Genetically predicted gynecologic surgery and risk of breast cancer in European population

doi:10.21203/rs.3.rs-3555679/v1

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Genetically predicted gynecologic surgery and risk of breast cancer in European population

https://doi.org/10.21203/rs.3.rs-3555679/v1

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Purpose

We conducted Mendelian randomization (MR) analyses to investigate the associations between gynecologic surgery and risk of breast cancer.

Methods

We performed MR using publicly accessible genome-wide association study (GWAS) datasets. Our primary analytical method was the inverse variance weighted (IVW) method. Additionally, we utilized complementary methods, including MR-Egger regression, weighted median, and MR-PRESSO. To assess potential horizontal pleiotropy, we conducted the MR-Egger intercept test and employed the global test for pleiotropic residuals and outliers through the MR-Presso method. We also assessed instrumental heterogeneity using the Cochran Q statistic. In addition, we conducted analyses of risk factors to further explore possible mediator relationships for causal inference.

Results

The initial findings from the IVW analysis reveal a statistically significant relationship between hysterectomy and ER- breast cancer (OR(Odds Ratio) = 82.73, 95% Confidence Interval (CI) = 1.45–4.73 × 10³, p = 0.032). These results were consistent with those obtained from MR-Egger regression, where bilateral ovariectomy demonstrates a statistically significant link with ER + breast cancer (OR = 6.42 × 10^− 2, 95% CI = 6.08 × 10^− 3 − 0.68, p = 0.022). Importantly, the robustness of these findings was confirmed in all sensitivity analyses.

Conclusion

Our study reveals an association between gynecological surgery and breast cancer and menorrhagia and irregular menstruation is a potential mediator.

Breast cancer

Hysterectomy

Bilateral oophorectomy

Mendelian randomization

Breast cancer is a common cancer that impacts women globally, standing as the leading cause of female mortality (Lam et al. 2023; Kansara et al. 2023).Clinically, breast cancer is categorized based on the expression of estrogen receptor (ER), progesterone receptor (PGR), and human epidermal growth factor receptor (HER2), resulting in luminal subtypes (luminal A,luminal B), HER²⁻positive subtype, and triple-negative breast cancer (Huppert et al. 2023; Han et al. 2023).While numerous high-risk factors linked to breast cancer's development and progression have been identified, the exact etiology of its various subtypes remains largely elusive. Given the malignancy's severity and substantial societal and economic consequences, early detection of breast cancer is crucial for tailoring personalized treatments to manage disease progression and alleviate its significant burden on society and healthcare.

Currently, gynecologic surgeries like bilateral oophorectomy and hysterectomy are believed to influence breast cancer risk. Recent observational studies suggest that bilateral oophorectomy is associated with a reduced risk of breast cancer, while hysterectomy may be linked to an increased risk(Lovett et al. 2023).However, these studies have not investigated the specific breast cancer subtypes involved. Furthermore, it remains unclear whether these observed relationships are causal or influenced by biases such as confounding, selection bias, or reverse causation. Mendelian randomization offers a valuable approach to assess exposures like hysterectomy and bilateral oophorectomy and their impact on outcomes by utilizing genotypes randomly assigned at meiosis (before conception) as instrumental variables (IVs) for breast cancer. Essentially, MR employs observational data to emulate a randomized controlled trial(Vithayathil et al. 2020; Gormley et al. 2020). Importantly, MR has the potential to mitigate confounding and reverse causality, thereby providing stronger evidence for causal inference, as long as certain assumptions of instrumental variable analysis are satisfied (Darrous et al. 2021; Dixon-Suen et al. 2022). Since genetic variants are randomly assigned at conception, MR analysis effectively mitigates the impact of confounding variables and aids in the identification of causal determinants for specific outcomes. MR is increasingly being employed to deduce plausible causal associations between risk factors and diseases (Chen et al. 2022).

Given the uncertainty surrounding the causal link between hysterectomy/bilateral oophorectomy and breast cancer, our study aimed to address this issue by identifying Single Nucleotide Polymorphisms (SNPs) linked to hysterectomy/bilateral oophorectomy. We achieved this through an extensive analysis of a large genome-wide association study (GWAS) dataset. We then evaluated the potential causal impact of these surgical procedures on breast cancer risk.

In summary, this research examined the impact of gynecologic surgeries on breast cancer risk, clarified the causal connection between gynecological surgery and breast cancer risk, and provided valuable insights for constructive recommendations on preventive intervention strategies.

Two-sample MR design

In our work, we employed a two-sample MR design to investigate the potential causal relationship between hysterectomy/bilateral oophorectomy and breast cancer. To uphold the validity of the MR design, we adhered to three critical assumptions:(1)Genetic variants used as instruments are strongly linked to the exposure of interest (p < 5 × 10^− 8)(Rosoff et al. 2020); (2)Genetic variants are not linked to other potential confounding factors.(3)Genetic instruments solely exert their influence on the outcomes through the specified exposure factors.All data utilized in this work are derived from publicly accessible sources. The statistical analysis was performed using the “TwoSampleMR” package (version 0.5.7) within the R program (version 4.3.1). Figure 1 presents a flowchart illustrating the study design.

SNP selection for hysterectomy and bilateral oophorectomy

We acquired genetic instrument variables for hysterectomy (sample size :462,933; ncase:46,411; Number of SNPs:9,851,867; ID: “ukb-b-3700”) and genetic instrument variables for bilateral oophorectomy (sample size:462,933; ncase:19,512; Number of SNPs:9,851,867; ID: “ukb-b-1962”) from the open gwas project(https://gwas.mrcieu.ac.uk/) of the UK Biobank phenotype.To establish these instrumental variables for exposure, we adhered to the criteria proposed by Martin Bahls et al., which met the criteria of genome-wide significance threshold and independence from linkage disequilibrium (r² < 0.001 and window size > 10,000kb) (Bahls et al. 2021). Consequently, based on these criteria, we got 34 SNPs for hysterectomy and 6 SNPs for bilateral oophorectomy as instrumental variables in our work (Supplementary File B and C).

To ensure the quality of control SNPs, a stringent screening process preceded our Mendelian randomization (MR) analysis. This process entailed several key steps:Firstly, we meticulously selected SNPs associated with the exposure variable, applying a stringent threshold of P < 5×10^− 8.Secondly, we assessed the presence of linkage among these SNP genes using linkage disequilibrium (LD), employing an LD threshold with an r² value of 0.001 and a 10,000 kb window.Thirdly, we systematically removed weak instrumental variables and excluded SNPs with F statistics (Chen et al. 2021; Zhao et al. 2023; Huang et al. 2023b; Lin et al. 2023)(F = beta2/se2) less than 10, where "beta" represented the genetic effect of each allele on the SNP, and "se" indicated the standard error.Fourthly, SNPs with ambiguous and palindromic characteristics (EAF > 0.42) were excluded from the coordination process.Finally, we utilized MR-pleiotropy and MR-PRESSO methods to identify and eliminate potential pleiotropic SNPs. Comprehensive details concerning these SNPs as instrumental variables are available in Supplementary File B and C.

Outcome data sources

We obtained summary data for various breast cancer subtypes from the IEU GWAS database:

(1)ER- breast cancer: Sample size = 6,881; Cases = 920; SNPs = 8,828,662; ID: ieu-a-1163.

(2)ER + breast cancer: Sample size = 175,475; Cases = 69,501; SNPs = 10,680,257; ID: ieu-a-1127.

(3)HER2- breast cancer: Sample size = 106,676; Cases = 7,355; SNPs = 16,379,314; ID: finn-b-C3_BREAST_HER2NEG_EXALLC.(4)For breast carcinoma in situ: Sample size = 103,522; Cases = 1,131; SNPs = 16,379,075; ID: finn-b-CD2_INSITU_BREAST_EXALLC.

Statistical analyses

To account for potential effects of instrumental variables, this study employed four MR analysis methods to assess the causal impact of gynecological surgery on breast cancer. Our primary analysis utilized the standard IVW method. Additionally, as a supplementary approach to IVW, we implemented MR-Egger regression, weighted median, and MR-PRESSO methods to further confirm the reliability and robustness of the MR results.

We assessed potential horizontal pleiotropic effects using MR-Egger regression intercepts. An intercept value near 0 with a P value greater than 0.05 suggests the absence of horizontal pleiotropy.To evaluate the influence of individual sensitivity SNPs on IVW testing, we performed a leave-one-out analysis. Visual representations of the results were provided through scatter plots, funnel plots, and forest plots.Furthermore, we performed Cochran's Q test, where a P value below 0.05 indicates the presence of heterogeneity. All MR analyses were carried out using the R software packages "two-sample MR" and "MRPresso."

To investigate the underlying mechanisms, we conducted additional MR analyses to assess the causal association between gynecological surgery and risk factors linked to breast cancer. Drawing from prior research, we selected several potential risk factors linked to breast cancer, including BMI, smoking, alcohol drinking, fasting insulin, total cholesterol, and menstrual irregularity(Lazúrová and Dravecká 2002; Duan et al. 2017; Del Riccio et al. 2023; Cohen et al. 2023; Brown et al. 2023; Liao et al.) (as detailed in Supplementary File B). We employed hysterectomy and bilateral oophorectomy as exposure variables and the mentioned risk factors as outcomes in the MR analysis. Our primary assessment method was IVW, with statistical significance set at a P value less than 0.05.

MR analysis of gynecologic surgeries with risk of breast cancer

Among the various hysterectomy phenotypes examined, the IVW analysis revealed a notable increase in the risk of ER-breast cancer (OR: 82.73, 95% CI: 1.45 to 4.73×10³; p = 0.032). Moreover, consistent results were obtained through MR-Egger analysis (OR:4.23×10⁵, 95% CI:13.37 to 1.34×10¹⁰; p = 0.021) (Table 1 and Fig. 2).For bilateral oophorectomy, a noteworthy decrease in the risk of ER⁺ breast cancer was noted (OR:6.42×10⁻², 95%CI: 6.08×10⁻³ to 0.68; p = 0.022) based on the IVW analysis and weighted median method. Both methods produced consistent and statistically significant results (Table 1 and Fig. 2, p < 0.05). Additionally, our analysis did not reveal any indication of a causal association between hysterectomy and the risk of ER+, HER2- breast cancer or breast cancer in situ, nor between bilateral oophorectomy and the risk of ER-, HER2- breast cancer, or breast cancer in situ (Table 1).

Table 1

Estimates of the causal association between gynecologic surgery and the risk of breast cancer.
Exposure	Outcome	Methods	OR (95% CI)	p
hysterectomy	ER⁻ Breast cancer	IVW	82.73(1.45,4.73×10³)	0.032*
		WM	190.80(0.51,7.08×10⁴)	0.081
		MR-Egger	4.23×10⁵ (13.37,1.34×10¹⁰)	0.021*
hysterectomy	ER⁺ Breast cancer	IVW	1.79(0.51,6.34)	0.363
		WM	0.74(0.25,2.19)	0.591
		MR-Egger	0.59(0.03,13.29)	0.741
hysterectomy	HER2⁻ breast cancer	IVW	4.25(0.46,38.55)	0.193
		WM	1.34(0.14,13.00)	0.790
		MR-Egger	0.76(0.003,152.95)	0.920
hysterectomy	Carcinoma in situ of breast	IVW	1.51(0.03,63.63)	0.832
		WM	0.27(0.002,43.89)	0.617
		MR-Egger	11.30(0.001,92349.14)	0.602
bilateral oophorectomy	ER⁻ Breast cancer	IVW	2.32(1.30×10^− 6,4.15×10⁶)	0.909
		WM	4.32×10³(1.79×10^− 5,1.04×10¹²)	0.395
		MR-Egger	4.26×10¹⁴(3.17×10^− 10,5.72×10³⁸)	0.300
bilateral oophorectomy	ER⁺ Breast cancer	IVW	6.42×10^− 2(6.08×10^− 3 ,0.68)	0.022*
		WM	2.79×10^− 2(1.46×10^− 3, 0.53)	0.017*
		MR-Egger	1.38×10^− 5(2.45×10^− 9, 0.08)	0.064
bilateral oophorectomy	HER2⁻ breast cancer	IVW	6.63(9.17×10^− 5,4.79×10⁵)	0.740
		WM	7.20×10^− 2(3.09×10⁻5,1.67×10²)	0.506
		MR-Egger	8.32×10^− 10(1.21×10^− 28,5.69×10⁹)	0.398
bilateral oophorectomy	Carcinoma in situ of breast	IVW	2.86(1.15×10^− 9,7.11×10⁹)	0.924
		WM	4.09×10^− 3(4.38×10^− 11,3.82×10⁵)	0.557
		MR-Egger	1.15×10^− 32(1.05×10^− 57,1.26×10^− 7)	0.067
Abbreviations: MR, Mendelian randomization; OR, odds ratio;CI, confidence interval;IVW, inverse variance weighted;WM, weighted median.*p < 0.05.

Sensitivity analyses

To assess the reliability and strength of our results, we performed a set of sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and MR-PRESSO test (Supplementary file D). The MR-Egger intercept test consistently provided P values greater than 0.05, suggesting the absence of horizontal pleiotropy. Although some results exhibited heterogeneity, this did not compromise the integrity of the Mendelian randomization (MR) analysis, as our study employed a random effect IVW method, which could help mitigate the heterogeneity in the outcomes. Moreover, the Egger intercept test did not identify any indications of pleiotropy, indicating that the MR analysis did not introduce pleiotropy bias, even in the presence of heterogeneity (Supplementary file D).

Risk factor estimates

To explore potential mediating confounders between gynecologic surgeries and the risk of breast cancer, we performed a MR analysis to explore the causal connections between these surgical procedures and common risk factors for breast cancer. Our findings revealed that hysterectomy was linked to a 1.1 times higher risk of experiencing menorrhagia and menstrual irregularities. Conversely, bilateral oophorectomy was linked to a 1.34 times increased risk of heavy menorrhagia and menstrual irregularities (Supplementary file E).In summary, based on our mediator analysis of risk factors, our findings suggest that menorrhagia and irregular menstruation may play a crutial role in the pathway from gynecologic surgery to breast cancer.

Mendelian randomization is a methodology that leverages genetic diversity to explore potential causal relationships between exposures and outcomes (Zhang et al. 2022; Huang et al. 2023a; Li et al. 2023).Utilizing a comprehensive genetic dataset and a two-sample MR analysis, our study furnishes compelling evidence indicating that hysterectomy significantly raises the risk of ER⁻ breast cancer (Odds Ratio [OR] = 82.73), while bilateral oophorectomy substantially decreases the risk of ER⁺ breast cancer (OR = 0.06).Given the prevalence of both gynecologic oncology and breast cancer among women, our findings offer novel insights into breast cancer risk reduction. They underscore the importance of regular breast examinations following gynecologic oncology surgery. However, our study did not uncover any connections between gynecological surgery and the risk of other breast cancer subtypes when employing the MR method.

Hysterectomy and bilateral oophorectomy are routinely performed in clinical practice, primarily due to the increasing prevalence of gynecologic neoplastic diseases such as cervical cancer, endometrial cancer, and ovarian cancer(Wang and Ding 2023; Baekelandt and Stuart 2023; Guo et al. 2023; Wang et al. 2023; Zhang et al. 2023; Motsa et al. 2023). Unfortunately, current observational studies lack conclusive evidence regarding the impact of gynecologic surgery on breast cancer incidence, particularly with respect to specific subtypes. While randomized controlled trials (RCTs) are considered the gold standard for establishing causal associations, the extended latency period and high costs associated with tracking patients from gynecological surgery to breast cancer diagnosis pose significant challenges to their implementation.Considering these practical limitations, MR analysis proves to be a reliable method for clarifying the causal connection between gynecological surgery and breast cancer.

Our study leverages comprehensive genetic data obtained from a substantial cohort of individuals in GWAS to establish compelling evidence for a causal association between gynecological surgery and breast cancer. We meticulously examined various subtypes of breast cancer to derive precise estimates of causal effects. While our findings may not pinpoint a specific carcinogenic mechanism, they do shed light on potential pathways that warrant further investigation. Moreover, our findings provide new insights that can guide future research, inspire innovative approaches to breast cancer prevention and treatment, and inform clinical practices.

Common risk factors for breast cancer, such as BMI, Ever versus never smoked, alcohol consumption, heavy menstrual bleeding, and irregular menstrual bleeding, can have a substantial impact on breast cancer-related health outcomes. In our mediator analyses, we detected a positive link between hysterectomy and the risk of experiencing menorrhagia and irregular menstruation, both of which have previously been recognized as factors that elevate the risk of breast cancer(Shetty et al. 2023; Dehesh et al. 2023).Additionally, smoking status is recognized as a significant contributor to breast cancer risk (Tang et al. 2021; Gram et al. 2022). Thus, further exploration is warranted to understand the mechanisms by which smoking behavior serves as a crucial intermediary factor in the pathway linking gynecologic surgery to breast cancer.

Our MR study has several inherent limitations that should be acknowledged.Firstly, we utilized aggregated-level data and conducted subgroup analyses based on ER status, but we were unable to stratify the breast cancer analysis according to other critical cancer risk variables such as BMI, smoking habits, alcohol consumption, and exogenous hormone use.Secondly, our study exclusively relied on pooled GWAS data from European individuals, limiting the generalizability of our results to broader populations.Thirdly, since MR analysis aims to infer causal associations by capitalizing on the random assortment of genetic instrument, it remains challenging to entirely disentangle mediation effects from pleiotropic effects using MR methodologies. Numerous genetic variations within our genome can influence one or more phenotypes, contributing to potential complexity in causal inference.Fourthly, while our study has shed light on the relationship between gynecological surgery and breast cancer, further investigations are essential to confirm the causal association and elucidate underlying mechanisms, especially concerning triple-negative breast cancer, given its poor clinical prognosis.Lastly, it is essential to acknowledge that the association between gynecological surgery and breast cancer may be influenced by factors such as potential pleiotropy, potentially leading to false-positive results in our study.

In conclusion, our study provides compelling evidence suggesting that hysterectomy may increase the risk of developing ER⁻ breast cancer, and bilateral oophorectomy may have a protective effect against ER⁺ breast cancer. Additionally, menorrhagia and irregular menstruation may play a crucial role in the pathway from gynecologic surgery to breast cancer.

Acknowledgements

We want to thank Open Gwas Project for sharing data.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding

This work was supported by a research fund from Chosun University 2023 .The funding organization had no role in the preparation of the manuscript.

Author contributions

Guoliang Feng: Conceptualization, Methodology, Software, Validation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Visualization. Hongyang Gong: Conceptualization, Methodology, Validation, Formal analysis, Resources, Data curation, Writing – review & editing, Supervision, Research administration, Funding acquisition.

Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data Availability

The code and dataset will be made available on request.

Ethics approval

This study used summary-level statistics from published studies and publicly available GWASs. No ethical approval was required for this study.

Consent to publish

The author read and proved the final manuscript for publication

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Genetically predicted gynecologic surgery and risk of breast cancer in European population

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Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Methods

Two-sample MR design

SNP selection for hysterectomy and bilateral oophorectomy

Outcome data sources

Statistical analyses

Results

MR analysis of gynecologic surgeries with risk of breast cancer

Sensitivity analyses

Risk factor estimates

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1