Abstract
To examine the role of germline genetic variations in inflammatory pathways as modifiers of time to recurrence (TTR) in patients with early stage breast cancer (BC), DNA from 997 early stage BC patients was genotyped for 53 tagging single nucleotide polymorphisms (SNPs) in 12 genes involved in inflammation. SNPs were analyzed separately for Caucasians versus African-Americans and Hispanics. Cox proportional hazards models were used to evaluate the association between SNPs in the inflammatory genes and TTR, adjusted for clinical and pathologic covariates. In univariable analyses of Caucasian women, the homozygous genotype of 12 SNPs, including 6 NFKB1 SNPs, 4 IL4 SNPs, and 2 IL13 SNPs, were significantly associated with a decrease in TTR compared with the heterozygous and/or corresponding homozygous genotype (P < 0.05). The significant NFKB1 and IL4 SNPs were in an area of high linkage disequilibrium (D' > 0.8). After adjusting for stage, age, and treatment, carriage of the homozygous genotypes for NFKB1 rs230532 and IL13rs1800925 were independently associated with a shorter TTR (P = 0.001 and P = 0.034, respectively). In African-American and Hispanic patients, expression of NFKB1 rs3774932, TNFrs1799964, and IL4rs3024543 SNPs were associated with a shorter TTR in univariable model. Only NFKB1 rs3774932 (P = 0.02) and IL4Rrs3024543 (P = 0.03) had independent prognostic value in the multivariable model These data support the existence of host genetic susceptibility as a component in recurrence risk mediated by pro-inflammatory and immune factors, and suggest the potential for drugs which modify immune responses and inflammatory genes to improve prognosis in early stage BC.