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Combined low levels of H4K16ac and H4K20me3 predicts poor prognosis in breast cancer

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Abstract

Background

Results of previous studies about the prognostic roles of histone H4 lysine 16 acetylation (H4K16ac) and histone H4 lysine 20 trimethylation (H4K20me3) in breast cancer were inconsistent. Cellular experiments revealed the interplays between H4K16ac and H4K20me3, but no population study explored the interaction between them on the prognosis.

Methods

H4K16ac and H4K20me3 levels in tumors were evaluated by immunohistochemistry for 958 breast cancer patients. Hazard ratios for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. Interaction was assessed on multiplicative scale. Concordance index (C-index) was calculated to verify the predictive performance.

Results

The prognostic roles of the low level of H4K16ac or H4K20me3 were significant only in patients with the low level of another marker and their interactions were significant. Moreover, compared with joint high levels of both them, only the combined low levels of both them was associated with a poor prognosis but not the low level of single one. The C-index of the clinicopathological model combined the joint expression of H4K16ac and H4K20me3 [0.739 for OS; 0.672 for PFS] was significantly larger than that of the single clinicopathological model [0.699 for OS, P < 0.001; 0.642 for PFS, P = 0.003] or the model combined with the single H4K16ac [0.712 for OS, P < 0.001; 0.646 for PFS, P < 0.001] or H4K20me3 [0.724 for OS, P = 0.031; 0.662 for PFS, P = 0.006].

Conclusions

There was an interaction between H4K16ac and H4K20me3 on the prognosis of breast cancer and the combination of them was a superior prognostic marker compared to the single one.

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Acknowledgements

We sincerely thank the patients who participated in this study, the staff who conducted the baseline and the follow-up data collection, and the medical staff in the breast departments of the Third Affiliated Hospital, and the Cancer Center of Sun Yat-Sen University. We also sincerely thank the funding of National Natural Science Foundation of China (81973115) and Science and Technology Planning Project of Guangdong Province, China (2019B030316002).

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Authors and Affiliations

  1. Department of Epidemiology and Health Statistics, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Rd, Guangzhou, 510080, Guangdong, China

    Bo Wang, Meng Zhou, Xing-li Gan & Ze-fang Ren

  2. Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Rd, Guangzhou, 510630, Guangdong, China

    Yue-xiang Ren, Zi-jin Weng, Xiao-fang Zhang, Jie-xia Guan & Lu-ying Tang

  3. Department of Pathology, The Sun Yat-Sen University Cancer Center, Guangzhou, 510080, Guangdong, China

    Yuan-zhong Yang

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Contributions

BW, MZ and ZFR designed and directed the study, wrote and/or revised the manuscript. YZY constructed the TMAs and contributed to the IHC. YXR, ZJW, XFZ, JXG, and LYT contributed to digital imaging of IHC-stained sections and the assessment of immunohistochemical expression. BW, MZ and XLG contributed to clinical data collection and curation. BW and MZ participated in the statistical analysis plan and interpretation of results. ZFR provided administrative support and supervision for the study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lu-ying Tang or Ze-fang Ren.

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Supplementary file 1: Figure S1.

Flow chart of the study cohort. Note: there were three people who missed the data of both H4K16ac and H4K20me3 level. H4K16ac, Histone H4 lysine 16 acetylation; H4K20me3, Histone H4 lysine 20 trimethylation. Figure S2. Restricted cubic splines of H4K16ac and H4K20me3 with breast cancer OS (a for H4K16ac, c for H4K20me3) and PFS (b for H4K16ac, d for H4K20me3). H4K16ac, Histone H4 lysine 16 acetylation; H4K20me3, Histone H4 lysine 20 trimethylation; OS, overall survival; PFS, progression-free survival. Figure S3. Kaplan-Meier survival curves of H4K16ac and H4K20me3 with breast cancer OS (a for H4K16ac, c for H4K20me3) and PFS (b for H4K16ac, d for H4K20me3). H4K16ac, Histone H4 lysine 16 acetylation; H4K20me3, Histone H4 lysine 20 trimethylation; OS, overall survival; PFS, progression-free survival. Table S1. Univariate association between the demographic and clinicopathological characteristics and the outcomes. Table S2. Univariate and multivariate association between H4K16ac and H4K20me3 levels in tumor tissues and the outcomes.

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Wang, B., Zhou, M., Gan, Xl. et al. Combined low levels of H4K16ac and H4K20me3 predicts poor prognosis in breast cancer. Int J Clin Oncol 28, 1147–1157 (2023). https://doi.org/10.1007/s10147-023-02378-y

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