rs2981582

This case-control study evaluated rare copy number variants (CNVs), protein-truncating variants, and missense mutations in DNA damage response genes for breast cancer association in Finnish cohorts. CYP2C19 deletion showed enrichment in triple-negative breast cancer (p=0.021). TEX15 c.7253dupT frameshift variant associated with hereditary breast cancer (p=0.018). FANCD2 c.2715+1G>A splice-site variant (rs201811817) showed 7.5-fold increased risk (p=0.036, OR=7.5). RECQL p.Ile156Met and POLG p.Leu392Val (rs145289229) missense variants also associated with breast cancer (p=0.043 and p=0.010, OR=2.1 respectively).

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.

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).

Large pooled case-control study of 49,608 breast cancer cases and 48,772 controls from 39 studies in the Breast Cancer Association Consortium independently confirmed four SNPs as breast cancer susceptibility loci. SNP rs614367 (CCND1 region) showed the strongest association (OR 1.21, P < 1×10⁻⁸) overall and OR 1.29 for hormone receptor-positive breast cancer. SNPs rs1011970 (CDKN2A/2B, OR 1.09), rs10995190 (ZNF365, OR 0.92), and rs704010 (ZMIZ1) were also significantly associated with breast cancer risk in women of European descent, while rs2380205 (10p15) showed limited evidence.

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.

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.

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.

Population-based case-control study of 1,484 breast cancer cases and 1,307 controls examining 13 GWAS-identified SNPs for breast cancer susceptibility. Confirmed associations for 7 SNPs (rs13387042, rs4973768, rs10941679, rs2981582, rs3817198, rs3803662, rs6504950), with women in the highest quintile of a polygenic risk score having 2.2-fold increased breast cancer risk (95% CI: 1.67-2.88) compared to the lowest quintile. No significant interactions were detected between genetic loci and reproductive/menstrual risk factors.

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.

This comprehensive review article traces the evolution of pharmacogenetics from single-gene analysis to whole-genome approaches. It discusses validated pharmacogenetic biomarkers with clinical impact including CYP2D6, CYP2C9, CYP2C19, TPMT, DPD, VKORC1, UGT1A1, and ADRB1/ADRB2, providing examples of how genetic variants affect drug metabolism and response. The paper emphasizes the importance of integrating pharmacogenetic information into clinical practice and drug development.

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.

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).