Genomic profiling in ovarian cancer retreated with platinum based chemotherapy presented homologous recombination deficiency and copy number imbalances of CCNE1 and RB1 genes
Abstract:Background
Ovarian carcinomas presenting homologous recombination deficiency (HRD), which is observed in about 50% of cases, are more sensitive to platinum and PARP inhibitor therapies. Although platinum resistant disease has a low chance to be responsive to platinum-based chemotherapy, a set of patients is retreated with platinum and some of them are responsive. In this study, we evaluated copy number alterations, HR gene mutations and HR deficiency scores in ovarian cancer patients with prolonge… Show more
“…The high genomic instability is attributable to the universal presence of TP53 mutations and the frequent alterations in the HR DNA repair pathway ( 23 ). The associations between intrinsic genomic features and platinum sensitivity were explored in-depth with NGS technology in several studies ( 24 , 25 ). However, all those studies derived only single variation, which lacked comprehensiveness and extensiveness.…”
Platinum-based chemotherapy is still the standard of care after cytoreductive surgery in the first-line treatment for epithelial ovarian cancer. This study aims to integrate novel biomarkers for predicting platinum sensitivity in EOC after initial cytoreductive surgery precisely. To this end, 60 patients were recruited from September 2014 to October 2019. Based on the duration of progress-free survival, 44 and 16 patients were assigned to platinum-sensitive and platinum-resistant group, respectively. Next generation sequencing was performed to dissect the genomic features of ovarian tumors obtained from surgery. Multiple genomic variations were compared between two groups, including single-nucleotide variant, single base or indel signature, loss of heterozygosity (LOH), whole-genome duplication (WGD), and others. The results demonstrated that patients with characteristics including positive SBS10a signature (p < 0.05), or FAM175A LOH (p < 0.01), or negative WGD (p < 0.01) were significantly enriched in platinum-sensitive group. Consistently, patients with positive SBS10a signature (15.8 vs. 10.1 months, p < 0.05), or FAM175A LOH (16.5 vs. 9.2 months, p < 0.05), or negative WGD (16.5 vs. 9.1 months, p < 0.05) have significantly longer PFS than those without these genetic features. By integrating these three biomarkers, a lasso regression model was employed to train and test for all patients, with the AUC value 0.864 in platinum sensitivity prediction. Notably, 388 ovarian cancer patients from TCGA dataset were leveraged as independent validation cohort with AUC value 0.808, suggesting the favorable performance and reliability of this model.
“…The high genomic instability is attributable to the universal presence of TP53 mutations and the frequent alterations in the HR DNA repair pathway ( 23 ). The associations between intrinsic genomic features and platinum sensitivity were explored in-depth with NGS technology in several studies ( 24 , 25 ). However, all those studies derived only single variation, which lacked comprehensiveness and extensiveness.…”
Platinum-based chemotherapy is still the standard of care after cytoreductive surgery in the first-line treatment for epithelial ovarian cancer. This study aims to integrate novel biomarkers for predicting platinum sensitivity in EOC after initial cytoreductive surgery precisely. To this end, 60 patients were recruited from September 2014 to October 2019. Based on the duration of progress-free survival, 44 and 16 patients were assigned to platinum-sensitive and platinum-resistant group, respectively. Next generation sequencing was performed to dissect the genomic features of ovarian tumors obtained from surgery. Multiple genomic variations were compared between two groups, including single-nucleotide variant, single base or indel signature, loss of heterozygosity (LOH), whole-genome duplication (WGD), and others. The results demonstrated that patients with characteristics including positive SBS10a signature (p < 0.05), or FAM175A LOH (p < 0.01), or negative WGD (p < 0.01) were significantly enriched in platinum-sensitive group. Consistently, patients with positive SBS10a signature (15.8 vs. 10.1 months, p < 0.05), or FAM175A LOH (16.5 vs. 9.2 months, p < 0.05), or negative WGD (16.5 vs. 9.1 months, p < 0.05) have significantly longer PFS than those without these genetic features. By integrating these three biomarkers, a lasso regression model was employed to train and test for all patients, with the AUC value 0.864 in platinum sensitivity prediction. Notably, 388 ovarian cancer patients from TCGA dataset were leveraged as independent validation cohort with AUC value 0.808, suggesting the favorable performance and reliability of this model.
“…CCNE1 and RB1 are cyclins related to cell cycle transition in the G1-S phase. Tumors with increased CCNE1 copy number are more resistant to platinum therapy, while RB1 loss is associated with high sensitivity to platinum therapy ( 49 , 50 ). Studies have shown that loss of RB1 protein expression is associated with longer OS and PFS ( 47 , 50 , 51 ).…”
Section: Molecular Mechanisms Of Platinum-based Chemotherapy Resistan...mentioning
Cisplatin is one of the most effective chemotherapy drugs for ovarian cancer, but resistance is common. The initial response to platinum-based chemotherapy is as high as 80%, but in most advanced patients, final relapse and death are caused by acquired drug resistance. The development of resistance to therapy in ovarian cancer is a significant hindrance to therapeutic efficacy. The resistance of ovarian cancer cells to chemotherapeutic mechanisms is rather complex and includes multidrug resistance, DNA damage repair, cell metabolism, oxidative stress, cell cycle regulation, cancer stem cells, immunity, apoptotic pathways, autophagy and abnormal signaling pathways. The present review provided an update of recent developments in our understanding of the mechanisms of ovarian cancer platinum-based chemotherapy resistance, discussed current and emerging approaches for targeting these patients and presented challenges associated with these approaches, with a focus on development and overcoming resistance.
Contents1. Introduction 2. Literature review methods 3. Molecular mechanisms of platinum-based chemotherapy resistance in ovarian cancer 4. Conclusions
“…4 A). This finding indicated that tumors with CNAs occurring in the SWI/SNF pathway might have DNA repair defects and are sensitive to DNA-damaging therapeutics [ 24 , 25 ]. Fig.…”
Background
Alterations in genes encoding chromatin regulatory proteins are prevalent in cancers and may confer oncogenic properties and molecular changes linked to therapy resistance. However, the impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types.
Methods
We comprehensively analyzed the genomic, transcriptomic and clinical data of The Cancer Genome Atlas (TCGA) dataset across 33 solid cancers.
Results
CNAs of the SWI/SNF components were identified in more than 25% of all queried cancers, and tumors harboring SWI/SNF CNAs demonstrated a worse overall survival (OS) than others in several cancer types. Mechanistically, the SCNA events in the SWI/SNF complex are correlated with dysregulated genomic features and oncogenic pathways, including the cell cycle, DNA damage and repair. Notably, the SWI/SNF CNAs were associated with homologous recombination deficiency (HRD) and improved clinical outcomes of platinum-treated ovarian cancer. Furthermore, we observed distinct immune infiltrating patterns and immunophenotypes associated with SWI/SNF CNAs in different cancer types.
Conclusion
The CNA events of the SWI/SNF components are a key process linked to oncogenesis, immune infiltration and therapeutic responsiveness across human cancers.
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