Functional polymorphism rs7072793 C > T affect individual susceptibility to breast cancer by modulating CD25 transcription activity

Abstract

Substantial evidence has demonstrated immune defects in breast cancer patients. They have decreased numbers of peripheral blood lymphocytes, but higher numbers of functionally suppressive CD4(+) CD25(+) Treg in both peripheral blood and tumor microenvironment. Constitutive high expression of CD25 is a pivotal characteristic of natural Treg cells. This study aims at investigating if CD25 variability affects breast carcinogenesis. Two polymorphisms (rs7072793 C > T, rs3118470 C > T) in the promoter of CD25 were selected and analyzed by a multiple independent case-control study to assess the association between CD25 genotypes and breast cancer risk. Genotyping a total of 1110 patients and 1060 healthy controls in Chinese populations showed that rs7072793 CT genotype had an odd ratio of 1.49 (95% confidence interval, 1.23-1.89) for developing breast cancer compared with CC genotype, the rs7072793 TT carriers had a further increased risk of breast cancer (OR = 2.11; 95% CI = 1.66-2.87). Furthermore, our transient transfection which focused on reporter gene expression modulated by CD25 promoter demonstrated that the presence of an rs7072793 T allele led to greater transcriptional activity than the C allele. Similarly, rs13347 T carriers were shown to have larger proportion of CD4(+) CD25(+) Tregs in the PBMCs than C carriers in the flow cytometry analysis. However, no significant differences were found in genotype frequencies at rs3118470 C > T site between cases and controls. Our findings suggest that rs7072793 C > T genetic variation in CD25 genes may be genetic modifier for developing breast cancer.

A Polymorphism rs12325489C>T in the LincRNA-ENST00000515084 Exon Was Found to Modulate Breast Cancer Risk via GWAS-Based Association Analyses

“…There were no age, stage, or histology restrictions. Similar to the southern Chinese population, controls (n = 980) were selected from a pool of 6000 individuals who had participated in a community-based screening program involving a health checkup [33] . Furthermore, the selection criteria for all controls were that they had no history of cancer, and were frequency matched to each set of cases on age (±5 years), with a response proportion of 90%.…”

Heterozygous Genetic Variations ofFOXP3in Xp11.23 Elevate Breast Cancer Risk in Chinese Population via Skewed X-Chromosome Inactivation

“…In the southern Chinese population, 799 individuals with breast cancer and 748 age (±5 years) frequency‐matched healthy controls who were enrolled between March 2002 and May 2009 in the Guangzhou area were used as the validation set I; population controls were randomly selected from a pool of 5,000 individuals who participated in a hospital‐based screening program for health checkup conducted in Guangdong province, with a response rate of 91% [Jiang et al, , ]. Similarly, in the northern Chinese population, 773 individuals with breast cancer and 996 age (±5 years) frequency‐matched healthy controls who were consecutively recruited from the Harbin area between June 2005 and April 2010 were employed as the validation set II; cancer‐free controls from the northern population were also randomly selected from a pool of 6,000 individuals who participated in a hospital‐based screening program for health checkup conducted in Harbin city, with a response rate of 92% [Li et al, ]. The tumor‐node‐metastasis classification and tumor staging were evaluated according to the 2002 American Joint Committee on Cancer staging system.…”

CD25: A potential tumor therapeutic target

“…A case‐control study of Chinese patients with one of the two polymorphisms of the CD25 gene promoter shows that patients with the rs7072793 T > C polymorphism are more susceptible to breast cancer. This polymorphism may change the function and expansion of CD25 in Treg cells leading to tumor immune escape 57 …”