rs1219648

A hospital-based case-control study in rural and urban India (1,204 cases; 1,212 controls) examined genetic and lifestyle risk factors for breast cancer. Four SNPs in FGFR2 (rs1219648, rs2420946, rs2981575, rs2981582) showed positive associations with breast cancer (ORs 1.32-1.47). Additional SNPs in obesity and metabolic genes (rs374748 in FBN2, rs2922763 in HNF4G, rs2116830 in KCNMA1, rs11121832 in MTHFR, rs16886165 in MAP3K1, rs11594610 in TCF7L2, rs2274459 in MLN) were associated with increased breast cancer risk. Waist-to-hip ratio ≥0.95 showed strong association (OR 3.78; 95% CI 2.92-4.89), and women living first 20 years in rural areas showed protective effect (OR 0.77).

Genome-wide association study of Ashkenazi Jewish women with familial breast cancer but no BRCA1/2 mutations identified 7 novel SNPs and confirmed 6 known variants. A 7-marker risk model including rs17663555, rs566164, rs11075884, FGFR2 haplotype (rs11200014, rs2981579, rs1078806, rs1219648, rs2420946, rs2981582), rs13387042, rs2046210 (ESR1), and rs3112612 (TOX3) achieved moderate discriminatory accuracy (AUC=0.74; 95% CI: 0.69-0.79) for predicting familial breast cancer risk in this population.

Case-control study of 816 Chinese Han women (388 breast cancer patients, 428 controls) examining seven FGFR2 SNPs found that rs2981578 A allele and AA genotype were protective (OR=0.761, p=0.007; AA genotype OR=0.496, p=0.0035), while rs3750817 CT genotype was a risk factor (OR=1.52, p=0.003) for breast cancer in this population.

Population-based case-control study of 1170 breast cancer cases and 2115 controls examining associations between four FGFR2 intronic SNPs and breast cancer risk. All four SNPs (rs11200014, rs2981579, rs1219648, rs2420946) showed significant associations with breast cancer (per-allele ORs: 1.22-1.29). Key finding: significant gene-environment interaction with smoking status, with former/current smokers carrying two copies of rs1219648 minor allele at highest risk (crude OR 2.11, 95% CI: 1.52-2.92) compared to never smokers without variant alleles.

This candidate gene association study examined 218 postmenopausal women at high breast cancer risk, testing 79 SNPs in steroid metabolism, receptor, cell cycle control, DNA repair, and carcinogen metabolism genes for associations with abnormal breast tissue cytomorphology (RPFNA atypia) as a biomarker for HRT-related breast cancer risk. Key findings: RAD54 Gln929Glu (rs3088074, OR=1.74), TFR Gly142Ser (rs3817672, OR=1.98, p=0.0025), VEGF 3'UTR (rs3025039, OR=2.12), and ACE I/D (rs4646994, OR=0.55) were associated with RPFNA atypia. RAD23B Ala249Val (rs1805329) showed strongest association with worsening cytomorphology on HRT versus off HRT (p=0.0009) and ERCC1 3'UTR (rs3212986) was borderline significant (p=0.0015). Results suggest DNA repair gene polymorphisms may modify breast tissue response to exogenous estrogens.

This paper applies a bias correction method for odds ratio estimates from GWAS discovery data, demonstrating that the 'winner's curse' affects initial effect size estimates. The authors applied conditional maximum likelihood estimation to correct bias in GWAS findings from multiple complex diseases (breast cancer, colorectal cancer, lung cancer, prostate cancer, type I and II diabetes) and show that bias-adjusted odds ratios are substantially more consistent with subsequent replication studies, with selection-adjusted confidence intervals providing better uncertainty quantification than uncorrected estimates.

This PhD thesis presents a comprehensive study of microRNA (miRNA) SNPs and their association with breast cancer risk in Australian Caucasian populations. The study identified three key findings: rs2910164 in MIR146A showed significant association (p=0.03 and p=0.00013 in two populations); rs353291 in MIR145 showed significant differences in allele frequencies (p=0.041 and p=0.023); and rs4284505/rs7336610 in the MIR17HG cluster showed significant association with protective effect (OR=0.75, 95% CI: 0.60-0.94, p=0.012).

Hemminki et al. (2010) conducted a case-control study of 1,415 German familial breast cancer patients and 1,830 controls to validate low-risk breast cancer susceptibility variants. The study found significant associations with FGFR2 (OR=1.43, p=1.24×10⁻¹²), TNRC9 (OR=1.33, p=1.54×10⁻⁷), and LSP1 variants. Notably, homozygous carriers showed higher risks: FGFR2 OR=2.05 and TNRC9 OR=1.62, while LSP1 showed a protective effect (OR=0.49) in homozygous carriers.

Case-control study in Japan (456 cases, 912 controls) demonstrating that FGFR2 intronic SNPs (rs2981579, rs1219648, rs2420946, rs2981582) are associated with breast cancer risk (OR=1.29-1.53 for rs2420946), with rs2420946 showing a population-attributable risk of 17.7%. The SNPs interact with reproductive risk factors including age at menarche (interaction p=0.019) and parity (interaction p=0.026), suggesting effects on reproductive hormone-related pathways.

This case-control study examined whether seven breast cancer susceptibility alleles (in FGFR2, TNRC9, MAP3K1, LSP1, and chromosomal regions 8q24 and 2q35) were associated with epithelial ovarian cancer risk. The pooled analysis of 1,383 ovarian cancer cases and 1,804 controls found no significant associations between these variants and ovarian cancer risk, with OR estimates for FGFR2 rs1219648 of 1.06 (95% CI=0.95-1.18) and rs2981582 of 1.04 (95% CI=0.93-1.15), suggesting that breast cancer risk alleles may be specific to breast cancer.

A case-control study (484 cases with oral clefts, 482 controls) of polymorphisms in FGF signaling pathway genes found increased risk for complete unilateral cleft lip and palate with FGF10 rs1448037 (OR=1.52), unilateral right cleft lip and palate with FGF3 rs4980700 (OR=1.83), and bilateral cleft lip and palate with tooth agenesis with FGF10 rs1448037 (OR=1.95) and FGFR2 rs1219648 (OR=2.02).

A nested case-control study of 692 invasive endometrial cancer cases and 1,723 controls within the Nurses' Health Study and Women's Health Study investigated whether seven breast cancer risk alleles were also associated with endometrial cancer risk. In contrast to breast cancer, the authors found an inverse association with rs2981582 (FGFR2) and endometrial cancer risk (OR=0.75, 95% CI: 0.60-0.95), and non-significant inverse associations with rs889312 (MAP3K1, OR=0.85) and rs1219648 (FGFR2, OR=0.86). No associations were observed with the other four SNPs, suggesting important biological differences between endometrial and breast cancer despite their shared hormone-related etiology.