1 fgfr2 genetic polymorphisms modify the association of oral contraceptive use with the risk of...
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FGFR2 Genetic Polymorphisms Modify the Association of Oral Contraceptive Use with the Risk of Breast Cancer in
Chinese Women
徐 望 红[email protected]
复旦大学公共卫生学院流行病学教研室上海市肿瘤研究所流行病室
研 究 背 景• Breast cancer
– most common cancer in women
– a hormone-related malignancy
– a complex and multi-factorial disease
– a result of interplays between different exposures and host susceptibility
• Oral contraceptives (OC)– exogenous hormones – classified as group 1 carcinogens Schneider HP, et al. Climacteric. 2005;8:311-6. Cogliano V, et al. Lancet Oncol. 2005;6:552-3.
– consistent positive association with breast cancer risk in western populations
Kahlenborn C, et al. Mayo Clin Proc. 2006;81(10):1290-302. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1996;347:1713-27.
– null association in Asian populations Kawai M, et al.Cancer Causes Control. 2010;21(1):135-45. Dorjgochoo T, et al. Int J Cancer. 2009;124(10):2442-9. Ursin G, et al. Am J Epidemiol. 1999;150(6):561-7. Huang CS, et al. Br J Cancer. 1999;80(11):1838-43. Yuan JM, et al. Cancer Res. 1988;48(7):1949-53.
• FGFR2 gene – well recognized breast cancer susceptibility gene
– multiple SNPs in association with breast cancer risk across ethnic groups
– a sex hormone-dependent role of FGFR2 gene in breast cancer
FGFR2 genetic polymorphisms may modify the
association between OC use and breast cancer
risk in Chinese women
研 究 假 设
材 料 与 方 法A two-stage population-based case-control study
SBCS-I (1996-1998)1459 of 1602 newly-diagnosed breast cancer cases at age 25-65 1556 of 1724 eligible controls 1193 (82%) cases and 1310 (84%) controls donated a blood sample
SBCS-II (2002-2005)1989 incident cases (83.7%) aged 25 to 70 years old1989 population controls (70.4%)969 (48.7%) cases and 975 (49.0%) controls provided a blood sample
Epidemiological dataDemographic characteristicsMenstrual and reproductive historyOCs use and postmenopausal HRTPrior disease historyPhysical activityTobacco and alcohol use Diet Weight historyFamily history of cancerMeasured body weight, height, and circumferences of the
waist and hips
Genotyping dataFrom a GWAS scan covering about 120 kb of the FGFR2
gene plus 10 kb region of its 5' upstream and 5 kb region of
its 3' downstream
Genotyping conducted using Affymetrix Genome-Wide
Human SNP array 6.0 following Affymetrix’s protocol 42 SNPs genotyped 19 had minor allele frequency of > 0.05
Imputation conducted using the program MACH 93 imputed SNPs 26 SNPs had minor allele frequency of > 0.05 and average imputation
quality score of > 0.90.
结 果
CharacteristicsStage I Study Stage II Study
Cases(n=1104)
Controls(n=1109)
P valueCases
(n=969 )Controls(n=975)
P value
Age (yrs), mean ± SD 47.6 ± 8.0 47.7 ± 8.3 0.75 51.4 ± 8.3 51.4 ± 8.3 0.91
Education, %
Elementary school or below 12.4 15.2 7.1 11.8
Middle school 44.3 42.7 42.9 42.0
High school 31.3 31.9 37.7 36.9
College or above 12.1 10.3 0.17 12.3 9.3 0.0016
Breast cancer in 1st degree relatives, % 3.4 2.6 0.31 5.7 3.4 0.02
Ever had breast fibroadenoma, % 9.5 4.6 <0.0001 10.0 6.5 0.0051
Age at menarche (yrs.), mean ± SD 14.5 ± 1.6 14.8 ± 1.7 0.0002 14.5 ± 1.7 14.7 ± 1.8 0.0037
Ever had a live birth, % 95.1 96.2 0.20 95.2 96.1 0.30
Number of live births, mean ± SD 1.5 ± 0.8 1.5 ± 0.9 0.15 1.3 ± 0.7 1.4 ± 0.8 0.005
Age at first live birth (yrs), mean ± SD 26.8 ± 4.1 26.3 ± 3.8 0.003 26.1 ± 3.7 25.7 ± 3.8 0.03
Post-menopausal, % 32.8 36.6 0.06 45.5 47.1 0.49
Age at menopause (yrs.), mean ± SD 48.1 ± 4.7 47.4 ± 5.0 0.04 48.7 ± 4.4 48.0 ± 4.5 0.03
Oral contraceptive use, % 22.1 22.2 0.95 18.1 18.5 0.82
Duration of OC use, mean ± SD 8.6 ± 31.4 9.4 ± 32.9 0.52 8.3 ± 31.6 7.5 ± 28.1 0.56
HRT use among postmenopausal women, % 3.1 5.0 0.18 8.4 4.6 0.02
Physical active in past 10 years, % 19.2 26.3 <0.0001 31.8 34.7 0.18
BMI (kg/m2), mean ± SD 23.6 ± 3.4 23.3 ± 3.4 0.02 24.0 ± 3.3 23.4 ± 3.3 <0.0001
a From χ2 test (categorical variables) or t test (continuous variables).
Table 1. Comparison of demographic characteristics between breast cancer
cases and controls, the Shanghai Breast Cancer Study
Sex hormones use Cases/Controls Adjusted OR (95%CI)Oral contraceptives use
Never 1654/1657 1.00Ever 419/426 0.98(0.83-1.14)
Type of OC usedNever 1654/1657 1.00Progesterone plus estrogen 328/324 1.06(0389-1.26)Progesterone only 42/52 0.86(0.57-1.31)Estrogen only 24/30 0.80(0.46-1.38)Others 25/20 1.30(0.72-2.37)
Duration of OC use Never 1654/1657 1.00
<18 months 208/225 0.95(0.77-1.16) ≥ 18 months 211/201 1.12(0.90-1.38)
P for trend=0.48HRT use (postmenopausal women only)
Never 753/822 1.00Ever 48/41 1.14(0.74-1.77)
Table 2. Association of sex hormones use and breast cancer risk among Chinese women, the Shanghai Breast Cancer Study
OR: adjusted for age, educational levels, age at menarche, menopausal status, breast cancer in 1st-degree relatives, number of live births and body mass index.
All subjects Non-OC users OC-users P for interaction
rs10749418
rs1649161
rs1649204
rs1047057
rs1649202
rs2556537
rs2278202
rs7090018
rs2912759
rs11199991
rs2912760
rs3750813
rs2981457
rs7073360
rs3135749
rs3135747
rs755793
rs3135739
rs3135737
rs3135736
rs12245334
rs9888022
rs2303568
rs2912787
rs2981449
rs3135730
rs2981432
rs10736303
rs9787582
rs11200014
rs1078806
rs2981575
rs1219648
rs1219643
rs2912774
rs2936870
rs17102287
rs2860197
rs2420946
rs2162540
rs2981582
rs2981581
rs3135715
rs7899765
rs1219627
ID
Study
1.4 .6 .8 1 1.21.41.61.8 2 2.22.42.62.8 3 3.23.4
All subject
rs10749418
rs1649161
rs1649204
rs1047057
rs1649202
rs2556537
rs2278202
rs7090018
rs2912759
rs11199991
rs2912760
rs3750813
rs2981457
rs7073360
rs3135749
rs3135747
rs755793
rs3135739
rs3135737
rs3135736
rs12245334
rs9888022
rs2303568
rs2912787
rs2981449
rs3135730
rs2981432
rs10736303
rs9787582
rs11200014
rs1078806
rs2981575
rs1219648
rs1219643
rs2912774
rs2936870
rs17102287
rs2860197
rs2420946
rs2162540
rs2981582
rs2981581
rs3135715
rs7899765
rs1219627
ID
Study
.58
.05
.05
.05
.31
.05
.16
.59
.49
.19
.09
.19
.77
.02
.02
.02
.02
.03
.03
.03
.03
.03
.01
.21
.67
.03
.97
.15
.11
.07
.02
.2
.57
.14
.49
.34
.08
.38
.37
.46
.07
.31
.35
.3
.13
p
.58
.05
.05
.05
.31
.05
.16
.59
.49
.19
.09
.19
.77
.02
.02
.02
.02
.03
.03
.03
.03
.03
.01
.21
.67
.03
.97
.15
.11
.07
.02
.2
.57
.14
.49
.34
.08
.38
.37
.46
.07
.31
.35
.3
.13
p
1.4 .6 .8 1 1.21.41.61.8 2 2.22.42.62.8 3 3.23.4
Ever
rs10749418
rs1649161
rs1649204
rs1047057
rs1649202
rs2556537
rs2278202
rs7090018
rs2912759
rs11199991
rs2912760
rs3750813
rs2981457
rs7073360
rs3135749
rs3135747
rs755793
rs3135739
rs3135737
rs3135736
rs12245334
rs9888022
rs2303568
rs2912787
rs2981449
rs3135730
rs2981432
rs10736303
rs9787582
rs11200014
rs1078806
rs2981575
rs1219648
rs1219643
rs2912774
rs2936870
rs17102287
rs2860197
rs2420946
rs2162540
rs2981582
rs2981581
rs3135715
rs7899765
rs1219627
ID
Study
1.4 .6 .8 1 1.21.41.61.8 2 2.22.42.62.8 3 3.23.4
All subject
rs10749418
rs1649161
rs1649204
rs1047057
rs1649202
rs2556537
rs2278202
rs7090018
rs2912759
rs11199991
rs2912760
rs3750813
rs2981457
rs7073360
rs3135749
rs3135747
rs755793
rs3135739
rs3135737
rs3135736
rs12245334
rs9888022
rs2303568
rs2912787
rs2981449
rs3135730
rs2981432
rs10736303
rs9787582
rs11200014
rs1078806
rs2981575
rs1219648
rs1219643
rs2912774
rs2936870
rs17102287
rs2860197
rs2420946
rs2162540
rs2981582
rs2981581
rs3135715
rs7899765
rs1219627
ID
Study
1.4 .6 .8 1 1.21.41.61.8 2 2.22.42.62.8 3 3.23.4
Never
rs1 0 7 4 9 4 1 8
rs1 6 4 9 1 6 1
rs1 6 4 9 2 0 4
rs1 0 4 7 0 5 7
rs1 6 4 9 2 0 2
rs2 5 5 6 5 3 7
rs2 2 7 8 2 0 2
rs7 0 9 0 0 1 8
rs2 9 1 2 7 5 9
rs1 1 1 9 9 9 9 1
rs2 9 1 2 7 6 0
rs3 7 5 0 8 1 3
rs2 9 8 1 4 5 7
rs7 0 7 3 3 6 0
rs3 1 3 5 7 4 9
rs3 1 3 5 7 4 7
rs7 5 5 7 9 3
rs3 1 3 5 7 3 9
rs3 1 3 5 7 3 7
rs3 1 3 5 7 3 6
rs1 2 2 4 5 3 3 4
rs9 8 8 8 0 2 2
rs2 3 0 3 5 6 8
rs2 9 1 2 7 8 7
rs2 9 8 1 4 4 9
rs3 1 3 5 7 3 0
rs2 9 8 1 4 3 2
rs1 0 7 3 6 3 0 3
rs9 7 8 7 5 8 2
rs1 1 2 0 0 0 1 4
rs1 0 7 8 8 0 6
rs2 9 8 1 5 7 5
rs1 2 1 9 6 4 8
rs1 2 1 9 6 4 3
rs2 9 1 2 7 7 4
rs2 9 3 6 8 7 0
rs1 7 1 0 2 2 8 7
rs2 8 6 0 1 9 7
rs2 4 2 0 9 4 6
rs2 1 6 2 5 4 0
rs2 9 8 1 5 8 2
rs2 9 8 1 5 8 1
rs3 1 3 5 7 1 5
rs7 8 9 9 7 6 5
rs1 2 1 9 6 2 7
ID
S tu d y
1.4 .6 .8 1 1 .2 1 .4 1 .6 1 .8 2 2 .2 2 .4 2 .6 2 .8 3 3 .2 3 .4
A ll su b je c t
Figure 1. Age-adjusted ORs and 95%CI for breast cancer with FGFR2 genetic polymorphisms by OC use, the Shanghai Breast Cancer Study
OR per allele: adjusted for age, educational levels, age at menarche, menopausal status, breast cancer in 1st-degree relatives, number of live births and body mass index
OC use
No. of MA
OC use
OC use OC use
No. of MA
No. of MA
No. of MA
rs2303568
rs3135730rs1078806
rs755793
Figure 2. Breast cancer odds ratios estimates for OC use according to the number of minor alleles of FGFR2 SNPs, the Shanghai Breast Cancer Study
Hap1: in the order of rs7073360, rs3135749, rs3135747, rs755793, rs3135739, rs3135737, rs3135736, rs12245334 and rs9888022. Hap2: in the order of rs2303568 and rs3135730.Hap3: in the order of rs7073360, rs3135749, rs3135747, rs755793, rs3135739, rs3135737, rs3135736, rs12245334, rs9888022, rs2303568, rs3135730 and rs1078806.OR: adjusted for age, educational levels, age at menarche, menopausal status, breast cancer in 1st-degree relatives, number of live births and body mass index.a additionally adjusted for oral contraceptive use.
Table 3. Haplotype analysis of FGFR2 with the risk of breast cancer under dominant model, the Shanghai Breast Cancer Study
All subjects a Non-OC users OC users Using OC<18 months Using OC ≥18 months
% OR(95%CI) P-value OR(95%CI) P-value OR(95%CI) P-value OR(95%CI) P-value OR(95%CI) P-value
Hap1
TAAACAATT 93.8 1.00 1.00 1.00 1.00 1.00
GGGGTGCCC 6.2 1.25(1.05-1.49) 0.01 1.12(0.92-1.36) 0.27 1.95(1.30-2.92) 0.0012 1.61(0.92-2.81) 0.09 2.41(1.33-4.37) 0.0004
Hap2
AA 92.5 1.00 1.00 1.00 1.00 1.00
GG 6.5 1.22(1.02-1.46) 0.03 1.08(0.88-1.32) 0.47 2.02(1.34-3.04) 0.0008 1.79(1.01-3.17) 0.05 2.29(1.27-4.15) 0.0018
Hap3
TAAACAATTAAA 62.9 1.00 1.00 1.00 1.00 1.00
TAAACAATTAAG 28.4 1.13(1.00-1.27) 0.04 1.08(0.95-1.23) 0.26 1.36(1.05-1.77) 0.02 1.20(0.84-1.72) 0.32 1.60(1.11-2.31)
GGGGTGCCCGGA 4.2 1.31(1.05-1.64) 0.02 1.13(0.88-1.45) 0.33 2.36(1.42-3.92) 0.0009 2.85(1.39-5.85) 0.004 2.34(1.15-4.76) <0.0001
讨 论• First study reporting the modifying effect of FGFR2 in the OCs-
breast cancer association
– effect of OC use in breast cancer depends on the genotypes of FGFR2 at
rs755793, rs2303568, 3135730 and rs1078806
– dose-response relationship between duration of OC use and cancer risk
among women carrying at least one minor allele at rs755793, rs2303568
and rs3135730 or those having two minor alleles at rs1078806
– unclear function of the loci and poorly understood mechanism underlying
the results
•Strengths
– population-based study design
– large sample size
– high participation rate
– homogeneous ethnic background
– extensive coverage of the FGFR2 gene
Limitations
possibility of chance
very few users of OCs containing estrogen or progesterone only
no enough statistical power to evaluate the interaction between
HRT use and FGFR2
Significance
test our hypothesis
provide a possible explain for the null OC-breast cancer
association in Chinese women
support the hormone-dependent nature of FGFR2 gene
important implications in personalized prevention of breast
cancer
致 谢美国 Vanderbilt 大学 上海市肿瘤研究所
• 高玉堂• 项永兵
• Wei Zheng• Xiao-ou Shu • Jirong Long• Qiuyin Cai• Qi Dai
上海市疾病预防控制中心• 卢伟• 郑莹• 顾凯• 鲍萍萍
复旦大学公共卫生学院• 赵根明
This research was supported by NSFC 30872180