Alicia Beeghly-Fadiel

Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence

BACKGROUND More than 1000 reports have been published in the past two decades on associations between variants in candidate genes and risk of breast cancer. Results have been generally inconsistent. We did a literature search and meta-analyses to provide a synopsis of the current understanding of the genetic architecture of breast-cancer risk. METHODS A systematic literature search for candidate-gene association studies of breast-cancer risk was done in two stages, using PubMed on or before Feb 28, 2010. A total of 24,500 publications were identified, of which 1059 were deemed eligible for inclusion. Meta-analyses were done for 279 genetic variants in 128 candidate genes or chromosomal loci that had at least three data sources. Variants with significant associations by meta-analysis were assessed using the Venice criteria and scored as having strong, moderate, or weak cumulative evidence for an association with breast-cancer risk. FINDINGS 51 variants in 40 genes showed significant associations with breast-cancer risk. Cumulative epidemiological evidence of an association was graded as strong for ten variants in six genes (ATM, CASP8, CHEK2, CTLA4, NBN, and TP53), moderate for four variants in four genes (ATM, CYP19A1, TERT, and XRCC3), and weak for 37 variants. Additionally, in meta-analyses that included a minimum of 10,000 cases and 10,000 controls, convincing evidence of no association with breast-cancer risk was identified for 45 variants in 37 genes. INTERPRETATION Whereas most genetic variants assessed in previous candidate-gene studies showed no association with breast-cancer risk in meta-analyses, 14 variants in nine genes had moderate to strong evidence for an association. Further evaluation of these variants is warranted. FUNDING US National Cancer Institute.

Association of Obesity-related Genetic Variants With Endometrial Cancer Risk: A Report From the Shanghai Endometrial Cancer Genetics Study

Obesity is a well-established risk factor for endometrial cancer, the most common gynecologic malignancy. Recent genome-wide association studies (GWAS) have identified multiple genetic markers for obesity. The authors evaluated the association of obesity-related single nucleotide polymorphisms (SNPs) with endometrial cancer using GWAS data from their recently completed study, the Shanghai Endometrial Cancer Genetics Study, which comprised 832 endometrial cancer cases and 2,049 controls (1996-2005). Thirty-five SNPs previously associated with obesity or body mass index (BMI; weight (kg)/height (m)(2)) at a minimum significance level of ≤5 × 10(-7) in the US National Human Genome Research Institutes GWAS catalog (http://genome.gov/gwastudies) and representing 26 unique loci were evaluated by either direct genotyping or imputation. The authors found that for 22 of the 26 unique loci tested (84.6%), the BMI-associated risk variants were present at a higher frequency in cases than in population controls (P = 0.0003). Multiple regression analysis showed that 9 of 35 BMI-associated variants, representing 7 loci, were significantly associated (P ≤ 0.05) with the risk of endometrial cancer; for all but 1 SNP, the direction of association was consistent with that found for BMI. For consistent SNPs, the allelic odds ratios ranged from 1.15 to 1.29. These 7 loci are in the SEC16B/RASAL, TMEM18, MSRA, SOX6, MTCH2, FTO, and MC4R genes. The associations persisted after adjustment for BMI, suggesting that genetic markers of obesity provide value in addition to BMI in predicting endometrial cancer risk.

Genetic polymorphisms in the MMP-7 gene and breast cancer survival.

Matrix metalloproteinase‐7 (MMP‐7) is a small secreted proteolytic enzyme with broad substrate specificity. Its expression has been shown to be associated with tumor invasion, metastasis and survival for a variety of cancers. We systematically evaluated single nucleotide polymorphisms (SNPs) in MMP‐7 in relation to breast cancer survival in a large follow‐up study. Included were 1,079 breast cancer cases that were recruited from 1996 to 1998 and followed for a median of 7.1 years as part of the Shanghai Breast Cancer Study (SBCS). Eleven SNPs, including 2 known functional promoter SNPs, were analyzed using the Affymetrix Targeted Genotyping System. Associations with survival were evaluated by Cox proportional hazards regression and Kaplan‐Meier functions. Statistically significant associations with disease‐free and/or overall survival (OS) were found for 5 polymorphisms; these associations were explained primarily by 2 SNPs (rs11568818 and rs11225297) that were in high linkage disequilibrium (LD) with the others. Patients homozygous for the rs11568818 rare allele (G) had a significantly worse prognosis (OS HR: 6.7, 95% CI: 2.4–18.6) than patients homozygous for the common allele (A). Significantly improved survival was seen for patients with the rs11225297 T allele, and this association occurred in a dose‐response manner; patients with AT (OS HR: 0.7, 95% CI: 0.5–0.9) and TT (OS HR: 0.3, 95% CI: 0.1–0.8) fared better than patients with AA (p‐value for trend: 0.001). Thus, common MMP‐7 genetic polymorphisms were found to be significant determinants of survival among Chinese women with breast cancer.

Polymorphisms in tissue inhibitors of metalloproteinases-2 and -3 and breast cancer susceptibility and survival.

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases which are involved in normal cellular processes and also in cancer development and progression. The purpose of this study was to evaluate polymorphisms in the TIMP‐2 and TIMP‐3 genes for their associations with breast cancer susceptibility and survival. Using data from the Shanghai Breast Cancer Study, 19 SNPs for each gene were evaluated for associations with breast cancer risk among 1,062 cases and 1,069 controls; associations with disease‐free and overall survival were evaluated among the cases. For TIMP‐2, women with the rs7501477 TT genotype were 3 times more likely to be breast cancer cases than women with the CC genotype (OR: 2.9, 95% CI: 1.2–7.0). For TIMP‐3, women with the rs9609643 AA genotype were 60% less likely to be breast cancer cases than women with the GG genotype (OR: 0.4, 95% CI: 0.2–1.0), whereas women with the rs8136803 TT genotype were 5 times more likely to be cases than women with the GG genotype (OR: 5.1, 95% CI: 1.1–24.3). Further, breast cancer cases with rs8136803 TT were almost 4 times more likely to have decreased disease‐free survival (HR: 3.9, 95% CI: 1.4–10.6) and had a trend toward decreased overall survival (HR: 1.9, 95% CI: 0.6–6.1). An important study limitation was that these 3 SNPs (rs7501477, rs9609643, rs8136803) had low minor allele frequencies which resulted in small numbers of homozygote individuals. Genetic variation in the TIMP‐2 and TIMP‐3 genes may contribute to individual differences in breast cancer susceptibility and survival.

Anthropometric measures and epithelial ovarian cancer risk among Chinese women: results from the Shanghai Women’s Health Study

Background:Studies of anthropometric measures and ovarian cancer risk have predominantly included women of European descent with mixed findings.Methods:Data from the prospective Shanghai Women’s Health Study (SWHS) were used to evaluate associations between anthropometric measures and risk of epithelial ovarian cancer (EOC). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression.Results:A total of 152 EOC cases occurred among 70 258 women. Increasing quartiles of weight, hip circumference, and weight gain during adulthood were associated with significantly increased EOC risks. Body mass index (BMI) was also associated; overweight (25⩽BMI<29.99) and obese women (BMI⩾30.0) had significantly increased risks (HR: 1.49, 95% CI: 1.05, 2.13, and HR: 2.42, 95% CI: 1.37, 4.28, respectively). No significant associations were observed for height, waist circumference, waist-to-hip ratio (WHR), and waist-to-height ratio (WHER).Conclusion:Results from this large prospective study of Chinese women support the hypothesis that general adiposity contributes to the aetiology of ovarian cancer.

Gene-Environment Interactions for Breast Cancer Risk Among Chinese Women: A Report From the Shanghai Breast Cancer Genetics Study

Genome-wide association studies have identified approximately 20 susceptibility loci for breast cancer. A cumulative genetic risk score (GRS) was constructed from 10 variants with replicated associations among participants of the Shanghai Breast Cancer Genetics Study (Shanghai, China, 1996-1998 and 2002-2005). Interactions between the GRS and 11 breast cancer risk factors were evaluated. Among the 6,408 study participants, no evidence of effect modification was found with the GRS for age at menarche, age at menopause, age at first live birth/parity, total months of breastfeeding, family history of breast cancer, history of benign breast disease, hormone replacement therapy, body mass index, waist/hip ratio, or regular physical activity. The effect of the GRS was least homogeneous by duration of menstruation; further analysis indicated a nominally significant interaction with one genetic variant. The mitochondrial ribosomal protein S30 gene (MRPS30) rs10941679 was associated with breast cancer risk only among women with more than 30 years of menstruation (odds ratio = 1.15, 95% confidence interval: 1.05, 1.26). Although this multiplicative interaction reached a nominal significance level (P = 0.037), it did not withstand correction for multiple comparisons. In conclusion, this study revealed no apparent interactions between genome-wide association study-identified genetic variants and breast cancer risk factors in the etiology of this common cancer.

Genetic Variation in VEGF Family Genes and Breast Cancer Risk: A Report from the Shanghai Breast Cancer Genetics Study

Background: In addition to mediating aspects of physiologic and pathologic angiogenesis, the VEGF family also contributes to carcinogenesis. Methods: We comprehensively characterized genetic variation across four VEGF family genes and evaluated associations with breast cancer risk with odds ratios (OR) and 95% CIs for participants of the two-stage case–control Shanghai Breast Cancer Genetics Study (SBCGS). Stage 1 evaluated 200 single nucleotide polymorphisms (SNP) across two VEGF ligands (VEGFA and VEGFC) and two VEGF receptors (FLT1/VEGFR1 and KDR/VEGFR2) among 2,079 cases and 2,148 controls. Five SNPs with promising associations were assessed in stage 2 among 4,419 cases and 1,851 controls. Results: Two SNPs were consistently associated with breast cancer risk across our two study stages and were significant in combined analyses. Compared with FLT1 rs9551471 major allele homozygotes (AA), reduced risks were associated with AG (OR = 0.92, 95% CI: 0.84–1.00) and GG (OR = 0.78, 95% CI: 0.64–0.95) genotypes (Ptrend = 0.005). Compared with VEGFA rs833070 major allele carriers (CC or CT), increased risk was associated with TT genotypes (OR = 1.26, 95% CI: 1.05–1.52, P = 0.016). Conclusion: Results from our study indicate that common genetic variation in VEGFA and FLT1 (VEGFR1) may contribute to breast cancer susceptibility. Impact: Our findings provide clues for future studies on VEGF family genes in relation to cancer susceptibility and survival. Cancer Epidemiol Biomarkers Prev; 20(1); 33–41; ©2011 AACR.

Matrix Metalloproteinase-2 Polymorphisms and Breast Cancer Susceptibility

Matrix metalloproteinase-2 (MMP-2) is a well-known mediator of cancer metastasis but is also thought to be involved in several aspects of cancer development, including cell growth and inflammation. We comprehensively characterized genetic variation across the MMP-2 gene and evaluated associations with breast cancer risk using a two-phase (phase 1 and phase 2) study design. A total of 39 polymorphisms were genotyped among 6,066 Chinese women participating in the Shanghai Breast Cancer Study, a population-based case-control study. Two MMP-2 promoter polymorphisms were found to have consistent results between phase 1 and phase 2 participants, and to be significantly associated with breast cancer risk among all genotyped participants. Minor allele homozygotes for rs11644561 (G/A) were found to have a decreased risk of breast cancer [odds ratio (OR), 0.6; 95% confidence interval (CI), 0.3-1.0] compared with major allele homozygotes, as were minor allele homozygotes for rs11643630 (T/G) compared with major allele homozygotes (OR, 0.8; 95% CI, 0.7-1.0). When analyzed together, a rare haplotype (4.4%) with both rs11644561 A and rs11643630 G was found to have a significantly reduced risk of breast cancer (OR, 0.6; 95% CI, 0.4-0.8). In addition, rare allele homozygotes for rs243865 (−1306 C/T) tended to have an increased risk of breast cancer (OR, 1.4; 95% CI, 0.9-2.4). Together, these findings support a role for MMP-2 genetic variation in breast cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1770–6)

Evaluation of Functional Genetic Variants for Breast Cancer Risk: Results From the Shanghai Breast Cancer Study

In previous studies among 1,144 cases and 1,256 controls recruited in stage 1 of the Shanghai Breast Cancer Study (SBCS I; 1996-1998), 18 known or potentially functional single nucleotide polymorphisms (SNPs) in 16 genes were found to be associated with breast cancer risk. The authors evaluated these associations among 1,918 cases and 1,819 controls recruited in stage 2 of the SBCS (SBCS II; 2002-2005) using genetic effect models and subgroup analyses predetermined from SBCS I results. Five SNPs (AHR rs2066853, ATM rs1003623, ESR1 rs2234693, GSTP1 rs1695, and SHBG rs6259) showed generally consistent results in SBCS I and SBCS II and statistically significant associations with breast cancer risk in combined analyses, mostly in subgroups defined by age or menopausal status. Further, the relation between breast cancer risk and SHBG rs6259 was found to vary by body mass index (weight (kg)/height (m)(2)) (P for interaction = 0.003). The strongest reduction in risk associated with SHBG rs6259 was found for lean (body mass index <23) postmenopausal minor allele carriers (odds ratio = 0.6, 95% confidence interval: 0.5, 0.8; P = 4.6 × 10(-4)). This biologically plausible and highly significant finding provides strong evidence for a true association among Asian women. This study also highlights the value of gene-environment interaction analyses in evaluating genetic factors for complex diseases.

Pathway analyses identify TGFBR2 as potential breast cancer susceptibility gene: results from a consortium study among Asians

Background: The TGF-β signaling pathway plays a significant role in the carcinogenic process of breast cancer. Methods: We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multistage, case–control study among Asian women. Results: In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies ≥ 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was carried out among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (stage III). Pooled analysis of all data indicated that minor allele homozygotes (GG) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared with major allele carriers (AG or AA; OR, 0.76; 95% CI, 0.65–0.89; P = 8.42 × 10−4). Conclusion: These findings support a role for common genetic variation in TGF-β signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility. Impact: These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets. Cancer Epidemiol Biomarkers Prev; 21(7); 1176–84. ©2012 AACR.