Discovering a qualitative transcriptional signature of homologous recombination defectiveness for prostate cancer

Li, Yawei; Zhao, Zhangxiang; Ai, Liqiang; Wang, Yuquan; Liu, Kaidong; Chen, Bin; Chen, Tingting; Zhuang, Shuping; Xu, Huanhuan; Zou, Min; Gu, Yunyan; Li, Xia

doi:10.1016/j.isci.2021.103135

Cited by 9 publications

(5 citation statements)

References 33 publications

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“…HRD score was also found to predict the immunogenicity of BRCA1/2 breast cancer in the study by Kraya et al (2019). Li et al (2021) found that prostate cancer patients with high HRD had higher immune infiltration and immune checkpoint gene expression, suggesting that prostate cancer patients with high HRD may respond to immune checkpoint inhibitors (ICIs). These studies further supported our results and demonstrated that ICIs may be a promising treatment modality for LGG patients with high HRD.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, poly ADP-ribose polymerase (PARP) inhibitors were approved for use by the Food and Drug Administration and recommended for the treatment of tumors with BRCA1/2 mutations, including pancreatic cancer and prostate cancer (Rescigno et al, 2018;Li et al, 2021;Zhuang et al, 2021). Tumors with BRCA1/2 mutations are often accompanied by homologous recombination deficiency (HRD), and cancer cells with HRD are more sensitive to PARP inhibitors (Rescigno et al, 2018;Chen et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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A Risk Model Developed Based on Homologous Recombination Deficiency Predicts Overall Survival in Patients With Lower Grade Glioma

Peng

Wang

et al. 2022

Front. Genet.

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The role of homologous recombination deficiency (HRD) in lower grade glioma (LGG) has not been elucidated, and accurate prognostic prediction is also important for the treatment and management of LGG. The aim of this study was to construct an HRD-based risk model and to explore the immunological and molecular characteristics of this risk model. The HRD score threshold = 10 was determined from 506 LGG samples in The Cancer Genome Atlas cohort using the best cut-off value, and patients with high HRD scores had worse overall survival. A total of 251 HRD-related genes were identified by analyzing differentially expressed genes, 182 of which were associated with survival. A risk score model based on HRD-related genes was constructed using univariate Cox regression, least absolute shrinkage and selection operator regression, and stepwise regression, and patients were divided into high- and low-risk groups using the median risk score. High-risk patients had significantly worse overall survival than low-risk patients. The risk model had excellent predictive performance for overall survival in LGG and was found to be an independent risk factor. The prognostic value of the risk model was validated using an independent cohort. In addition, the risk score was associated with tumor mutation burden and immune cell infiltration in LGG. High-risk patients had higher HRD scores and “hot” tumor immune microenvironment, which could benefit from poly-ADP-ribose polymerase inhibitors and immune checkpoint inhibitors. Overall, this big data study determined the threshold of HRD score in LGG, identified HRD-related genes, developed a risk model based on HRD-related genes, and determined the molecular and immunological characteristics of the risk model. This provides potential new targets for future targeted therapies and facilitates the development of individualized immunotherapy to improve prognosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Risk Model Developed Based on Homologous Recombination Deficiency Predicts Overall Survival in Patients With Lower Grade Glioma

Peng

Wang

et al. 2022

Front. Genet.

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“…Initially, this approach was used to calculate the HRD score in ovarian and breast cancer samples. Later, it was also extended to the analysis of other tumors in which BRCA1 and BRCA2 alterations are involved, such as pancreatic and prostate cancer [ 155 ] ( Table 2 ).…”

Section: Homologous Recombination Deficiency: a New Bioinformatics Ch...mentioning

confidence: 99%

Bioinformatics: From NGS Data to Biological Complexity in Variant Detection and Oncological Clinical Practice

et al. 2022

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The use of next-generation sequencing (NGS) techniques for variant detection has become increasingly important in clinical research and in clinical practice in oncology. Many cancer patients are currently being treated in clinical practice or in clinical trials with drugs directed against specific genomic alterations. In this scenario, the development of reliable and reproducible bioinformatics tools is essential to derive information on the molecular characteristics of each patient’s tumor from the NGS data. The development of bioinformatics pipelines based on the use of machine learning and statistical methods is even more relevant for the determination of complex biomarkers. In this review, we describe some important technologies, computational algorithms and models that can be applied to NGS data from Whole Genome to Targeted Sequencing, to address the problem of finding complex cancer-associated biomarkers. In addition, we explore the future perspectives and challenges faced by bioinformatics for precision medicine both at a molecular and clinical level, with a focus on an emerging complex biomarker such as homologous recombination deficiency (HRD).

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“…Androgen receptor (AR) signaling plays a central role in both primary PCa and CRPC, and thus is the major pathway for the development of targeted therapy 3 . Recent large‐scale omics studies have identified additional oncogenic drivers and subtypes of PCa and CRPC, including gene fusion between the TMPRSS2 and ETS family members, loss of tumor suppressors P53 and RB1, SPOP mutation, activation of the PI3K signaling, among others 4–6 . In addition, single‐cell sequencing of patient tissues of different stages has greatly advanced our understanding of the heterogeneity and reprogramming of the PCa microenvironment throughout disease progression, potentiating therapeutic opportunities from both the immune and non‐immune compartments of the tumor niche 7,8 …”

Section: Introductionmentioning

confidence: 99%

“…3 Recent large-scale omics studies have identified additional oncogenic drivers and subtypes of PCa and CRPC, including gene fusion between the TMPRSS2 and ETS family members, loss of tumor suppressors P53 and RB1, SPOP mutation, activation of the PI3K signaling, among others. [4][5][6] In addition, single-cell sequencing of patient tissues of different stages has greatly advanced our understanding of the heterogeneity and reprogramming of the PCa microenvironment throughout disease progression, potentiating therapeutic opportunities from both the immune and non-immune compartments of the tumor niche. 7,8 Stressors in the tumor microenvironment such as hypoxia, nutrient unavailability, accumulation of reactive oxygen species, and low pH, can drastically perturb the homeostasis of endoplasmic reticulum (ER), causing ER stress.…”

Section: Introductionmentioning

confidence: 99%

The functional implication of ATF6α in castration‐resistant prostate cancer cells

et al. 2023

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Stress in the endoplasmic reticulum (ER) may perturb proteostasis and activates the unfolded protein response (UPR). UPR activation is frequently observed in cancer cells and is believed to fuel cancer progression. Here, we report that one of the three UPR sensors, ATF6α, was associated with prostate cancer (PCa) development, while both genetic and pharmacological inhibition of ATF6α impaired the survival of castration‐resistance PCa (CRPC) cells. Transcriptomic analyses identified the molecular pathways deregulated upon ATF6α depletion, and also discovered considerable disparity in global gene expression between ATF6α knockdown and Ceapin‐A7 treatment. In addition, combined analyses of human CRPC bulk RNA‐seq and single‐cell RNA‐seq (scRNA‐seq) public datasets confirmed that CRPC tumors with higher ATF6α activity displayed higher androgen receptor (AR) activity, proliferative and neuroendocrine (NE) like phenotypes, as well as immunosuppressive features. Lastly, we identified a 14‐gene set as ATF6α NE gene signature with encouraging prognostic power. In conclusion, our results indicate that ATF6α is correlated with PCa progression and is functionally relevant to CRPC cell survival. Both specificity and efficacy of ATF6α inhibitors require further refinement and evaluation.

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Discovering a qualitative transcriptional signature of homologous recombination defectiveness for prostate cancer

Cited by 9 publications

References 33 publications

A Risk Model Developed Based on Homologous Recombination Deficiency Predicts Overall Survival in Patients With Lower Grade Glioma

A Risk Model Developed Based on Homologous Recombination Deficiency Predicts Overall Survival in Patients With Lower Grade Glioma

Bioinformatics: From NGS Data to Biological Complexity in Variant Detection and Oncological Clinical Practice

The functional implication of ATF6α in castration‐resistant prostate cancer cells

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