A Functional Variant Near XCL1 Gene Improves Breast Cancer Survival via Promoting Cancer Immunity

Abstract

Background: Most genome-wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are conducted for mortality or recurrence after diagnosis. We identified the risk genetic variants associated with breast cancer progression and investigated the underlying biological mechanisms that influence breast cancer progression.

Methods: We conducted a GWAS on breast cancer progression in estrogen receptor-positive patients. Using variants imputation and integrated analysis, one single-nucleotide polymorphism (SNP) was focused. A series of experimental approaches, including cell-based analyses and CRISPR/Cas9 genome-editing system were then used to determine the transcription factor responsible for the regulation at this region. Two-step Mendelian randomization (MR) analysis, using expression quantitative trait loci as instrument variables, was applied to confirm the causal effect for the gene expression on breast cancer progression.

Findings: We identified 24 risk SNPs with P < 1 x 10^-5. Following imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, P = 2.43 x 10^-5) was found to be a functional variant associated with breast cancer progression and XCL1 gene expression, that is because the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer progression, which promoted XCL1 expression, but not to the G allele of rs1024176. In breast cancer tissues, we applied MR approach to confirm higher XCL1 expression was correlated with higher type 1 dendritic cells (DC1) signatures and favorable disease progression, through the causal effect of rs1024176-A allele.

Interpretation: Our study suggested the rs1024176 is a causal variant in breast cancer recurrence through mediating XCL1-induced DC1 recruitment in tumor microenvironment.

Funding: Academia Sinica Peak Project and Ministry of Science and Technology, Taiwan.

Declaration of Interest: The authors declare that they have no competing interests.

Ethical Approval: This project was approved by the ethics committee of the institutional review board of the Taipei Veterans General Hospital (number 2013-05-27B), Tri-Service General Hospital (number 1-101-05-007) and Academia Sinica (AS-IRB01-13025), and informed consent was obtained from all participants before we collected personal data, in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines.

Keywords: Breast Cancer Survival; GWAS; Mendelian Randomization; MYBL2; Type 1 dendritic cells; XCL1