A functional variant near XCL1 gene improves breast cancer survival via promoting cancer immunity. Issue 8 (25th January 2020)

• Record Type: Journal Article
• Authors: Chou, Wen‐Cheng; Hsiung, Chia‐Ni; Chen, Wei‐Ting; Tseng, Ling‐Ming; Wang, Hui‐Chun; Chu, Hou‐Wei; Hou, Ming‐Feng; Yu, Jyh‐Cherng; Shen, Chen‐Yang
• Is Part Of: International journal of cancer. Volume 146:Issue 8(2020)
• Page Start: 2182
• Page End: 2193
• Publication Date: 2020-01-25
• Subjects: breast cancer survival -- XCL1 -- MYBL2 -- type 1 dendritic cells -- Mendelian randomization; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32855
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Most genome‐wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are for recurrence and mortality. We conducted a GWAS on breast cancer survival after diagnosis in estrogen receptor‐positive patients, including 953 Taiwanese patients with 159 events. Through Cox proportional hazard models estimation, we identified 24 risk SNPs with p < 1 × 10 −5 . Based on imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, p = 2.43 × 10 −5 ) was found to be a functional variant associated with breast cancer survival and XCL1 gene expression. A series of experimental approaches, including cell‐based analyses and CRISPR/Cas9 genome‐editing system, were then used and identified the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer survival, which promoted XCL1 expression, but not to the G allele of rs1024176. The chemokine XCL1 attracts type 1 dendritic cells (DC1s) to the tumor microenvironment. In breast cancer tissues, we applied a two‐step Mendelian randomization analysis, using expression quantitative trait loci as instrumental variables, to confirm higher XCL1 expression was correlated with higher DC1 signatures and favorable disease progression, through the causal effect of rs1024176‐A allele. Our study supports the genetic effect on preventing breast cancer survival through XCL1‐induced DC1 recruitment in tumor microenvironment. Abstract : What's new? Although many prognostic predictors have been identified, the factors that determine patient differences in breast cancer progression and survival are not fully understood. This study addresses the important role of cancer immune control in promoting human breast cancer survival. Using genetic, cell‐based, and multi‐omic analyses, the authors find that one of the most significant SNP, rs1024176 at 1q24.2 could be a functional variant regulating XCL1 gene expression and thus recruiting type 1 dendritic cells to the breast tumor microenvironment. These findings reveal a pathway to prevent breast cancer progression through XCL1‐induced type 1 dendritic cells recruitment in the tumor microenvironment.