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Translational Therapeutics

Upregulation of CXCL1 and LY9 contributes to BRCAness in ovarian cancer and mediates response to PARPi and immune checkpoint blockade

British Journal of Cancer volume 127, pages 916–926 (2022)Cite this article

Subjects

Abstract

Background

Mutations in BRCA1 or BRCA2 (BRCA1/2) cause homologous recombination deficiency (HRD). Ovarian cancer (OvCa) patients harbouring HRD beyond BRCA1/2 mutation result in a state referred to as “BRCAness”. OvCa with BRCAness could benefit from PARP inhibitors. This study aims to identify a signature to detect the BRCAness population at the transcriptome level.

Methods

We used a rank-based algorithm to develop a qualitative BRCAness signature for OvCa. Upregulation of CXCL1 with downregulation of SV2A and upregulation of LY9 with downregulation of CHRNB3 were constructed as the BRCAness signature (2 gene pairs, 2-GPS) for OvCa.

Results

OvCa samples that were classified as BRCAness by 2-GPS showed improved overall survival, progression-free survival and exhibited increased multi-omics alterations in homologous recombination genes and enhanced sensitivity to immune checkpoint blockade. BRCAness cells were sensitive to PARP inhibitors. By biological experiments, we validated SKOV3 cells and patients with HRD exhibited higher expression of CXCL1 than SV2A and higher expression of LY9 than CHRNB3 at mRNA level. Both SKOV3 and A2780 with HRD were sensitive to mitomycin C, cisplatin and olaparib.

Conclusions

In conclusion, 2-GPS could robustly predict BRCAness OvCa at the individual level and extend the population who may benefit from PARP inhibitors.

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Fig. 1: 2-GPS, the prognostic performance and the multi-omics landscape of BRCAness.
Fig. 2: Functional analysis of BRCAness-related genes.
Fig. 3: Immune landscape in OvCa with BRCAness.
Fig. 4: Drug efficacy in BRCAness cells and DDR-related BRCAness interaction network.
Fig. 5: Construction of HRD in OvCa cells and cell viability assay.
Fig. 6: The expression of 2-GPS in OvCa cells and patients.

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Data availability

The datasets used and analysed during this study are available from public databases.

Code availability

Codes are implemented in the R environment and are publicly available on GitHub: https://github.com/ttchen0714/BRCAness-signature.

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Acknowledgements

Not applicable.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 61673143 to YG; No. 81673036 to YX), the Outstanding Youth Foundation of Heilongjiang Province of China (No. YQ2021H005 to YG) and the HMU Marshal Initiative Funding (No. HMUMIF-21023 to YG and HL).

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Author notes

  1. These authors contributed equally: Tingting Chen, Tong Yu.

Authors and Affiliations

  1. Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China

    Tingting Chen, Shuping Zhuang, Yiding Geng, Liqiang Ai, Bo Chen, Yawei Li, Yan Xu & Yunyan Gu

  2. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China

    Tong Yu, Junwen Xue, Jiayi Wang & Haihai Liang

  3. The Sino-Russian Medical Research Center of Jinan University, the Institute of Chronic Disease of Jinan University, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China

    Zhangxiang Zhao & Haihai Liang

  4. Department of Pharmacy, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China

    Jinghao Wang

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Contributions

YX and YYG conceived the original idea and supervised the study. TTC carried out the data processing, analysis and wrote the manuscript; TY carried out the biological experiment and wrote the manuscript; SPZ, YDG, LQA, BC, ZXZ and YWL. carried out the data collection. JWX, JHW and HHL carried out the biological experiment. All authors have approved the final manuscript.

Corresponding authors

Correspondence to Yan Xu or Yunyan Gu.

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The authors declare no competing interests.

Ethical approval and consent to participate

The study was approved by the Ethics Committees at Harbin Medical University. All patients or their guardians provided written informed consent prior to obtaining samples. This study was performed in accordance with the Declaration of Helsinki and its amendments.

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Chen, T., Yu, T., Zhuang, S. et al. Upregulation of CXCL1 and LY9 contributes to BRCAness in ovarian cancer and mediates response to PARPi and immune checkpoint blockade. Br J Cancer 127, 916–926 (2022). https://doi.org/10.1038/s41416-022-01836-0

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