Theranostics 2020; 10(9):3939-3951. doi:10.7150/thno.39341 This issue Cite

Research Paper

Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer

Zhiyuan Wu1,2*, Sihan Li2*, Xuemei Tang1, Yue Wang2, Weiwei Guo2, Guojun Cao1, Kun Chen1, Min Zhang2✉, Ming Guan1,3✉, Da Yang2,4,5✉

1. Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
2. Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, PA 15261, USA.
3. Central Laboratory, Huashan Hospital, Fudan University, Shanghai 200040, China.
4. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
5. Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
*These authors equally contributed to this manuscript.

Citation:
Wu Z, Li S, Tang X, Wang Y, Guo W, Cao G, Chen K, Zhang M, Guan M, Yang D. Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer. Theranostics 2020; 10(9):3939-3951. doi:10.7150/thno.39341. https://www.thno.org/v10p3939.htm
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Abstract

Graphic abstract

Rationale: Loss of DNA damage repair (DDR) in the tumor is an established hallmark of sensitivity to DNA damaging agents such as chemotherapy. However, there has been scant investigation into gain-of-function alterations of DDR genes in cancer. This study aims to investigate to what extent copy number amplification of DDR genes occurs in cancer, and what are their impacts on tumor genome instability, patient prognosis and therapy outcome.

Methods: Retrospective analysis was performed on the clinical, genomics, and pharmacogenomics data from 10,489 tumors, matched peripheral blood samples, and 1,005 cancer cell lines. The key discoveries were verified by an independent patient cohort and experimental validations.

Results: This study revealed that 13 of the 80 core DDR genes were significantly amplified and overexpressed across the pan-cancer scale. Tumors harboring DDR gene amplification exhibited decreased global mutation load and mechanism-specific mutation signature scores, suggesting an increased DDR proficiency in the DDR amplified tumors. Clinically, patients with DDR gene amplification showed poor prognosis in multiple cancer types. The most frequent Nibrin (NBN) gene amplification in ovarian cancer tumors was observed in 15 out of 31 independent ovarian cancer patients. NBN overexpression in breast and ovarian cancer cells leads to BRCA1-dependent olaparib resistance by promoting the phosphorylation of ATM-S1981 and homology-dependent recombination efficiency. Finally, integration of the cancer pharmacogenomics database of 37 genome-instability targeting drugs across 505 cancer cell lines revealed significant correlations between DDR gene copy number amplification and DDR drug resistance, suggesting candidate targets for increasing patient treatment response.

Principal Conclusions: DDR gene amplification can lead to chemotherapy resistance and poor overall survival by augmenting DDR. These amplified DDR genes may serve as actionable clinical biomarkers for cancer management.

Keywords: DNA damage repair, chemotherapy resistance, pharmacogenetics


Citation styles

APA
Wu, Z., Li, S., Tang, X., Wang, Y., Guo, W., Cao, G., Chen, K., Zhang, M., Guan, M., Yang, D. (2020). Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer. Theranostics, 10(9), 3939-3951. https://doi.org/10.7150/thno.39341.

ACS
Wu, Z.; Li, S.; Tang, X.; Wang, Y.; Guo, W.; Cao, G.; Chen, K.; Zhang, M.; Guan, M.; Yang, D. Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer. Theranostics 2020, 10 (9), 3939-3951. DOI: 10.7150/thno.39341.

NLM
Wu Z, Li S, Tang X, Wang Y, Guo W, Cao G, Chen K, Zhang M, Guan M, Yang D. Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer. Theranostics 2020; 10(9):3939-3951. doi:10.7150/thno.39341. https://www.thno.org/v10p3939.htm

CSE
Wu Z, Li S, Tang X, Wang Y, Guo W, Cao G, Chen K, Zhang M, Guan M, Yang D. 2020. Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer. Theranostics. 10(9):3939-3951.

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