scholarly journals Optimized detection of somatic allelic imbalances specific for homologous recombination deficiency improves the prediction of clinical outcomes in ovarian cancer

2021 ◽  
Author(s):  
Fernando Ramon Perez-Villatoro ◽  
Julia Casado ◽  
Anniina Farkkila
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Clinical Outcomes ◽  
Repair Deficiency ◽  
Improve Patient Selection ◽  
Dna Repair Deficiency ◽  
Tumor Types ◽  
Improve Patient ◽  
Pan Cancer

Specific patterns of genomic allelic imbalances (AIs) have been associated with Homologous recombination DNA-repair deficiency (HRD). We performed a systematic pan-cancer characterization of AIs across tumor types, revealing unique patterns in ovarian cancer. Using machine learning on a multi-omics dataset, we generated an optimized algorithm to detect HRD in ovarian cancer (ovaHRDscar). ovaHRDscar improved the prediction of clinical outcomes in three independent validation cohorts (PCAWG, HERCULES, TERVA). Characterization of 98 spatiotemporally distinct tumor samples indicated ovary/adnex as the preferred site to assess HRD. In conclusion, ovaHRDscar improves the detection of HRD in ovarian cancer with the premise to improve patient selection for HR-targeted therapies.

scholarly journals Inferring Homologous Recombination Deficiency of Ovarian Cancer From the Landscape of Copy Number Variation at Subchromosomal and Genetic Resolutions

2021 ◽  
Vol 11 ◽  
Author(s):  
Meng Zhang ◽  
Si-Cong Ma ◽  
Jia-Le Tan ◽  
Jian Wang ◽  
Xue Bai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Copy Number Variation ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Homologous Recombination Deficiency ◽  
Number Variation ◽  
Cancer Genome Atlas ◽  
Tumor Types ◽  
Pan Cancer

BackgroundHomologous recombination deficiency (HRD) is characterized by overall genomic instability and has emerged as an indispensable therapeutic target across various tumor types, particularly in ovarian cancer (OV). Unfortunately, current detection assays are far from perfect for identifying every HRD patient. The purpose of this study was to infer HRD from the landscape of copy number variation (CNV).MethodsGenome-wide CNV landscape was measured in OV patients from the Australian Ovarian Cancer Study (AOCS) clinical cohort and >10,000 patients across 33 tumor types from The Cancer Genome Atlas (TCGA). HRD-predictive CNVs at subchromosomal resolution were identified through exploratory analysis depicting the CNV landscape of HRD versus non-HRD OV patients and independently validated using TCGA and AOCS cohorts. Gene-level CNVs were further analyzed to explore their potential predictive significance for HRD across tumor types at genetic resolution.ResultsAt subchromosomal resolution, 8q24.2 amplification and 5q13.2 deletion were predominantly witnessed in HRD patients (both p < 0.0001), whereas 19q12 amplification occurred mainly in non-HRD patients (p < 0.0001), compared with their corresponding counterparts within TCGA-OV. The predictive significance of 8q24.2 amplification (p < 0.0001), 5q13.2 deletion (p = 0.0056), and 19q12 amplification (p = 0.0034) was externally validated within AOCS. Remarkably, pan-cancer analysis confirmed a cross-tumor predictive role of 8q24.2 amplification for HRD (p < 0.0001). Further analysis of CNV in 8q24.2 at genetic resolution revealed that amplifications of the oncogenes, MYC (p = 0.0001) and NDRG1 (p = 0.0004), located on this fragment were also associated with HRD in a pan-cancer manner.ConclusionsThe CNV landscape serves as a generalized predictor of HRD in cancer patients not limited to OV. The detection of CNV at subchromosomal or genetic resolution could aid in the personalized treatment of HRD patients.

scholarly journals Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jeremy Setton ◽  
Pier Selenica ◽  
Semanti Mukherjee ◽  
Rachna Shah ◽  
Isabella Pecorari ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cancer Susceptibility ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Breast And Ovarian Cancer ◽  
Population Database ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

AbstractPathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4–5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.

scholarly journals c-MYC and Epithelial Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jeyshka M. Reyes-González ◽  
Pablo E. Vivas-Mejía
Keyword(s):  
Patient Outcome ◽  
Ovarian Cancer ◽  
Standard Of Care ◽  
Initial Response ◽  
Platinum Resistance ◽  
Therapy Regimen ◽  
Clinical Challenge ◽  
Tumor Types ◽  
Improve Patient

Ovarian cancer is the deadliest of gynecological malignancies with approximately 49% of women surviving 5 years after initial diagnosis. The standard of care for ovarian cancer consists of cytoreductive surgery followed by platinum-based combination chemotherapy. Unfortunately, despite initial response, platinum resistance remains a major clinical challenge. Therefore, the identification of effective biomarkers and therapeutic targets is crucial to guide therapy regimen, maximize clinical benefit, and improve patient outcome. Given the pivotal role of c-MYC deregulation in most tumor types, including ovarian cancer, assessment of c-MYC biological and clinical relevance is essential. Here, we briefly describe the frequency of c-MYC deregulation in ovarian cancer and the consequences of its targeting.

Abstract WMP9: Does Repeat Images Improve Patient Selection and Clinical Outcomes in Patients Transferred for Endovascular Thrombectomy?

Stroke ◽  
2019 ◽  
Vol 50 (Suppl_1) ◽  
Author(s):  
Amrou Sarraj ◽  
Michael Chen ◽  
Nitin Goyal ◽  
Ameer Hassan ◽  
Haris Kamal ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Patient Selection ◽  
Endovascular Thrombectomy ◽  
Improve Patient Selection ◽  
Improve Patient

Evaluation of BRCA1/2 and homologous recombination defects in ovarian cancer and impact on clinical outcomes.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5511-5511 ◽  
Author(s):  
Melinda S. Yates ◽  
Kirsten Timms ◽  
Molly S Daniels ◽  
Holly D. Oakley ◽  
Mark F. Munsell ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Clinical Outcomes ◽  
Germline Mutation ◽  
Large Scale ◽  
Recurrent Ovarian Cancer ◽  
State Transitions ◽  
Cancer Genes ◽  
The Impact

5511 Background: Recent studies show that germline or somatic BRCA1/2 mutations and homologous recombination (HR) defects can be used to predict response to PARP inhibitors in recurrent ovarian cancer. However, the impact of defects in BRCA1/2 and HR genes on overall clinical outcomes are not yet defined for patients undergoing neoadjuvant chemotherapy (NACT) versus upfront surgical debulking (USD). Methods: Previously untreated ovarian cancer patients were prospectively enrolled under approved IRB protocol. Germline and tumor BRCA1/2 mutation testing and methylation were analyzed when sufficient tumor and blood was available. Mutation in 21 additional hereditary cancer genes (including HR genes) was also evaluated. Tumor HR defects were scored on LOH, telomeric allelic imbalance, and large-scale state transitions (as previously described). Presence of germline or somatic BRCA1/2 mutations, BRCA1 methylation, HR score ≥42, or germline mutation in other HR genes were defined together as HRD positive. Results: Of 299 enrolled patients, 129 (43%) received USD and 170 (57%) received NACT. Patients receiving USD had better outcomes compared to NACT, including overall survival (OS, 65.8 vs 45.2 months, p = 0.0003) and event free survival (EFS, 24.8 vs 15.6 months, p < 0.0001). In the overall cohort, EFS was significantly longer for HRD positive patients vs HRD negative (20.5 vs 16.3 months, p = 0.0268). Patients with somatic and germline BRCA1/2 mutations had longer OS vs BRCA1/2 negative (65.3 vs 46.1 months, p = 0.0403). Overall outcomes were worse in NACT compared to USD, but impact of BRCA1/2 mutations and HR defects was stronger in this group. NACT patients with any HR defect had longer EFS (19.7 vs 14.5 months, p = 0.0247). NACT patients with BRCA1/2 germline mutations had longer OS (65.3 vs 38.3 months, p = 0.0230). NACT patients with BRCA1/2 germline mutation had longer EFS (22.6 vs 14.6 months, p = 0.0047). OS and EFS in USD patients were significantly changed based on only debulking status; mutation or HR status did not have a statistically significant effect. Conclusions: While HR defects and BRCA1/2 mutations influence overall outcomes for ovarian cancer patients, the impact is stronger in NACT compared to USD.

Clinical assays for assessment of homologous recombination DNA repair deficiency

2020 ◽  
Vol 159 (3) ◽  
pp. 887-898
Author(s):  
Elizabeth H. Stover ◽  
Katherine Fuh ◽  
Panagiotis A. Konstantinopoulos ◽  
Ursula A. Matulonis ◽  
Joyce F. Liu
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Repair Deficiency ◽  
Dna Repair Deficiency
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