DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations

Yang, Mei; Fan, Yanhui; Wu, Zhi‐Yong; Gu, Jin; Feng, Zhendong; Zhang, Qiangzu; Han, Shunhua; Zhang, Zhonghai; Xu, Li; Hsueh, Yi-Ching; Ni, Yanxiang; Li, Xiaoling; Li, Jieqing; Hu, Meixia; Li, Weiping; Gao, Hong‐Fei; Yang, Ciqiu; Zhang, Chunming; Zhang, Liulu; Zhu, Teng; Cheng, Minyi; Ji, Fei; Xu, Juntao; Cui, Hening; Tan, Guangming; Zhang, Michael Q.; Liang, Changhong; Liu, Zaiyi; Song, You‐Qiang; Niu, Gang; Wang, Kun

doi:10.1016/j.ebiom.2021.103446

Cited by 5 publications

(3 citation statements)

References 40 publications

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“…The mutated somatic variants from every clone or clonal composition were mapped to the 60 signaling pathways to obtain composite scores of signaling pathways in different forms. Ceramide signaling pathways with different clonal distributions were also compared between BM + and BM-samples by Activity Profiles of Signalling Pathways (APSPs) [26].…”

Section: Framework Of Damage Assessment Of Genomic Mutations (Dagm) M...mentioning

confidence: 99%

RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding

Lin,

Wu,

Zhang

et al. 2024

J Exp Clin Cancer Res

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Background Ceramide metabolism is crucial in the progress of brain metastasis (BM). However, it remains unexplored whether targeting ceramide metabolism may arrest BM. Methods RNA sequencing was applied to screen different genes in primary and metastatic foci and whole-exome sequencing (WES) to seek crucial abnormal pathway in BM + and BM-patients. Cellular arrays were applied to analyze the permeability of blood–brain barrier (BBB) and the activation or inhibition of pathway. Database and Co-Immunoprecipitation (Co-IP) assay were adopted to verify the protein–protein interaction. Xenograft and zebrafish model were further employed to verify the cellular results. Results RNA sequencing and WES reported the involvement of RPTOR and ceramide metabolism in BM progress. RPTOR was significantly upregulated in BM foci and increased the permeability of BBB, while RPTOR deficiency attenuated the cell invasiveness and protected extracellular matrix. Exogenous RPTOR boosted the SPHK2/S1P/STAT3 cascades by binding YY1, in which YY1 bound to the regions of SPHK2 promoter (at -353 ~ -365 nt), further promoting the expression of SPHK2. The latter was rescued by YY1 RNAi. Xenograft and zebrafish model showed that RPTOR blockade suppressed BM of non-small cell lung cancer (NSCLC) and impaired the SPHK2/S1P/STAT3 pathway. Conclusion RPTOR is a key driver gene in the brain metastasis of lung cancer, which signifies that RPTOR blockade may serve as a promising therapeutic candidate for clinical application.

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Section: Framework Of Damage Assessment Of Genomic Mutations (Dagm) M...mentioning

confidence: 99%

RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding

Lin,

Wu,

Zhang

et al. 2024

J Exp Clin Cancer Res

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“…In 2021, a novel approach was taken to investigate the relationship between germline genomic mutations and the risk of breast cancer using AI. The Damage Assessment of Genomic Mutations (DAGM) framework was established, employing AI technology to create a computational model [ 31 ]. The DAGM model inputs all germline mutations of an individual and calculates their cumulative effects on gene expression as reflected in cellular signaling pathways.…”

Section: Advancements In the Application Of Artificial Intelligence F...mentioning

confidence: 99%

Review: Predictive approaches to breast cancer risk

Huang,

Xu,

Yang

2023

Heliyon

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“…In our previous study on the etiology of germline genomes in patients with various types of breast cancer, we proposed a potential solution 49 . By mapping germline rare coding variants (gRCVs) onto a quantitative set of signaling pathway profiles using the DAGM approach, we can easily model the functional patterns of cells driven by germline genomes in these patients.…”

Section: Introductionmentioning

confidence: 99%

A Genome-Informed Functional Modeling Approach to Evaluate the Responses of Breast Cancer Patients to CDK4/6 Inhibitors-Based Therapies and Simulate Real-World Clinical Trials

Yang

Liu

Hsueh

et al. 2023

Preprint

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Breast cancer patients exhibit diverse responses to CDK4/6 inhibitor (CDK4/6i)-based therapies, and identifying eligible patients remains a challenge. Artificial intelligence (AI) has demonstrated the potential to address complex clinical problems. Here, we applied a novel AI-based approach, named as CDK4/6i Response Model (CRM), which combined a previously published method and a scoring model based on random forest algorithm for evaluating breast cancer patients' sensitivity to CDK4/6i-based therapies. To train the CRM, we transformed the genomic data of 980 breast cancer patients from the TCGA database into signaling pathway activity profiles (APSP) by utilizing the modified Damage Assessment of Genomic Mutations (DAGM) algorithm. To mimic the mechanism of action of CDK4/6 inhibitors, a scoring model was then trained to classify the HR+/HER2- and HR-/HER2- breast cancer molecular subtypes by the differential APSP features between the two, which reasonably reflected the potential role played by CDK4/6 molecules in HR+/HER2- breast cancer cells. The effectiveness of the CRM's ability was verified by accurately classifying HR+/HER2- and HR-/HER2- breast cancer patients in a separate local patient cohort (n = 343) in Guangdong, China. Significantly, the scores were observed to be distinct (p = 0.025) between CDK4/6i-treated patients with different responses. Furthermore, breast cancer patients belonging to different subtypes were grouped into five distinct populations based on the scores assigned by the CRM. The results showed not only the heterogenetic responses across subtypes but also more than half of HR+/HER2+ patients might be benefited from CDK4/6i-based treatment. The CRM empowered us to conduct in-silico clinical trials (ICT) on different types of cancer patients responding to CDK4/6i-based therapies. In this study, we performed twin ICT of previously disclosed clinical trials (NCT02246621,NCT02079636,NCT03155997,NCT02513394,NCT02675231), and observed concerted results as the real-world clinical outcomes. These findings show the potential of CRM as a companion diagnostic for CDK4/6i-based therapies and demonstrate promising applications by ICT to guide pan-cancer treatment using CDK4/6 inhibitors in the clinical ends.

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DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations

Cited by 5 publications

References 40 publications

RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding

RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding

Review: Predictive approaches to breast cancer risk

A Genome-Informed Functional Modeling Approach to Evaluate the Responses of Breast Cancer Patients to CDK4/6 Inhibitors-Based Therapies and Simulate Real-World Clinical Trials

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