Evaluating 17 breast cancer susceptibility loci in the Nashville breast health study

Abstract

Background Genome-wide association studies (GWAS) have discovered multiple genetic loci associated with breast cancer risk. Investigating these loci would be helpful to evaluate previous findings and identify causal variants for breast cancer. We evaluated index SNPs in17 of these loci in a study of 1,511 cases and 1,454 controls of European descent. Methods We investigated the overall association with breast cancer and among subtypes defined as ER+ (estrogen receptor positive), ER− (estrogen receptor negative) and TNBC (triple-negative breast cancer). Combined effects of SNPs on breast cancer risk were assessed via a genetic risk score (GRS). We evaluated the contribution of both genetic variants and traditional risk factors to a breast cancer risk assessment model. Results Five of the 17 SNPs were significantly associated (P ≤ 0.05) with overall breast cancer in the same direction as previously reported: rs13387042 (2q35/TNP1), rs4973768 (3p24/SLC4A7), rs2046210 (6q25/ESR1), rs1219648 (10q26/FGFR2), and rs4784227 (16q12/TOX3). When stratified by breast cancer subtype, all five SNPs were associated (P<0.05) with ER+ cancer, three with ER− cancer (rs13387042, rs1219648, and rs4784227), and one with TNBC (rs1219648). A GRS, based on those five significant SNPs, showed strong association with overall breast cancer with ORs (95% CI) of 1.48 (1.22–1.79), 1.85 (1.52–2.25) and 2.26 (1.82–2.80), respectively, for each quartile, (P = 2.0×10−15). Traditional risk factors, including previous benign breast disease, breast cancer family history and parity, were significantly associated with breast cancer risk in the present study. These factors, together with the GRS, were used to build a breast cancer risk assessment model with a c statistic of 0.6321 from receiver operating characteristic (ROC) analysis. The contribution of the GRS to the model was greater than prior benign breast disease, family history and parity with the c statistic change of 0.0374, 0.0324, 0.0103, 0.0012, respectively. Conclusions Our study demonstrates that five SNPs were associated with overall breast cancer, with stronger association for ER+ than ER− cancer as previously reported, and suggests that a risk assessment model incorporating the GRS from five loci is useful in identifying women at high risk of breast cancer.

Association of multiple genetic variants with breast cancer susceptibility in the Han Chinese population

“…The p53 gene expression of correlates with BC prognosis [ 21 , 22 ]. Previously, the SNP rs704010 in the ZMIZ1 gene was found to correlate with an increased risk of breast cancer (OR = 1.03) and ER+ BC (OR = 1.02) in women with European ancestry [ 23 ]. Turnbull et al also found rs704010 that the minor allele of “A“have significantly association with BC risk (per-allele OR = 1.38 for stage 1; per-allele OR = 1.13 for stage 2; Combined p = 3.7*10-9) [ 24 ].…”

ALDH1A1 mRNA expression in association with prognosis of triple-negative breast cancer

“…The NBHS is a population-based, case-control study of incident breast cancer among 2,726 women, aged 25 to 75 years, who were newly diagnosed with primary breast cancer between 2001 and 2011 [ 18 , 21 ]. Information on demographic, anthropometric, medical, reproductive, and other characteristics was ascertained through telephone interview by trained interviewers using a structured questionnaire.…”

Evaluation of significant genome-wide association studies risk — SNPs in young breast cancer patients

“…rs4973768 lies in the untranslated region (3’UTR) of the sodium bicarbonate (Na+HCO3-) cotransporter NBCn1 (SLC4A7) [30]. The Nashville Breast Health Study evaluated this SNP in 1511 cases with a mean age of 53.3 years (range 25–75 years) and identified an association with ER-positive breast cancer [31]. Further, a significant association of SNP rs4973768 with increased breast cancer risk was replicated among different ethnicities in mixed age patients [32, 33].…”