No association between genetic variants in angiogenesis and inflammation pathway genes and breast cancer survival among Chinese women

Abstract

Background: Angiogenesis and inflammation are implicated in breast cancer prognosis; however, the role of individual germline variation in related genes is unknown.

Methods: A two-stage candidate pathway association study was conducted among 6983 Chinese women. Stage 1 included 2884 women followed for a median of 5.7 years; Stage 2 included 4099 women followed for a median of 4.0 years. Cox proportional hazards regression was used to estimate the effects of genetic variants on disease-free survival (DFS) and overall survival (OS).

Results: Stage 1 included genotyping of 506 variants in 22 genes; analysis was conducted for 370 common variants. Nominally significant associations with DFS and/or OS were found for 20 loci in ten genes in Stage 1; variants in 19 loci were successfully genotyped and evaluated in Stage 2. In analyses of both study stages combined, nominally significant associations were found for nine variants in seven genes; none of these associations surpassed a significance threshold level corrected for the total number of variants evaluated in this study.

Conclusions: No association with survival was found for 370 common variants in 22 angiogenesis and inflammation pathway genes among Chinese women with breast cancer.

Impact: Our data do not support a large role for common genetic variation in 22 genes in breast cancer prognosis; research on angiogenesis and inflammation genes should focus on common variation in other genes, rare host variants, or tumor alterations.

Keywords: Angiogenesis genes; Breast cancer survival; CCL2; CCL5; CCR2; COL18A1; Chinese women; DFS; DNA; ER; FGFR4; FLT1; Genetic variants; HER2; HIF1A; HPGD; IL10; IL1B; IL6; Inflammation pathway genes; KDR; MAF; MMP1; MMP13; MMP2; MMP3; MMP7; MMP9; OS; PLAU; POSTN; PR; PTGES; PTGIS; PTGS2; SBCS; SBCSS; SERPINE1; SWHS; Shanghai Breast Cancer Study; Shanghai Breast Cancer Survival Study; Shanghai Women's Health Study; TGFB1; THBS1; VEGFA; chemokine (C-C motif) ligand 2; chemokine (C-C motif) ligand 5; chemokine (C-C motif) receptor 2; collagen, type XVIII, alpha 1; deoxyribonucleic acid; disease-free survival; estrogen receptor; fibroblast growth factor receptor 4; fms-related tyrosine kinase 1; human epidermal growth factor receptor 2; hydroxyprostaglandin dehydrogenase; hypoxia inducible factor 1, alpha subunit; interleukin 1, beta; interleukin 10; interleukin 6; kb; kilobase; kinase insert domain receptor; matrix metallopeptidase 1; matrix metallopeptidase 13; matrix metallopeptidase 2; matrix metallopeptidase 3; matrix metallopeptidase 7; matrix metallopeptidase 9; minor allele frequency; overall survival; periostin, osteoblast specific factor; plasminogen activator, urokinase; progesterone receptor; prostaglandin E synthase; prostaglandin I2 synthase; prostaglandin-endoperoxide synthase 2; serpin peptidase inhibitor, clade E, member 1 (previously known as PAI1); thrombospondin 1; transforming growth factor, beta 1; vascular endothelial growth factor A.