MYBL2 alternative splicing-related genetic variants reduce the risk of triple-negative breast cancer in the Chinese population

Xinyu Chen; Jin Feng; Yuan Zhang; Jiarui Liu; Lijia Zhang; Pu Zeng; Langbo Wen; Xin Wang; Yi Zhang

doi:10.3389/fgene.2023.1150976

MYBL2 alternative splicing-related genetic variants reduce the risk of triple-negative breast cancer in the Chinese population

Front Genet. 2023 Apr 18:14:1150976. doi: 10.3389/fgene.2023.1150976. eCollection 2023.

Authors

Xinyu Chen¹, Jin Feng², Yuan Zhang¹, Jiarui Liu¹, Lijia Zhang¹, Pu Zeng¹, Langbo Wen¹, Xin Wang³, Yi Zhang¹

Affiliations

¹ Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, China.
² Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
³ Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China.

Abstract

Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, and studies have found an association between the Myb proto-oncogene like 2 (MYBL2) gene and TNBC development; however, the specific mechanisms underlying development remain unknown. Recent studies have reported the association of alternative splicing (AS) with cancer, providing new approaches to elucidate the carcinogenesis mechanism. This study aimed to identify MYBL2 AS-related genetic variants that influence the risk of developing TNBC, providing new ideas for probing the mechanism of TNBC and novel biomarkers for TNBC prevention. Methods: We conducted a case-control study of 217 patients with TNBC and 401 cancer-free controls. The CancerSplicingQTL database and HSF software were used to screen for MYBL2 AS-related genetic variants. The association of sample genotypes with the risk of TNBC development and with clinicopathological features was analysed via unconditional logistic regression. Combining multiple platforms, the candidate sites were subjected to biological function analysis. Results: Two AS-associated SNPs, rs285170 and rs405660, were identified using bioinformatics analysis. Logistic regression analysis showed that both rs285170 (OR = 0.541; 95% CI = 0.343-0.852; p = 0.008) and rs405660 (OR = 0.642; 95% CI = 0.469-0.879; p = 0.006) exhibited protective effects against TNBC under the additive model. Stratification analysis showed that these two SNPs had more significant protective effects in the Chinese population aged ≧50 years. Additionally, we found that rs405660 was associated with the risk of lymph node metastasis (OR = 0.396, 95% CI = 0.209-0.750, p = 0.005) in TNBC. Functional analysis revealed that both rs285170 and rs405660 are associated with splicing of exon 3 and that the exon 3-deleted spliceosome does not increase breast cancer risk. Conclusion: We found for the first time that MYBL2 AS-related genetic variants are associated with reduced TNBC susceptibility in the Chinese population, especially in women aged ≧50 years.

Keywords: MYB proto-oncogene like 2; SNP; alternative splicing; susceptibility; triple-negative breast cancer.

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (No. 82060620) and the Research Foundation Project for graduate students of Zunyi Medical University in China (No. ZYK88). Guizhou Science and Technology Program Project (No. Qiankehe Foundation - ZK[2023] General 502), the National Natural Science Foundation of China (Grant No. 31960209), the “Thousand” Level Project of Training High-Level Innovative Talents in Guizhou Province (Grant No. fzc20200612), Guizhou Science and Technology Fund Project (Grant No. (2020)1Y093), Zunyi Science and Technology Fund Project (Grant No. Zun Shi Ke He HZ Zi 2021-40), Future Eminent Clinician Plan of Zunyi Medical University (Grant No. 2022-02).