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IKZF3 amplification frequently occurs in HER2-positive breast cancer and is a potential therapeutic target

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Abstract

Breast cancer is one of the leading causes of cancer death in women, and although treatment outcome has substantially improved in the past decades, advanced or metastatic breast cancers still carry a poor prognosis. Gene amplification is one of the frequent genetic alterations in cancer, and oncogene amplification may be associated with cancer aggressiveness and oncogenicity. Targeting amplified genes such as HER2 has vastly improved disease outcome and survival, and anti-HER2 therapeutics have revolutionized the standard of care in HER2 breast cancer. Besides currently known druggable gene amplifications including ERBB2 and FGFR2, other frequently amplified genes are relatively less well known for function and clinical significance. By querying four large databases from TCGA and AACR-Genie, from a total of 11,890 patients with invasive ductal breast carcinoma, we discover IKZF3, CCND1, ERBB2 to be consistently amplified across different cohorts. We further identify IKZF3 as a frequently amplified gene in breast cancer with a prevalence of 12–15% amplification rate. Interestingly, IKZF3 amplification is frequently co-amplified with ERBB2/HER2, and is also associated with worse prognosis compared to IKZF3 non-amplified cancers. Analysis of HER2 breast cancer patients treated with trastuzumab revealed decrease in both ERBB2/HER2 and IKZF3 expression. Further investigation using the DepMap for gene dependency by genome-wide CRISPR screening revealed dependence on IKZF3 in HER2 breast cancer cell lines. Our study utilized an integrative analysis of large-scale patient genomics, transcriptomics and clinical data to reveal IKZF3 as a frequently amplified gene, and suggest a potential role of IKZF3 as a druggable target for HER2 breast cancer.

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Abbreviations

BC:

Breast cancer

DAVID:

Database for Annotation, Visualization, and Integrated Discovery

DFS:

Disease-free survival

GEPIA:

Gene Expression Profiling Interactive Analysis

GO:

Gene ontology

HER2:

Epidermal growth factor receptor 2

IMiDs:

Immunomodulatory imide drugs

IPA:

Ingenuity pathway analysis

IDC:

Invasive ductal breast carcinoma

KEGG:

Kyoto Encyclopedia of Genes and Genomes

mBC:

Metastatic breast cancer

OS:

Overall survival

PFS:

Progression-free survival

PROTACs:

Proteolysis targeting chimeras

TCGA:

The Cancer Genome Atlas

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Acknowledgements

This study was partially funded by the grants to JIL: MOST 110-2314-B-A49A-549 (Ministry of Science and Technology), CI-109-8 (Yen Tjing Ling Medical Foundation), Taiwan Clinical Oncology Research Foundation, and 109DHA0100490 (Taipei Veterans General Hospital internal grant).

Funding

Hsinchu Science Park Bureau,Ministry of Science and Technology,Taiwan,MOST 110-2314-B-A49A-549,Jiun-I Lai

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Authors and Affiliations

  1. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chih-Yi Lin, Chung-Jen Yu, Chia-I Shen & Jiun-I Lai

  2. Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chia-I Shen

  3. School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chia-I Shen, Chun-Yu Liu, Ta-Chung Chao & Ling-Ming Tseng

  4. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

    Chun-Yu Liu, Ta-Chung Chao & Jiun-I Lai

  5. Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chun-Yu Liu

  6. Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan

    Chun-Yu Liu, Ta-Chung Chao, Chi-Cheng Huang, Ling-Ming Tseng & Jiun-I Lai

  7. Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

    Chi-Cheng Huang & Ling-Ming Tseng

  8. Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

    Jiun-I Lai

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CJY, CIS, CYL, JIL: data collection, analysis and curation. CJY, CYL, JIL: drafting of the manuscript. CYL, TCC, CCH, LMT, JIL: conceptualization of the project. All authors read and approved the final manuscript.

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Lin, CY., Yu, CJ., Shen, CI. et al. IKZF3 amplification frequently occurs in HER2-positive breast cancer and is a potential therapeutic target. Med Oncol 39, 242 (2022). https://doi.org/10.1007/s12032-022-01812-x

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