Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

Abstract

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

“…PIK3CA mutations have been reported in urothelial papilloma cases [111]. PIK3CA gene amplification has been observed in recurrent ovarian cancer [112] and yolk sac tumors [113].…”

Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans

“…In CD4+ T-cells, significant DEG are involved in cytotoxic T-cell activation ( IL7R 40 ), histone modification ( H3F3B 41 ), and transcriptional regulation ( MYC 42 ). We observed three cell sub-groups (cluster 3, 8, and 16; Figure 3a ; Table S12 ).…”

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

“…Gains in murine chromosome cytoband regions 6qD1-G3, 15qD3-F3, and 15qA1-D3 were present in ID8-IP cells ( Figure 1B, green circles). These correspond to human cytobands 12p12.1, 8q24.2, and 8q24.3, with the latter two representing one of the most amplified regions in HGSOC (Cancer Genome Atlas Research, 2011, Li et al, 2019. The gain in cytoband 15qA1-D3 is in addition to chromosome 15 polyploidy detected by ID8 karyotype analyses (Roby et al, 2000).…”

“…Gains at 8q24 occur in the majority of HGSOC tumors and encompass the MYC oncogene at 8q24.21 (Gorringe, George et al, 2010). MYC facilitates pluripotent stem cell generation and contributes to HGSOC chemoresistance (Fagnocchi & Zippo, 2017, Kumari, Folk et al, 2017, Li, Bonazzoli et al, 2019. Although MYC expression is generally high in HGSOC, the clinical significance of this change remains unclear.…”