Clinicogenomic characteristics and synthetic lethal implications of germline homologous recombination‐deficient hepatocellular carcinoma

http://www.jbc.org/article/S0021925822007979/pdf

RAD54B mutations enhance the sensitivity of ovarian cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors

The aim of this study was to assess homologous recombination deficiency (HRD) status and its correlation with carboplatin treatment response in early triple-negative breast cancer (TNBC) patients. 

Association between homologous recombination deficiency status and carboplatin treatment response in early triple-negative breast cancer

Abstract Objective: Predicting the early recurrence rate is important in improving the treatment and prognosis of ovarian cancer (OC). A homologous recombination deficiency (HRD) score serves as a prognostic factor in OC. Whether the HRD score can be used as a new marker for OC prognosis must be further explored. Methods: 69 patients with OC were enrolled in the study. We performed retrospective HRD genetic tests to obtain their HRD scores. The correlation test for tumor recurrence was performed using the Kaplan-Meier test and a Cox risk regression analysis. Results: No significant difference was found between the HRD score and the recurrence rate at the 1-year and full-time follow-up, rate of platinum-resistant recurrence. However, we demonstrated a strong association between the HRD score and hemoglobin (Hb) levels ( P =0.004). Interestingly, Hb levels before initial cancer treatment ( P =0.046) and neoadjuvant chemotherapy (NACT) ( P =0.040) displayed independent influences on the 1-year recurrence rate. The 1-year recurrence rate was significantly higher in patients with low Hb levels (≤107 g/L) than in patients with high Hb levels (&gt;107 g/L). Besides, it was significantly higher in patients who underwent NACT (based on high Suidan scores) than in patients who did not. Moreover, recurrence curves showed a significant association between NACT and the 1-year recurrence rate. Conclusions: For non-maintenance-treated patients, there is insufficient evidence that the HRD score can be used as a marker of short-term prognosis in OC. Hb levels and Suidan scores are expected to be new markers for predicting the 1-year recurrence rate in OC. 

The use of homologous recombination deficiency (HRD) scores in predicting the prognosis of ovarian cancer

Simple Summary We evaluated the levels of AKR1B1 and AKR1B10 in 99 patients with high-grade serous ovarian cancer and their association with clinicopathological characteristics, survival, and response to chemotherapy. An immunohistochemical analysis showed that higher AKR1B1 levels correlated with a better disease-free survival of patients whereas we saw no differences for AKR1B10 levels. A multivariant Cox analysis identified high AKR1B1 levels as an important prognostic factor for both overall and disease-free survival. A further analysis revealed no association between AKR1B1 and AKR1B10 levels and response to chemotherapy. Abstract Although aldo-keto reductases (AKRs) have been widely studied in cancer, no study to date has examined the roles of AKR family 1 members B1 (AKR1B1) and B10 (AKR1B10) in a large group of ovarian cancer patients. AKR1B1 and AKR1B10 play a significant role in inflammation and the metabolism of different chemotherapeutics as well as cell differentiation, proliferation, and apoptosis. Due to these functions, we examined the potential of AKR1B1 and AKR1B10 as tissue biomarkers. We assessed the immunohistochemical levels of AKR1B1 and AKR1B10 in tissue paraffin sections from 99 patients with high-grade serous ovarian cancer (HGSC) and compared these levels with clinicopathological characteristics, survival, and response to chemotherapy. A higher immunohistochemical AKR1B1 expression correlated with a better overall and disease-free survival of HGSC patients whereas AKR1B10 expression did not show any significant differences. A multivariant Cox analysis demonstrated that a high AKR1B1 expression was an important prognostic factor for both overall and disease-free survival. However, AKR1B1 and AKR1B10 were not associated with different responses to chemotherapy. Our data suggest that AKR1B1 is involved in the pathogenesis of HGSC and is a potential prognostic biomarker for this cancer.

/pdf/akr1b1-as-a-prognostic-biomarker-of-high-grade-serous-clf9nj88.pdf

AKR1B1 as a Prognostic Biomarker of High-Grade Serous Ovarian Cancer

Background: Homologous recombination (HR) pathway defects in cancers induced abrogation of cell-cycle checkpoints resulting the accumulation of DNA damage, mitotic catastrophe and cell death. Cancers with BRCA1/2 loss and other accumulation of similar genomic scars resulting in HRD displayed increased sensitivity to chemotherapy. Our study aimed to explore HRD score genetic mechanisms and subsequent clinical outcomes in human cancers especially ovarian cancer. Methods: We analyzed TCGA data of HRD score in 33 cancer types and evaluated HRD score distribution and difference among tumor stages and between primary and recurrent tumor tissues. Weighted Gene Co-Expression Network Analysis (WGCNA) was performed to identify highly correlated genes representing essential modules contributing to HRD score and distinguish the hub genes and significant pathways. We verified HRD status predicting role in patients overall survival (OS) with univariate and multivariate Cox regression analysis and built the predicting model for patient survival. Results: We found that HRD score increased with the rising of tumor stage except for stage IV. HRD score tended to grow up higher in recurrent tumor tissue than in primary counterpart (p=0.083). We constructed 15 co-expression modules with WGCNA, identified co-expressed genes and pathways impacting HRD score and concluded that HRD score was tightly associated with tumor cells replication and proliferation. Combined HRD score ≥42 was associated with shorter OS in altogether 33 cancer types (HR=1.010, 95%CI: 1.008-1.011, p <0.001). However, in ovarian cancer which ranked the highest HRD score among cancers, HRD ≥42 cohort was significantly associated with longer OS (HR=0.99, 95%CI:0.98-0.99, p<0.0001). We also built a predicting model for the 3-year and 5-year survival in HGSC patients. Conclusion: Quantitative HRD score representing the accumulated genomic scars was dynamically increasing in proliferating tumor cells, since HRD score was tightly correlated to tumor cell division and replication. We highlighted HRD score biomarker role in prognosis prediction of ovarian cancer.

Dynamically Accumulating Homologous Recombination Deficiency Score Served as an Important Prognosis Factor in High-Grade Serous Ovarian Cancer

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Dynamically Accumulating Homologous Recombination Deficiency Score Served as an Important Prognosis Factor in High-Grade Serous Ovarian Cancer