A functional variant near XCL1 gene improves breast cancer survival via promoting cancer immunity

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.

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype

“…MYBL2 is a transcription factor involved in cell cycle, however there is evidence that it may also be implicated in immune activation or in immune response-promoting processes. Indeed, MYBL2 may mediate increase mutational load by inducing APOBEC expression (26), may promote XCL1 expression in breast cancer which is associated with a type 1 dendritic cell signature and improved survival (27) and may be implicated in chromosomal instability (28). In our paper, MYBL2 provided significant prognostic information beyond stage but not to a model containing stage and PIK3CA mutation.…”

Effects of Inflammatory Response Genes on the Immune Microenvironment in Colorectal Cancer

“…LTB4R is a potent chemoattractant involved in in ammatory and immune responses to the paeoni ora-like signaling pathway [17], which is involved in all in ammatory diseases [18]. XCL1 promotes antitumor activity [19], and XCL1 expression is also signi cantly related to the number of tumor in ltrating CD8 + T cells as well as the expression of PD-L1 in tumor cells [20]. GAL methylation status may be an important marker for predicting clinical prognosis in patients who are with head and neck squamous cell carcinoma [21].…”

Construction of an Immunogenomic Risk Score for Prognostication in Colon Cancer

“…We will collect colon cancer patients with tumor sites to verify our results in future study. Furthermore, the effects of the IRGs on colon cancer development remain unclear, although cancer progression has been linked to CD1B (Lee et al, 2019), XCL1 (Chou et al, 2020;Tamura et al, 2020), PLCG1 (Wells and Grandis, 2003), NGF (Retamales-Ortega et al, 2017;Garrido et al, 2019), and OXTR (Ma et al, 2019). Therefore, the underlying mechanisms require further investigation using in vivo and in vitro experiments.…”