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. 2024 Jun 14:14:1408132.
doi: 10.3389/fonc.2024.1408132. eCollection 2024.

Relationship between age at menarche and breast cancer in individuals, as well as in first-degree kin and estrogen receptor status: a Mendelian randomization study

Zhijun Zhao  1 , Jinming Zhang  2 , Xiaofeng Tian  1
Affiliations

Relationship between age at menarche and breast cancer in individuals, as well as in first-degree kin and estrogen receptor status: a Mendelian randomization study

Zhijun Zhao et al. Front Oncol. .

Abstract

Target: We executed a Mendelian randomization (MR) investigation employing two distinct cohorts of genetic instrumental variables to elucidate the causal nexus between age at menarche (AAM) and the incidence of disparate breast cancer (BC) subtypes, in addition to the incidence of BC among first-degree kin.

Methods: We aggregated statistical data pertaining to AAM and BC from various consortia representing a homogenous population cohort. MR analysis was conducted employing inverse variance weighted (IVW) methodology as the principal approach, complemented by weighted median and MR-Egger regression techniques for an exhaustive evaluation. To evaluate the presence of pleiotropy, we applied the MR-Egger intercept test, MR-PRESSO, and leave-one-out sensitivity analysis.

Results: Upon exclusion of confounding SNP, an increment of one standard deviation in AAM was inversely correlated with the incidence of BC. (odds ratio [OR] 0.896, 95% confidence interval [CI] 0.831-0.968)/(OR 0.998, 95% CI 0.996-0.999) and estrogen receptor-positive (ER+) BC incidence (OR 0.895, 95% CI 0.814-0.983). It was also associated with reducing the risk of maternal BC incidence (OR 0.995, 95% CI 0.990-0.999) and sibling BC incidence (OR 0.997, 95% CI 0.994-0.999). No significant association was found between AAM and estrogen receptor-negative (ER-) BC incidence (OR 0.936, 95% CI 0.845-1.037).

Conclusion: Our study substantiated the causal relationship between a delayed AAM and a diminished risk of BC in probands, as well as in their maternal progenitors and siblings. Furthermore, the analysis suggests that AAM exerts a considerable potential causal influence on the risk of developing Luminal-a/b subtype of BC.

Keywords: Mendelian randomization study; age at menarche; breast cancer; estrogen receptor; first-degree relatives.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of MR study delineating the causal inference from AAM to BC incidence.
Figure 2
Figure 2
Causality of AAM with BC (BCAC) OR chart for AAM and BC (BCAC).
Figure 3
Figure 3
Causality of AAM with BC (MRC-IEU) OR chart for AAM and BC (MRC-IEU).
Figure 4
Figure 4
Summary figures of causality of AAM with BC (BCAC) (MRC-IEU). (A) Scatter Plot. (B) Forest Plot. (C) Funnel Plot. (D) Leave-One-Out Plot. The scatter plot demonstrates a negative correlation between AAM and BC. Leave-one-out analysis indicates that the comprehensive effect remains unchanged or reverses after the removal of any SNP, suggesting the reliability of the results. This supports the presence of a negative correlation between the AAM and BC. Forest Plot demonstrates a negative correlation between AAM and BC. Funnel Plot exhibits a symmetrical pattern.
Figure 5
Figure 5
Summary figures of causality of AAM with BC. (A) Scatter Plot. (B) Forest Plot. (C) Funnel Plot. (D) Leave-One-Out Plot. The scatter plot demonstrates a negative correlation between AAM and BC. Leave-one-out analysis indicates that the comprehensive effect remains unchanged or reverses after the removal of any SNP, suggesting the reliability of the results. This supports the presence of a negative correlation between the AAM and BC. Forest Plot demonstrates a negative correlation between AAM and BC. Funnel Plot exhibits a symmetrical pattern.
Figure 6
Figure 6
Causality of AAM with ER+ BC OR chart for AAM and ER+ BC.
Figure 7
Figure 7
Causality of AAM with ER- BC OR chart for AAM and ER- BC.
Figure 8
Figure 8
Summary figures of causality of AAM with ER+ BC (A) Scatter Plot. (B) Forest Plot. (C) Funnel Plot. (D) Leave-One-Out Plot.
Figure 9
Figure 9
Summary figures of causality of AAM with ER- BC (A) Scatter Plot. (B) Forest Plot. (C) Funnel Plot. (D) Leave-One-Out Plot.
Figure 10
Figure 10
Causality of AAM with maternal BC OR chart for AAM and BC (mother).
Figure 11
Figure 11
Causality of AAM with sibling BC OR chart for AAM and BC (siblings).
Figure 12
Figure 12
Summary figures of causality of AAM with maternal BC. (A) Scatter Plot. (B) Forest Plot. (C) Funnel Plot. (D) Leave-One-Out Plot. The scatter plot demonstrates a negative correlation between AAM and BC. Leave-one-out analysis indicates that the comprehensive effect remains unchanged or reverses after the removal of any SNP, suggesting the reliability of the results. This supports the presence of a negative correlation between the AAM and BC. Forest Plot demonstrates a negative correlation between AAM and BC. Funnel Plot exhibits a symmetrical pattern.
Figure 13
Figure 13
Summary figures of causality of AAM with sibling BC. (A) Scatter Plot. (B) Forest Plot. (C) Funnel Plot. (D) Leave-One-Out Plot. The scatter plot demonstrates a negative correlation between AAM and BC. Leave-one-out analysis indicates that the comprehensive effect remains unchanged or reverses after the removal of any SNP, suggesting the reliability of the results. This supports the presence of a negative correlation between the AAM and BC. Forest Plot demonstrates a negative correlation between AAM and BC. Funnel Plot exhibits a symmetrical pattern.
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