.26) in examined TC cell lines. Conclusions:BRAF-like and RAS-like tumors are characterized by distinct metabolic phenotypes with RAS-like TC more likely to utilize OXPHOS to meet metabolic demands. Therapeutic strategies targeting oncogene-driven signaling pathways and cancer metabolism based on distinct metabolic phenotypes may provide an individualized approach to TC therapy.
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