Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR)?=?1.43, 95?% confidence interval (CI)?=?1.26?C1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR?=?1.39, 95?% CI?=?1.20?C1.61) and ER-negative (per-allele OR?=?1.55, 95?% CI?=?1.28?C1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14?C1.68), 1.48 (1.25?C1.74), and 1.58 (1.28?C1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95?% CI) of 1.26 (1.12?C1.43) at rs1219648, 1.22 (1.07?C1.38) at rs2981582, 1.21 (1.07?C1.36) at rs2981579, and 1.18 (1.04?C1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95?% CI) of 1.16 (1.00?C1.34), 1.15 (1.02?C1.29), and 1.15 (1.01?C1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90?% for those with a combination of 6 or more risk alleles, compared to patients with ??3 risk alleles.     

2q35 rs13387042和8q24 rs13281615单核苷酸多态性与中国东北汉族绝经前妇女乳腺癌风险关系

背景与目的：乳腺癌作为中国女性最常见的恶性肿瘤,每年的新发数量和死亡数量分别占全世界的12.2%和9.6%,但与中国乳腺癌患者明显相关的基因多态位点至今尚不清楚。本研究旨在探讨2q35 rs13387042和8q24 rs13281615单核苷酸多态性与中国北方汉族绝经前妇女乳腺癌风险关系,为预防和治疗乳腺癌提供循证依据。方法：采用多重单碱基延伸单核苷酸多态性分型技术(SNaPshot)分析方法,检测了280例绝经前乳腺癌患者和287例绝经前正常对照者2q35 rs13387042和8q24 rs13281615多态性位点基因型,并比较不同基因型和等位基因与乳腺癌风险的关系。结果：2q35 rs13387042多态性位点基因型频率在乳腺癌和对照样本之间差异有统计学意义(P=0.017);8q24 rs13281615多态性位点基因型频率在乳腺癌和对照样本之间差异无统计学意义(P=0.967)。Logistic回归分析结果显示,对于2q35 rs13387042位点,与GG相比,GA和GA+AA基因型携带者显著增加乳腺癌的患病风险(OR=1.793,95%CI：1.177～2.733,P=0.007;OR=1.691,95%CI：1.122～2.550,P=0.012),而AA携带者与乳腺癌的患病风险无关(OR=0.572,95%CI：0.104～3.153,P=0.521);与G等位基因相比,A等位基因显著增加乳腺癌的患病风险(OR=1.505,95%CI：1.033～2.193,P=0.033)。对于8q24rs13281615位点,与AA相比,AG、GG和AG+GG基因型携带者与乳腺癌的患病风险无关(OR=0.992,95%CI：0.660～1.490,P=0.968;OR=1.047,95%CI：0.642～1.708,P=0.853;OR=1.007,95%CI：0.682～1.487,P=0.971);与A等位基因相比,G等位基因不增加乳腺癌患病风险(OR=1.021,95%CI：0.809～1.288,P=0.863)。结论：本实验证实2q35 rs13387042多态性位点能够增加中国北方汉族绝经前妇女乳腺癌易感风险,而8q24 rs13281615多态性位点与中国北方汉族绝经前妇女乳腺癌易感性无明显相关性。     

Replication of five GWAS-identified loci and breast cancer risk among Hispanic and non-Hispanic white women living in the Southwestern United States

Genome-wide association studies (GWAS) have identified several loci as being associated with breast cancer in mostly European populations. We focus on TNRC9 rs3803662, FGFR2 rs1219648 and rs2981582, MAP3K1 rs889312, and 2q35 rs13387042, to replicate in the 4-Corner’s Breast Cancer Study of Hispanic (N = 565 cases and 714 controls) and non-Hispanic white (NHW) women (N = 1177 cases and 1330 controls). We evaluate associations by ethnicity, menopausal status, and tumor ER/PR status after adjusting for genetic admixture. TNRC9 AA genotype was associated with significant increased risk among NHW women (OR 1.54, 95% CI 1.14, 2.08; P trend 0.003). Both polymorphisms of FGFR2 were associated with statistically significant increased risk for NHW and Hispanic women; MAP3K1 was not associated with risk among either ethnic group. The polymorphism on 2q35 was associated with a statistically significant increased risk among Hispanic women (OR 1.53, 95% CI 1.08, 2.15 for the AA genotype; P trend = 0.004). Associations were significantly different among pre/peri-menopausal women for TNRC9 (P heterogeneity 0.008) and for 2q35 (P heterogeneity 0.08) for NHW and Hispanic women. Both FGFR2 polymorphisms reduced risk of ER−/PR− tumors in the presence of the minor allele among NHW women. Among Hispanic women, polymorphisms of the FGFR2 gene were associated with almost a twofold increase risk of an ER+/PR+ tumor, while non-significantly inversely associated with ER−/PR− tumors. Our data replicated some of the previously reported GWAS findings. Differences in associations were detected for NHW and Hispanic women by menopausal status and by ER/PR status of tumors.     

Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, pooled analyses, and genome-wide association studies

To address the association between variants and breast cancer, an increasing number of articles on genetic association studies, genome-wide association studies (GWASs), and related meta- and pooled analyses have been published. Such studies have prompted an updated assessment of the associations between gene variants and breast cancer risk. We searched PubMed, Medline, and Web of Science and retrieved a total of 87 meta- and pooled analyses, which addressed the associations between 145 gene variants and breast cancer. Analyses met the following criteria: (1) breast cancer was the outcome, (2) the articles were all published in English, and (3) in the recent published meta- and pooled analyses, the analyses with more subjects were selected. Among the 145 variants, 46 were significantly associated with breast cancer and the other 99 (in 62 genes) were not significantly associated with breast cancer. The summary ORs for the 46 significant associations (P < 0.05) were further assessed by the method of false-positive report probability (FPRP). Our results demonstrated that 10 associations were noteworthy: CASP8 (D302H), CHEK2 (*1100delC), CTLA4 (+49G>A), FGFR2 (rs2981582, rs1219648, and rs2420946), HRAS (rare alleles), IL1B (rs1143627), LSP1 (rs3817198), and MAP3K1 (rs889312). In addition, eight GWASs were identified, in which 25 loci were obtained (14 in nine genes, six near a gene or genes, and five intergenic loci). Of the 25 SNPs, 20 were noteworthy: C6orf97 (rs2046210 and rs3757318), FGFR2 (rs2981579, rs1219648, and rs2981582), LSP1 (rs909116), RNF146 (rs2180341), SLC4A7 (rs4973768), MRPS30 (rs7716600), TOX3 (rs3803662 and rs4784227), ZNF365 (rs10995190), rs889312, rs614367, rs13281615, rs13387042, rs11249433, rs1011970, rs614367, and rs1562430. In summary, in this review of genetic association studies, 31.7% of the gene-variant breast cancer associations were significant, and 21.7% of these significant associations were noteworthy. However, in GWASs, 80% of the significant associations were noteworthy.     

Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women

FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERK-signalingpathway and have been identified from genome-wide associationstudies to be breast cancer susceptibility genes. Potentialinteractions of these genes and their role with respect to tumormarkers, hormonal factors and race on breast cancer risk havenot been explored. We examined FGFR2 and MAP3K1 variants, breasttumor characteristics and hormone exposures in a population-basedcase–control sample of 1225 European-American (EA) and584 African-American (AA) women. FGFR2 rs1219648 and rs2981582genotypes were significantly associated with breast cancer inEA only in estrogen receptor-positive (ER+), progesterone receptor-positive(PR+) and HER2/Neu-negative (HER2–) tumors. MAP3K1 wasnot associated with breast cancer in EA women, but it was associatedwith breast cancer in AA women, again limited to ER+, PR+ andHER2– tumors. An interaction was observed between combinedhormone replacement therapy use and FGFR2 rs1219648 genotypeson breast cancer risk in EA women (P = 0.010). Finally, we observeda significant interaction between MAP3K1 rs889312 and FGFR2rs2981582 (P = 0.022) in AA but not EA women. These resultsconfirm that FGFR2 and MAP3K1 are involved in breast cancersusceptibility and confer their effects primarily in ER+ andPR+ tumors. We further report that these genes confer theireffects in HER2– tumors, interact with one another toconfer breast cancer susceptibility in AA women and interactwith hormone exposures in AA and EA women. Abbreviations: AA, African-American; CHRT, combined hormone replacement therapy; CI, confidence interval; EA, European-American; ER, estrogen receptor; GWAS, genome-wide association study; MAPK, mitogen-activated protein kinase; OR, odds ratio; PR, progesterone receptor; SNP, single nucleotide polymorphism Received September 15, 2008; revised October 21, 2008; accepted October 23, 2008.     

Breast cancer susceptibility alleles and ovarian cancer risk in 2 study populations

Recent genome-wide scans identified several novel breast cancer risk alleles, including variants of the FGFR2, MAP3K1 and LSP1 genes, and a study of associations between these alleles and characteristics of breast cancer patients reported a borderline significant correlation between the number of FGFR2 minor alleles and family history of breast/ovarian cancer. Given these results and similarities in the etiology of breast and ovarian cancer, we examined the association between 7 novel breast cancer susceptibility alleles and epithelial ovarian cancer risk in 2 large study populations. Our analysis included 1,173 cases and 1,201 controls from a New England-based Case-Control study and 210 cases and 603 controls from the prospective Nurses' Health Study. We used logistic regression to estimate the odds ratio (OR) for individuals heterozygous or homozygous for the minor allele at each locus, compared to individuals with the wild-type genotype. We examined the associations separately in each population and, after testing for heterogeneity in the results, pooled the estimates using a random effects model. There was no clear association between these polymorphisms and ovarian cancer risk in either population. The pooled per allele OR for FGFR2 was 1.06 (95% confidence interval (CI)=0.95-1.18) for rs1219648 and 1.04 (95% CI=0.93-1.15) for rs2981582. We had more than 80% power to detect a log-additive OR of 1.16-1.18 per allele at the alpha=0.05 level in the pooled analysis. Our results do not provide strong support for an association between these breast cancer susceptibility alleles and epithelial ovarian cancer risk.     

Case-Control Study on the Fibroblast Growth Factor Receptor 2 Gene Polymorphisms Associated with Breast Cancer in Chinese Han Women

Purpose

Genetic variation in fibroblast growth factor receptor 2 (FGFR2) is a newly described risk factor for breast cancer. This study aimed to evaluate the association of four single nucleotide polymorphisms (SNPs) in FGFR2 with breast cancer in Han Chinese women.

Methods

Two hundred three women with breast cancer and 200 breast cancer-free age-matched controls were selected. Four SNPs (rs2981579, rs1219648, rs2420946, and rs2981582) and their haplotypes were analyzed to test for their association with breast cancer susceptibility. The presence of the four FGFR2 SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis.

Results

A statistically significant difference was observed in the frequency of rs2981582 in the FGFR2 gene (p<0.05) between case and control groups. In subjects stratified by menopausal status, rs2981582 TT, rs2420946 AA, and rs1219648 CC were significantly associated with the risk of breast cancer in postmenopausal subjects, but no significant associations between these four SNPs and the risk of breast cancer were identified in premenopausal subjects. Further, there was no significant association between hormone receptor status (estrogen receptor and progesterone receptor) and breast cancer risk. Six common (> 3%) haplotypes were identified. Three of these haplotypes, CGTC (odds ratio [OR], 0.613; 95% confidence interval [CI], 0.457-0.82; p=0.001), TGTC (OR, 6.561; 95% CI, 2.064-20.854; p<0.001), and CATC (OR, 12.645; 95% CI, 1.742-91.799; p=0.001) were significantly associated with breast cancer risk.

Conclusion

Our findings indicated that the SNP rs2981582 and haplotypes CGTC, TGTC, and CATC in FGFR2 may be associated with an increased risk of breast cancer in Han Chinese women.     

Novel breast cancer risk alleles and endometrial cancer risk

Genome-wide association studies have identified several novel risk alleles for breast cancer. We hypothesized that genetic variants that are associated with breast cancer, a hormone-related disease, would also be associated with endometrial cancer, another hormone-related disease. We conducted a case-control study nested within the Nurses' Health Study and the Women's Health Study to investigate the associations between these 7 newly identified risk alleles for breast cancer and endometrial cancer risk using 692 invasive endometrial cancer cases and 1,723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer. In contrast to the breast cancer findings, we did not observe an increased risk of endometrial cancer. We observed an inverse association among rs2981582 (FGFR2) variant carriers [OR= 0.75 (95% CI: 0.60-0.95)]. We also observed a nonsignificant inverse association with rs889312 (MAP3K1) variant carriers [OR = 0.85 (95% CI: 0.68-1.05)] and rs1219648 (FGFR2) variant carriers [OR= 0.86 (95% CI: 0.69-1.06) and endometrial cancer risk. We did not observe associations with the other single nucleotide polymorphisms (SNPs) and endometrial cancer risk. Replication studies investigating these polymorphisms and endometrial cancer risk are warranted. However, our findings do suggest the potential importance of biological differences between endometrial and breast cancer with respect to the genes identified in the scans. The molecular mechanisms underlying these differences remain to be defined.     

Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study

Introduction

Genome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status.

Methods

We genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods.

Results

Multiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant.

Conclusions

Our results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor.     

Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population

Genome-Wide Association Studies have identified several loci associated with breast cancer (BC) in populations of different ethnic origins. One of the strongest associations was found in the FGFR2 gene, and MAP3K1 has been proposed as a low-penetrance BC risk factor. In this study, we evaluated the associations among FGFR2 SNPs rs2981582, rs2420946, and rs1219648; and MAP3K1 rs889312, with BC risk in 351 BRCA1/2-negative Chilean BC cases and 802 controls. All the SNPs studied were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC, in a dose-dependent manner. Subjects with 3 risk alleles were at a significantly increased risk of BC compared with subjects with 0–2 risk alleles, in both familial BC and early-onset non-familial BC (OR = 1.47, 95 % CI 1.04–2.07, P = 0.026 and OR = 2.04 95 % CI 1.32–3.24, P < 0.001, respectively). In the haplotype analysis, the FGFR2 rs2981582 T / rs2420946 T / rs1219648 G haplotype (ht2) was associated with a significantly increased BC risk compared with the rs2981582 C / rs2420946 C / rs1219648 A haplotype in familial BC and in non-familial early-onset BC (OR = 1.32, 95 % CI 1.06–1.65, P = 0.012; OR = 1.46, 95 % CI 1.11–1.91, P = 0.004, respectively). When the FGFR2 ht2 and MAP3K1 rs889312 were evaluated as risk alleles, the risk of BC increased in a dose-dependent manner as the number of risk alleles increased (P trend <0.0001), indicating an additive effect. Nevertheless, there is no evidence of an interaction between FGFR2 ht2 and the MAP3K1 rs889312 C allele. These findings suggest that genetic variants in the FGFR2 and MAP3K1 genes may contribute to genetic susceptibility to BC.     

Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry

Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case-control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04-1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10-1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00-1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.     

Association between polymorphisms within the susceptibility region 8q24 and breast cancer in a Chinese population

Recent publications have found associations between single-nucleotide polymorphisms (SNPs) in 8q24 and the risk of breast cancer (BC) in some populations, but the conclusions are inconsistent. In order to further investigate the association between variants in this region and BC risk in Chinese population, we conducted an independent hospital-based case–control study to discern the effects of these SNPs on BC risk. We genotyped three 8q24 SNPs (rs13281615, rs6983267, and rs9642880) in 485 cases and 530 cancer-free controls. The results indicated that the rs13281615 G allele significantly increased BC risk, with an odds ratio (OR) of 1.23 (95 % confidence interval (CI)?=?1.03–1.46) under the allelic model. Besides, stratification analysis reported that the significant association remained in the estrogen receptor (ER)+/progesterone receptor (PR)+ subgroup with a P value of 0.007 under the allelic model (OR?=?1.33, 95 % CI?=?1.08–1.63). For the rs9642880 variant, only a feeble association was observed for the GT genotype compared with the GG genotype (OR?=?1.33, 95 % CI?=?1.01–1.74). In addition, there was a negligible association between rs6983267 and BC risk in the ER?/PR? subgroup. However, no significant finding was observed in the overall participants. The findings suggested that polymorphisms in 8q24 may contribute to susceptibility to BC risk. However, functional studies are warranted to further elucidate the mechanisms of the association.     

Quantitative assessment of the effect of FGFR2 gene polymorphism on the risk of breast cancer

Fibroblast growth factor receptor 2 is a tyrosine kinase receptor that is a member of the family of individually distinct fibroblast growth factor receptors involved in cell proliferation, invasiveness, motility, and angiogenesis. Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent. After that, a number of studies reported that the rs2981582, rs1219648, and rs2420946 polymorphism in FGFR2 has been implicated in BC risk. However, studies on the association between these polymorphism and BC remain conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 46,747 cases and 87,342 controls from 16 published case–control studies was performed. Overall, significantly elevated BC risk was associated with rs2981582, rs1219648, and rs2420946 risk allele when all studies were pooled into the meta-analysis. Significant results were also observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the subgroup analysis by ethnicity, source of controls, significantly increased risks were found for these polymorphisms in all genetic model. In conclusion, this meta-analysis suggests that rs2981582, rs1219648, and rs2420946 polymorphisms in FGFR2 are associated with elevated BC risk.     

The Relationship Between Eight GWAS‐Identified Single‐Nucleotide Polymorphisms and Primary Breast Cancer Outcomes

Background.

Several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease-free survival (DFS) and overall survival (OS) rates.

Patients and Methods.

A cohort of 739 white women with early-stage breast cancer was genotyped for eight GWAS-identified SNPs (rs2981582, rs1219648 [FGFR2], rs3803662, rs12443621, rs8051542 [TOX3], rs999737 [RAD51L1], rs6504950 [17q23], and rs4973768 [3p24]). Relationships between SNPs and breast cancer outcomes were evaluated using Cox proportional hazard regression models. The cumulative effects of SNPs on breast cancer outcomes were assessed by computing the number of at-risk genotypes.

Results.

At a median follow-up of 121 months (range: 188–231 months) for survivors, 237 deaths (32%) and 186 breast cancer events (25%) were identified among the 739 patients. After adjusting for age, clinical stage, and treatment, rs12443621 (16q12; p = .03) and rs6504950 (17q23; p = .008) were prognostic for OS but not DFS. A higher risk for death was also found in the multivariable analysis of patients harboring three or four at-risk genotypes of the GWAS SNPs compared to patients carrying two or less at-risk genotypes (hazard ratio: 1.60, 95% confidence interval: 1.23–2.24; p = .0008).

Conclusion.

The study results suggest that previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), may influence breast cancer prognosis or comorbid conditions associated with overall survival. The precise molecular mechanisms through which these risk SNPs, as well as others that were not included in the analysis, influence clinical outcomes remain to be determined.     

Genetic variants in fibroblast growth factor receptor 2 (FGFR2) contribute to susceptibility of breast cancer in Chinese women

Fibroblast growth factor receptor 2 (FGFR2) belongs to the FGFR family, which plays an important role in cell growth, invasiveness, motility and angiogenesis. In human breast cancer, expression of FGFR2 is estrogen receptor (ER)-dependent and correlates with a lower rate of apoptosis. Recently, whole-genome association studies have identified several single-nucleotide polymorphisms (SNPs) of FGFR2 as novel breast cancer susceptibility loci. In the present study of 1049 breast cancer patients and 1073 cancer-free controls, we assessed whether polymorphisms of FGFR2 are associated with breast cancer risk in Chinese women and whether these associations are stronger in women with a reproductive history suggestive of greater exposure to endogenous estrogens. We genotyped three FGFR2 polymorphisms (rs2981582C/T, rs1219648A/G and rs2420946C/T) using the SNPstream 12-plex platform. Each of the three SNPs was significantly associated with increased breast cancer risk in a dose-dependent manner. Compared with women with 0-2 risk loci, those with 3 risk loci had a 1.36-fold increased odds of breast cancer (95% confidence interval = 1.13-1.62, P = 0.001). In stratified analyses, associations between the presence of 3 risk loci and breast cancer were stronger among women with ER- and/or progesterone receptor-positive cancers, premenopausal women and women with an older age at first live birth. Furthermore, there was a significant additive interaction between risk genotypes and menopausal status (P for multiplication interaction/additive interaction: 0.083/0.037). These findings indicate that genetic variants in FGFR2 may contribute to breast cancer occurrence in Chinese women, possibly through pathways related to estrogen and/or progesterone.     

Association of genetic variants at 8q24 with breast cancer risk.

Recent whole genome association studies of prostate, breast, and colorectal cancer have identified susceptibility loci on 8q24. We genotyped three variants associated with prostate cancer (rs10090154, rs13254738, and rs7000448), one associated with both prostate and colorectal cancer (rs6983267), and one associated with breast cancer (rs13281615) in a series of 1,499 breast cancer cases and 1,390 controls. 1,267 (85%) of the cases had two primary breast cancers. Our analysis provides further evidence of the relationship between rs13281615 and risk of breast cancer, with heterozygote odds ratio (OR) 1.30 95% confidence interval (CI) 1.09-1.54 and homozygote OR 1.52 (95% CI, 1.22-1.89; P trend = 0.00003), and confirms the prediction that the risk is substantially higher in this genetically enriched series (OR per allele, 1.24; 95% CI, 1.12-1.38) than in a large series of mainly unselected cases (reported OR per allele, 1.08; 95% CI, 1.05-1.11). We observed a protective effect of rs13254738 for breast cancer (allelic OR, 0.88; 95% CI, 0.78-0.98; P = 0.02), which is supported by the Cancer Genetic Markers of Susceptibility data (pooled allelic OR, 0.88; 95% CI, 0.81-0.96; P = 0.003). None of the other three single nucleotide polymorphisms, two associated with prostate (rs10090154 and rs7000448) and one with both prostate and colorectal cancers (rs6583267), was associated with breast cancer risk in our study. This evidence of a protective effect for breast cancer of one variant (rs13254738) that has been associated previously with a 1.25-fold increased risk of prostate cancer, with no effect for the two other variants, indicates that the effects of the risk alleles clustered at 8q24 are cancer site specific.     

FGFR2 is a breast cancer susceptibility gene in Jewish and Arab Israeli populations.

Genetic variation in FGFR2 is a newly described risk factor for breast cancer. We estimated the relative risk and contribution of FGFR2 polymorphisms to breast cancer risk in diverse ethnic groups within Jewish and other Middle Eastern populations. We genotyped four FGFR2 single nucleotide polymorphisms (SNP) and tested for association of these SNPs and haplotypes with breast cancer risk in a population-based case-control study of 1,529 women with breast cancer and 1,528 controls. We found significant associations between breast cancer risk and all four studied SNPs in FGFR2 (P trend for all SNPs < 0.0001). In ethnicity-specific analysis, all four SNPs were significantly associated with breast cancer risk in Ashkenazi and Sephardi Jews, with a similar but not significant trend in Arabs. Haplotype analysis identified five common haplotypes (>1%). The previously described AAGT risk haplotype was significantly associated with breast cancer risk in Ashkenazi [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.07-1.45; P = 0.0059] and Sephardi Jews (OR, 1.46; 95% CI, 1.17-1.80; P = 0.0006) compared with the reference GGAC haplotype. The AAAC haplotype was significantly associated with breast cancer risk in Sephardi Jews (OR, 1.97; 95% CI, 1.16-3.35; P = 0.0125) but not in Ashkenazi Jews (OR, 0.83; 95% CI, 0.41-1.62; P = 0.5613) or in Arabs (OR, 1.31; 95% CI, 0.80-2.14; P = 0.2881). Genetic variation in FGFR2, identified by rs1219648, may account for a substantial fraction of breast cancer in Arab (12%), Ashkenazi (15%), and Sephardi Jewish (22%) populations. The identification of population-specific risk haplotypes in FGFR2 is likely to help identify causal variants for breast cancer.     

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.     

贵州汉族人群乳腺癌与FGFR2 rs1219648多态性相关性研究*

目的:探讨贵州汉族人群成纤维细胞生长因子受体2（fibroblast growth factor receptor 2,FGFR2）基因单核苷酸多态性与女性乳腺癌易感性之间的相关性。方法:运用聚合酶链反应- 序列特异性引物（PCR-SSP ）方法分析106 例女性乳腺癌患者和116 例正常对照女性FGFR2 基因内含子5 rs 1219648 多态性的分布情况。结果:乳腺癌组FGFR2 基因单核苷酸多态性位点rs 1219648 的基因型（TT,TC,CC）频率分别为50.00% 、25.47% 和24.53% ,对照组分别为29.31% 、48.28% 和22.41% ,乳腺癌组与对照组T 等位基因频率分别为62.74% 和53.45% ,C 等位基因频率分别为37.26% 和46.55% ,FGFR2 rs 1219648 基因型频率及等位基因频率在乳腺癌组与对照组中的分布差异均有统计学意义（P<0.05）。 结论:FGFR2 基因内含子5 的单核苷酸位点rs 1219648 多态性与乳腺癌可能具有相关性。携带FGFR2 rs 1219648 的TT等位基因型的人群可能更易患乳腺癌。      

Genetic variants at chromosome 9p21, 10p15 and 10q22 and breast cancer susceptibility in a Chinese population

A recent genome-wide association study (GWAS) has identified a new subset of breast cancer susceptibility loci on chromosomes 9, 10, and 11 in populations of European descent. However, because of the genetic heterogeneity, the role of these loci in non-European descent populations is still unclear. To evaluate the relationships between genetic variants in these regions identified by GWAS and breast cancer risk in Chinese women, we genotyped four common SNPs at 9p21(rs1011970 and rs10757278), 10p15 (rs2380205), and 10q22 (rs1250009) in a two-stage case-control study with a total of 1792 breast cancer cases and 1,867 controls. We found that rs1250009 at 10q22 was consistently associated with risk of breast cancer in stage 1 and stage 2, with a per-allele OR of 1.13 (95% CI 1.02-1.25) after two stages combined (P = 0.023). However, no significant associations were observed between the other three SNPs and breast cancer risk. Our results suggest that the genetic variants at 10q22 may play an important role in breast cancer development in Chinese women, and rs1250009 may be a candidate marker for breast cancer susceptibility.