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Theranostics 2021; 11(9):4403-4420. doi:10.7150/thno.53737 This issue Cite

Research Paper

Intratumor heterogeneity of breast cancer detected by epialleles shows association with hypoxic microenvironment

Yihan Wang2, Yan Zhang1,3✉, Yan Huang3, Chuangeng Chen3, Xingda Zhang4, Ying Xing5, Yue Gu3, Mengyan Zhang3, Li Cai5, Shouping Xu4✉, Baoqing Sun1✉

1. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 51000, China.
2. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
3. School of Life Science and Technology, Computational Biology Research Center, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China.
4. Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.
5. The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China.

✉ Corresponding authors: Yan Zhang, Email: zhangtyoedu.cn; Baoqing Sun, Email: sunbaoqing163.com; Shouping Xu, Email: shoupingxuedu.cn

Citation:
Wang Y, Zhang Y, Huang Y, Chen C, Zhang X, Xing Y, Gu Y, Zhang M, Cai L, Xu S, Sun B. Intratumor heterogeneity of breast cancer detected by epialleles shows association with hypoxic microenvironment. Theranostics 2021; 11(9):4403-4420. doi:10.7150/thno.53737. https://www.thno.org/v11p4403.htm
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Abstract

Graphic abstract

Rationale: In breast cancer, high intratumor DNA methylation heterogeneity can lead to drug-resistant, metastasis and poor prognosis of tumors, which increases the complexity of cancer diagnosis and treatment. However, most studies are limited to average DNA methylation level of individual CpGs and ignore heterogeneous DNA methylation patterns of cell subpopulations within the tumor. Thus, quantifying the variability in DNA methylation pattern in sequencing reads is valuable for understanding intratumor heterogeneity.

Methods: We performed Reduced Representation Bisulfite Sequencing and RNA sequencing for tumor core and tumor periphery regions within one breast tumor. By developing a method named “epialleJS” based on Jensen-Shannon divergence, we detected the differential epialleles between tumor core and tumor periphery (CPDEs). We then explored the correlation between intratumor methylation heterogeneity and hypoxic microenvironment in TCGA breast cancer cohort.

Results: More than 70% of CPDEs had higher epipolymorphism in tumor core than tumor periphery, and these CPDEs had lower methylation in tumor core. The CPDEs with lower methylation in tumor core may associate with hypoxic tumor microenvironment. Moreover, we identified a signature of five hypoxia-related DNA methylation markers which can predict the prognosis of breast cancer patients, including a CpG site cg15190451 in gene SLC16A5. Furthermore, immunohistochemical analysis confirmed that the expression of SLC16A5 was associated with clinicopathological characteristics and survival of breast cancer patients.

Conclusions: The analysis of intratumor DNA methylation heterogeneity based on epialleles reveals that disordered methylation patterns in tumor core are associated with hypoxic microenvironment, which provides a framework for understanding biological heterogeneous behavior and guidance for developing effective treatment schemes for breast cancer patients.

Keywords: breast cancer, intratumor DNA methylation heterogeneity, epiallele, methylation patterns, hypoxic microenvironment.

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APA
Wang, Y., Zhang, Y., Huang, Y., Chen, C., Zhang, X., Xing, Y., Gu, Y., Zhang, M., Cai, L., Xu, S., Sun, B. (2021). Intratumor heterogeneity of breast cancer detected by epialleles shows association with hypoxic microenvironment. Theranostics, 11(9), 4403-4420. https://doi.org/10.7150/thno.53737.

ACS
Wang, Y.; Zhang, Y.; Huang, Y.; Chen, C.; Zhang, X.; Xing, Y.; Gu, Y.; Zhang, M.; Cai, L.; Xu, S.; Sun, B. Intratumor heterogeneity of breast cancer detected by epialleles shows association with hypoxic microenvironment. Theranostics 2021, 11 (9), 4403-4420. DOI: 10.7150/thno.53737.

NLM
Wang Y, Zhang Y, Huang Y, Chen C, Zhang X, Xing Y, Gu Y, Zhang M, Cai L, Xu S, Sun B. Intratumor heterogeneity of breast cancer detected by epialleles shows association with hypoxic microenvironment. Theranostics 2021; 11(9):4403-4420. doi:10.7150/thno.53737. https://www.thno.org/v11p4403.htm

CSE
Wang Y, Zhang Y, Huang Y, Chen C, Zhang X, Xing Y, Gu Y, Zhang M, Cai L, Xu S, Sun B. 2021. Intratumor heterogeneity of breast cancer detected by epialleles shows association with hypoxic microenvironment. Theranostics. 11(9):4403-4420.

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