Reproductive history and risk of hormone-related cancers in women: a Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

PENG Qinghui ¹ , ZHAO Jian ^2,3 , LIN Yidie ¹ , YAO Qiang ¹ , LI Zijun ¹ ,  ZHU Cairong ¹

1. Department of Epidemiology and Health Statistics, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, P. R. China;
3. MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK;

Corresponding author：

ZHU Cairong, Email: cairong.zhu@hotmail.com

Keywords：

Reproductive history; Hormone-related cancer; Mendelian randomization analysis; Causality

DOI：

10.7507/1672-2531.202311171

Video：

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Objective To investigate whether there is a causal relationship between reproductive history (number of children, age at first birth) and the risk of hormone-related cancers (breast, endometrial, and ovarian) in women. Methods Univariate and multivariate Mendelian randomization (MR) methods were used to investigate the causal effects of the number of children (childlessness in infertile women and number of children ever born in fertile women) and age at first birth on three hormone-related cancers. The inverse variance weighting method was used for the primary analysis, and sensitivity analyses and reliability tests were used to ensure the reliability of the results. Results Univariate MR showed that infertile women had a higher risk of breast cancer compared with fertile women (OR=1.07, 95%CI 1.05 to 1.09, P<0.001). Multivariate MR showed that among fertile women, after accounting for the effect of age at first birth, higher number of children ever born may be associated with lower risk of breast cancer (OR=0.61, 95%CI 0.43 to 0.85, P<0.01). Neither univariate nor multivariate MR found a causal relationship between age at first birth and hormone-related cancers, and no causal relationship was found between the number of children ever born and endometrial and ovarian cancers; sensitivity analyses and reliability tests demonstrated that the results were unlikely to be affected by heterogeneity and horizontal pleiotropy. Conclusion The more children a normal woman has, the lower her risk of breast cancer. Infertile women face a higher risk of breast cancer.

Citation： PENG Qinghui, ZHAO Jian, LIN Yidie, YAO Qiang, LI Zijun, ZHU Cairong. Reproductive history and risk of hormone-related cancers in women: a Mendelian randomization study. Chinese Journal of Evidence-Based Medicine, 2024, 24(8): 879-886. doi: 10.7507/1672-2531.202311171 Copy

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2.	Losada-García A, Cortés-Ramírez SA, Cruz-Burgos M, et al. Hormone-related cancer and autoimmune diseases: a complex interplay to be discovered. Front Genet, 2022, 12: 673180.
3.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
4.	Kapil U, Bhadoria AS, Sareen N, et al. Reproductive factors and risk of breast cancer: a review. Indian J Cancer, 2014, 51(4): 571-576.
5.	Ali AT. Reproductive factors and the risk of endometrial cancer. Int J Gynecol Cancer, 2014, 24(3): 384-393.
6.	O'leary P, Boyne P, Flett P, et al. Longitudinal assessment of changes in reproductive hormones during normal pregnancy. Clin Chem, 1991, 37(5): 667-672.
7.	Akhmedkhanov A, Zeleniuch-Jacquotte A, Toniolo P. Role of exogenous and endogenous hormones in endometrial cancer: review of the evidence and research perspectives. Ann N Y Acad Sci, 2001, 943: 296-315.
8.	Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med, 2006, 166(9): 1027-1032.
9.	Albrektsen G, Heuch I, Hansen S, et al. Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. Br J Cancer, 2005, 92(1): 167-175.
10.	Adami HO, Hsieh CC, Lambe M, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet, 1994, 344(8932): 1250-1254.
11.	Woods KL, Smith SR, Morrison JM. Parity and breast cancer: evidence of a dual effect. Br Med J, 1980, 281(6237): 419-421.
12.	Sung HK, Ma SH, Choi JY, et al. The effect of breastfeeding duration and parity on the risk of epithelial ovarian cancer: a systematic review and meta-analysis. J Prev Med Public Health, 2016, 49(6): 349-366.
13.	Raglan O, Kalliala I, Markozannes G, et al. Risk factors for endometrial cancer: an umbrella review of the literature. Int J Cancer, 2019, 145(7): 1719-1730.
14.	Jia L, Lv W, Liang L, et al. The causal effect of reproductive factors on breast cancer: a two-sample Mendelian randomization study. J Clin Med, 2023, 12(1): 347.
15.	McGuire V, Hartge P, Liao LM, et al. Parity and oral contraceptive use in relation to ovarian cancer risk in older women. Cancer Epidemiol Biomarkers Prev, 2016, 25(7): 1059-1063.
16.	Katagiri R, Iwasaki M, Abe SK, et al. Reproductive factors and endometrial cancer risk among women. JAMA Netw Open, 2023, 6(9): e2332296.
17.	D'Urso S, Arumugam P, Weider T, et al. Mendelian randomization analysis of factors related to ovulation and reproductive function and endometrial cancer risk. BMC Med, 2022, 20(1): 419.
18.	Farland LV, Wang S, Rich-Edwards JW, et al. History of infertility and risk of breast cancer: a prospective cohort study. Breast Cancer Res Treat, 2023, 199(1): 185-193.
19.	Cetin I, Cozzi V, Antonazzo P. Infertility as a cancer risk factor - a review. Placenta, 2008, 29(Suppl B): 169-177.
20.	Swerdlow DI, Kuchenbaecker KB, Shah S, et al. Selecting instruments for Mendelian randomization in the wake of genome-wide association studies. Int J Epidemiol, 2016, 45(5): 1600-1616.
21.	Ahmed M, Mäkinen VP, Mulugeta A, et al. Considering hormone-sensitive cancers as a single disease in the UK biobank reveals shared aetiology. Commun Biol, 2022, 5(1): 614.
22.	Mathieson I, Day FR, Barban N, et al. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus. Nat Hum Behav, 2023, 7(5): 790-801.
23.	Mills MC, Tropf FC, Brazel DM, et al. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour. Nat Hum Behav, 2021, 5(12): 1717-1730.
24.	Zhang H, Ahearn TU, Lecarpentier J, et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet, 2020, 52(6): 572-581.
25.	O'Mara TA, Glubb DM, Amant F, et al. Identification of nine new susceptibility loci for endometrial cancer. Nat Commun, 2018, 9(1): 3166.
26.	Phelan CM, Kuchenbaecker KB, Tyrer JP, et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat Genet, 2017, 49(5): 680-691.
27.	Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
28.	Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res, 2023, 4: 186.
29.	Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations. 2019.
30.	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
31.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
32.	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
33.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
34.	Burgess S, Thompson SG. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol, 2015, 181(4): 251-260.
35.	Doldi N, Gessi A, Destefani A, et al. Polycystic ovary syndrome: anomalies in progesterone production. Hum Reprod, 1998, 13(2): 290-293.
36.	Hilton HN, Clarke CL, Graham JD. Estrogen and progesterone signalling in the normal breast and its implications for cancer development. Mol Cell Endocrinol, 2018, 466: 2-14.
37.	Lundberg FE, Iliadou AN, Rodriguez-Wallberg K, et al. The risk of breast and gynecological cancer in women with a diagnosis of infertility: a nationwide population-based study. Eur J Epidemiol, 2019, 34(5): 499-507.
38.	Colditz GA, Baer HJ, Rulla MT. 995 breast cancer. In: Schottenfeld D, Fraumeni JF. Cancer epidemiology and prevention. Oxford: Oxford University Press, 2006.
39.	Russo J, Moral R, Balogh GA, et al. The protective role of pregnancy in breast cancer. Breast Cancer Res, 2005, 7(3): 131-142.
40.	Liu R, Kitamura Y, Kitamura T, et al. Reproductive and lifestyle factors related to breast cancer among Japanese women: an observational cohort study. Medicine (Baltimore), 2019, 98(51): e18315.
41.	Macmahon B, Cole P, Lin TM, et al. Age at first birth and breast cancer risk. Bull World Health Organ, 1970, 43(2): 209-221.
42.	Li CI, Malone KE, Daling JR, et al. Timing of menarche and first full-term birth in relation to breast cancer risk. Am J Epidemiol, 2008, 167(2): 230-239.
43.	Colditz GA, Bohlke K, Berkey CS. Breast cancer risk accumulation starts early: prevention must also. Breast Cancer Res Treat, 2014, 145(3): 567-579.

1. Henderson BE, Feigelson HS. Hormonal carcinogenesis. Carcinogenesis, 2000, 21(3): 427-433.
2. Losada-García A, Cortés-Ramírez SA, Cruz-Burgos M, et al. Hormone-related cancer and autoimmune diseases: a complex interplay to be discovered. Front Genet, 2022, 12: 673180.
3. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
4. Kapil U, Bhadoria AS, Sareen N, et al. Reproductive factors and risk of breast cancer: a review. Indian J Cancer, 2014, 51(4): 571-576.
5. Ali AT. Reproductive factors and the risk of endometrial cancer. Int J Gynecol Cancer, 2014, 24(3): 384-393.
6. O'leary P, Boyne P, Flett P, et al. Longitudinal assessment of changes in reproductive hormones during normal pregnancy. Clin Chem, 1991, 37(5): 667-672.
7. Akhmedkhanov A, Zeleniuch-Jacquotte A, Toniolo P. Role of exogenous and endogenous hormones in endometrial cancer: review of the evidence and research perspectives. Ann N Y Acad Sci, 2001, 943: 296-315.
8. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med, 2006, 166(9): 1027-1032.
9. Albrektsen G, Heuch I, Hansen S, et al. Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. Br J Cancer, 2005, 92(1): 167-175.
10. Adami HO, Hsieh CC, Lambe M, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet, 1994, 344(8932): 1250-1254.
11. Woods KL, Smith SR, Morrison JM. Parity and breast cancer: evidence of a dual effect. Br Med J, 1980, 281(6237): 419-421.
12. Sung HK, Ma SH, Choi JY, et al. The effect of breastfeeding duration and parity on the risk of epithelial ovarian cancer: a systematic review and meta-analysis. J Prev Med Public Health, 2016, 49(6): 349-366.
13. Raglan O, Kalliala I, Markozannes G, et al. Risk factors for endometrial cancer: an umbrella review of the literature. Int J Cancer, 2019, 145(7): 1719-1730.
14. Jia L, Lv W, Liang L, et al. The causal effect of reproductive factors on breast cancer: a two-sample Mendelian randomization study. J Clin Med, 2023, 12(1): 347.
15. McGuire V, Hartge P, Liao LM, et al. Parity and oral contraceptive use in relation to ovarian cancer risk in older women. Cancer Epidemiol Biomarkers Prev, 2016, 25(7): 1059-1063.
16. Katagiri R, Iwasaki M, Abe SK, et al. Reproductive factors and endometrial cancer risk among women. JAMA Netw Open, 2023, 6(9): e2332296.
17. D'Urso S, Arumugam P, Weider T, et al. Mendelian randomization analysis of factors related to ovulation and reproductive function and endometrial cancer risk. BMC Med, 2022, 20(1): 419.
18. Farland LV, Wang S, Rich-Edwards JW, et al. History of infertility and risk of breast cancer: a prospective cohort study. Breast Cancer Res Treat, 2023, 199(1): 185-193.
19. Cetin I, Cozzi V, Antonazzo P. Infertility as a cancer risk factor - a review. Placenta, 2008, 29(Suppl B): 169-177.
20. Swerdlow DI, Kuchenbaecker KB, Shah S, et al. Selecting instruments for Mendelian randomization in the wake of genome-wide association studies. Int J Epidemiol, 2016, 45(5): 1600-1616.
21. Ahmed M, Mäkinen VP, Mulugeta A, et al. Considering hormone-sensitive cancers as a single disease in the UK biobank reveals shared aetiology. Commun Biol, 2022, 5(1): 614.
22. Mathieson I, Day FR, Barban N, et al. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus. Nat Hum Behav, 2023, 7(5): 790-801.
23. Mills MC, Tropf FC, Brazel DM, et al. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour. Nat Hum Behav, 2021, 5(12): 1717-1730.
24. Zhang H, Ahearn TU, Lecarpentier J, et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet, 2020, 52(6): 572-581.
25. O'Mara TA, Glubb DM, Amant F, et al. Identification of nine new susceptibility loci for endometrial cancer. Nat Commun, 2018, 9(1): 3166.
26. Phelan CM, Kuchenbaecker KB, Tyrer JP, et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat Genet, 2017, 49(5): 680-691.
27. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
28. Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res, 2023, 4: 186.
29. Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations. 2019.
30. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
31. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
32. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
33. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
34. Burgess S, Thompson SG. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol, 2015, 181(4): 251-260.
35. Doldi N, Gessi A, Destefani A, et al. Polycystic ovary syndrome: anomalies in progesterone production. Hum Reprod, 1998, 13(2): 290-293.
36. Hilton HN, Clarke CL, Graham JD. Estrogen and progesterone signalling in the normal breast and its implications for cancer development. Mol Cell Endocrinol, 2018, 466: 2-14.
37. Lundberg FE, Iliadou AN, Rodriguez-Wallberg K, et al. The risk of breast and gynecological cancer in women with a diagnosis of infertility: a nationwide population-based study. Eur J Epidemiol, 2019, 34(5): 499-507.
38. Colditz GA, Baer HJ, Rulla MT. 995 breast cancer. In: Schottenfeld D, Fraumeni JF. Cancer epidemiology and prevention. Oxford: Oxford University Press, 2006.
39. Russo J, Moral R, Balogh GA, et al. The protective role of pregnancy in breast cancer. Breast Cancer Res, 2005, 7(3): 131-142.
40. Liu R, Kitamura Y, Kitamura T, et al. Reproductive and lifestyle factors related to breast cancer among Japanese women: an observational cohort study. Medicine (Baltimore), 2019, 98(51): e18315.
41. Macmahon B, Cole P, Lin TM, et al. Age at first birth and breast cancer risk. Bull World Health Organ, 1970, 43(2): 209-221.
42. Li CI, Malone KE, Daling JR, et al. Timing of menarche and first full-term birth in relation to breast cancer risk. Am J Epidemiol, 2008, 167(2): 230-239.
43. Colditz GA, Bohlke K, Berkey CS. Breast cancer risk accumulation starts early: prevention must also. Breast Cancer Res Treat, 2014, 145(3): 567-579.

Chinese Journal of Evidence-Based Medicine

Reproductive history and risk of hormone-related cancers in women: a Mendelian randomization study

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