Abstract
Background
As breast and ovarian cancers may have similar etiologies, this study aimed to evaluate the hypothesis that breast cancer shares common genetic susceptibility variants with ovarian cancer.
Methods
Ten genetic variants in 9 loci were previously identified to be associated with ovarian cancer risk among Caucasian women; an additional 353 variants in high linkage disequilibrium (r2≥0.6) among Han Chinese were identified. Data were available from the Affymetrix Genome Wide Array (6.0) or MACH imputation for 25 and 78 common genetic variants (minor allele frequency (MAF) ≥0.05), respectively. Associations with breast cancer risk were evaluated by additive logistic regression models among 2, 918 breast cancer cases and 2, 324 controls.
Results
No associations with breast cancer risk were evident for 103 ovarian cancer susceptibility variants in five loci. Four loci were not evaluated, as they included only rare variants (MAF<0.05).
Conclusions
Ovarian cancer susceptibility variants identified in Caucasian women were not associated with breast cancer risk among 5, 242 Chinese women.
Impact
These findings suggest that breast and ovarian cancer may not share common susceptibility variants among Chinese women.
Keywords: Genetic Variants, Breast Cancer, Ovarian Cancer
Introduction
Breast and ovarian cancer are hormonally driven, and have similar etiologies, including inherited mutations in BRCA1 or BRCA2 (1). We hypothesized that these cancers may share common genetic susceptibility variants. To date, genome-wide association studies (GWAS) have identified 10 ovarian cancer susceptibility variants; these studies have included only Caucasian women (2). To the best of our knowledge, no previous studies have evaluated the association between ovarian cancer susceptibility variants and breast cancer risk.
Methods
Study population
This analysis included a total of 2, 918 breast cancer cases from the Shanghai Breast Cancer Study (SBCS), Shanghai Breast Cancer Survival Study (SBCSS), and the Shanghai Women’s Health Study (SWHS), and 2, 324 controls from SBCS and SWHS. Detailed study design and data collection procedures have been described previously (3, 4). Study protocols were approved by the relevant review boards of all institutions, and informed consent was obtained from all participants.
Variant Selection, Genotyping, and Imputation
Genetic variants associated with ovarian cancer susceptibility were identified in the GWAS catalog (2). Linkage disequilibrium (LD) among Han Chinese was assessed using SNAP (5). Independence of loci was defined using an r2≥0.6. Genotyping and imputation methods and quality control have been previously described (3). Briefly, genotyping data was from the Affymetrix Genome Wide Array (6.0); only variants with quality control values ≥0.95 were included. Imputation was conducted using MACH; only data with quality scores (RSQ >0.3 (mean 0.98, median 1.00) were included. Further, only common genetic variants (MAF≥0.05) were evaluated.
Statistical Analysis
Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between breast cancer risk and genetic variants using additive effect models that included adjustment for age and education. Effect measure modification was evaluated with stratified analyses and the likelihood ratio test. Quanto was used for power calculations (6). All other analyses were conducted with SAS version 9.2 (SAS institute Inc., Cary, North Carolina). All statistical tests were two-tailed, and statistical significance was defined by a p-value ≤0.05.
Results
As shown in Figure 1, in addition to the 10 original ovarian cancer susceptibility variants in the GWAS catalog, 353 additional variants in linkage disequilibrium (LD; r2≥0.6) among Han Chinese were identified. Genotyped (N=51) or imputed (N=141) data was available for 192 variants; however, 89 were excluded from analysis (MAF<0.05). Thus, 25 genotyped and 78 imputed common (MAF≥0.05) variants, including 5 original and 98 additional ovarian cancer susceptibility variants were evaluated. No associations with breast cancer risk in additive effect models adjusted for age and education were identified (Full results in Supplementary Table 1; summary findings in Table 1). These 103 variants represent five of the nine loci identified. Three loci were not evaluated as they included only uncommon variants (MAF<0.05). One locus was not evaluated as it included only one variant (rs8170), for which neither genotyping nor imputed data was available. However, according to HapMap, this variant also has a very low MAF among Han Chinese (0.004).
Figure 1.
Study Design Schematic
Table 1.
Ovarian Cancer Susceptibility Variants and Breast Cancer Risk
| Breast Cancer Risk |
|||||||
|---|---|---|---|---|---|---|---|
| Locus | Variant 1 | Location (HG18) | Data 2 | Alleles 3 | MAF3 | OR (95% CI) | P value |
| 1 | rs7521902 | ch1: 22363311 | Imputed | A/c | 47.9 | 1.01 (0.93–1.09) | 0.883 |
| 2 | rs2072590 | ch2: 176750879 | Imputed | C/a | 25.2 | 1.07 (0.98–1.17) | 0.153 |
| 3 | rs2665390 | ch3: 157880443 | Imputed | T/c | LT 5% | NA | NA |
| 4 | rs10088218 | ch8: 129613131 | Genotyped | G/a | LT 5% | NA | NA |
| 5 | rs3814113 | ch9: 16905021 | Not Available | T/c | NA | NA | NA |
| 5 | rs7032221 | ch9: 16904895 | Genotyped | A/g | 26.1 | 0.99 (0.90–1.08) | 0.745 |
| 6 | rs12794435 | ch11: 25164280 | Not Available | A/g | NA* | NA | NA |
| 7 | rs2084881 | ch17: 43712119 | Imputed | G/a | 13.7 | 1.06 (0.94–1.18) | 0.345 |
| 7 | rs9303542 | ch17: 43766499 | Imputed | A/g | 14.7 | 0.95 (0.85–1.07) | 0.416 |
| 8 | rs8170 | ch19: 17389704 | Not Available | A/g | NA** | NA | NA |
| 9 | rs2363956 | ch19: 17255124 | Imputed | T/g | 31.3 | 0.97 (0.88–1.05) | 0.423 |
Original GWAS Variants in Bold
Imputed by MACH 1.0 or Genotyped by Affymetrix Genome Wide Array (6.0) among 5,242 Chinese women
Major and minor (M/m) alleles and minor allele frequency (MAF) based on genotypes among 2,324 controls
Four SNPs in perfect LD (r2, D' = 1) had MAF LT 5%
MAF LT 5% in CHB according to HapMap; no variants in LD identified by SNAP
Stratified analyses by menopausal status, ER, PR, and tumor stage were conducted to evaluate effect measure modification. Two variants in locus 7 (rs7207826 and rs136870) were associated with increased risk among ER+ tumors, while one variant in locus 5 (rs1416745) was associated with a decreased risk among late stage tumors. However, these nominally significant associations did not withstand correction for multiple comparisons.
Discussion
In this large, population-based, case-control study, we did not observe any significant associations between ovarian cancer susceptibility variants and breast cancer risk. To the best of our knowledge, this is the first study aimed to evaluate the association between ovarian cancer susceptibility variants and breast cancer risk. Two studies have evaluated the association between breast cancer susceptibility variants and ovarian cancer risk (7, 8). The first included 7 variants and found no association (7). The second included 11 variants, and found a significant association between rs4954956 and ovarian cancer risk (OR: 1.07; 95% CI: 1.01–1.13) (8).
Strengths of this study include the large study population, the use of both genotyped and imputed data to maximize genetic coverage, and sufficient power to detect associations for common genetic variants. For a variant with a MAF of 20%, this study had greater than 78% power to detect an OR of 1.15. A limitation of this study is that rare variants (MAF<5%) were not evaluated, as very large studies are needed for adequate power. Notably, of the ten original ovarian cancer susceptibility variants, four had low MAFs among Han Chinese (rs2665390 rs10088218 rs12794435 and rs8170). Therefore, differences in the genetic architecture of ovarian cancer between Chinese and Caucasian populations may influence our results. Notably, all ten ovarian cancer susceptibility variants identified to date are from studies of Caucasian women.
In conclusion, we found no evidence for an association between ovarian cancer susceptibility variants and breast cancer risk among Chinese women. Resequencing and fine-mapping of ovarian cancer susceptibility loci for evaluation of rare variants may be necessary to fully evaluate associations with breast cancer risk.
Supplementary Material
Acknowledgments
The authors wish to thank the participants and research staff of the SBCS, SBCSS, and the SWHS for their contributions and commitment to this project, Regina Courtney for DNA preparation, and Samantha Stansel for assistance with the submission of this manuscript.
Grant Support
This research was supported by grants from the NIH/NCI, including R01CA124558 and R01CA64277, and R01CA90899. Dr. Beeghly-Fadiel is supported in part by a grant from the NIH/NICHHD (5K12 HD043483-09). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. DNA extraction and genotyping was conducted at the Survey and Biospecimen and Functional Genomic Resource Laboratory, at the Vanderbilt Microarray Shared Resource, which is supported in part by the Vanderbilt Ingram Center (P30CA68485). Xiangyu Ma (from the Third Military Medical University in China) is supported by the China Scholarship Council (CSC) while the author is visiting the Vanderbilt Epidemiology Center in the United States.
Footnotes
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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