Age of natural menopause onset in BRCA1/2 carriers – systematic review and meta-analysis

Łukasz Kępczyński^†1,2, Katarzyna Połatyńska³, Jordan Sałamunia⁴, Tadeusz Kałużewski⁴, Andrzej Kużawczyk⁵, Agnieszka Gach¹

¹Department of Genetics, Polish Mother’s Memorial Hospital Research Institute (Łódź, Poland); ²Laboratory of Molecular Biology, Department of Internal Medicine, Kidney and Diabetes, Medical University of Łódź (Łódź, Poland); ³Department of Neurology, Polish Mother’s Memorial Hospital Research Institute (Łódź, Poland); ⁴Laboratory of Medical Genetics of the “Genos” Partnership R&D Division (Łódź, Poland). ⁵Institute IurisMed – Independent Medical Examiners (Kutno, Poland);

 

Abstract

The influence of germinal BRCA1 and BRCA2 on age of natural menopause remains inconclusive and controversial. 4 studies and our original, unpublished data from families, affected by BRCA1 or BRCA2 mutations, consisted of at least two postmenopausal female siblings with differing mutation status, combining data from 1535 germinal BRCA1 and BRCA2 mutation carriers and 3191 control individuals, does not support the hypothesis of association between germinal mutation of “breast cancer genes” and premature menopause.

Introduction

„Breast cancer genes” BRCA1 and BRCA2 are by far the most widely studied human genes, and consequences of germline mutations of both genes for cancer risk are very well described [1]. Non-oncological implications of germline BRCA1 and BRCA2 genes, complicating reproductive health, including early natural menopause, reduced ovarian reserve and unresolved association between BRCA1 and BRCA2 mutation, premature ovarian failure and CGG repeat number in FMR1 gene, are far less described [2, 3, 4, 5, 6].

Woman’s reproductive lifespan is limited by the age of menarche and age of natural menopause (ANM). Timing of both events are determined by genetic and environmental factors, with relatively high heritability for ANM, estimated on around 50% [7]. At least intragenic 3 loci (SYCP2L, UIMC1, and MCM8) and a least 1 intergenic locus (13q34) are associated with ANM across different ethnic populations [8], and can be treated as quantitative trait loci (QTL) for ANM. Loci for premature menopause were also identified, with most widely studied association between premature ovarian failure (POF) and number of CGG repeats in FMR1 gene [9].

The influence of germinal BRCA1 and BRCA2 on AMN remains inconclusive and controversial. Hence, we conducted a comprehensive systematic review and meta-analysis of BRCA1 and BRCA2 mutation on ANM.

Material and Methods

PubMed database was searched for abstracts by two reviewers (ŁK and KP) using the keywords: (“BRCA1” OR “BRCA2” OR “hereditary breast cancer”) AND (“menopause”). We identified 193 citation; both reviewers independently reviewed potentially relevant studies subsequently excluded studies which were not case-control, cohort or cross-sectional studies. Additionally, reference lists from systematic reviews or meta-analyses, dealing with the topic of menopause and BRCA1 and BRCA2 germinal mutations, were also checked to identify eligible studies. Studies dealing only with risk-reducing salpingo-oophrectomy (RRSO) and influence of ANM on breast and/or ovary cancer risk were excluded. Two studies (see Table 1) not reporting dispersion measures and not reporting ANM in control group were left in tabular summary, yet were excluded from meta-analysis. Discrepancies in retrieved list were resolved by consensus. We also included our original, unpublished data from families, affected by BRCA1 or BRCA2 mutations, consisted of at least two postmenopausal female siblings with differing mutation status (Table 2). As most of the data reported median and range for ANM, we estimated mean and standard deviation using Hozo et al. approach [10]. Meta-analysis was done using random effects model on standardized mean differences. Statistical analysis was conducted using R (version 3.6.1. The R Foundation for Statistical Computing).

Results and Discussion

Our database search retrieved 193 articles by initial strategy, and 6 studies, combining data from 2121 germinal BRCA1 and BRCA2 mutation carriers and 3741 control subjects [11, 12, 13, 14, 15, 16]. Four of the studies used Kaplan-Meier approach to asses the differences between carriers and non-carriers [12, 13, 16], two studies were excluded from meta-analysis, as they reported no dispersion measures (and we were unable unambiguously derive those data from Figures) [13] or did not report data from control group [15]. We also included original data from 7 mutation carriers and 9 non-carrier siblings, summarized in Table 2. Studies included in presented meta-analysis combined data from 1535 germinal BRCA1 and BRCA2 mutation carriers and 3191 control individuals. Results of preformed meta-analysis are presented in Figure 1. Results only from group affected with BRCA1 mutation was similar to group combining carriers of either mutations (data not shown). Shortage of data from carriers of germinal BRCA2 mutation did not enabled draw significant conclusions.

Three studies reported association BRCA1 and BRCA2 with premature menopause [11, 12, 14], two studies reported no evidence of that association [13, 16]. Meta-analysis results does not support the hypothesis of association between germinal mutation of “breast cancer genes” and premature menopause. Nevertheless, data from all included studies are prone to selection biases as cessation of observation due to RRSO or cancer-related and treatment-related menopause. Only carefully designed prospective study may resolve the true association between BRCA1 and BRCA2 and early menopause.

Study	BRCA1/2 Positive	BRCA1 Positive	BRCA2 Positive	Controls	Geographical region
Rzepka-Górska et al., 2006	Median = 45.5 [45] (Range: 39 – 52)	Median = 45.5 [45] (Range: 39 – 52)	NA[1]	Median = 48.2 [90] (Range: 43 – 53)	Poland
Lin et al., 2012[2]	Median = 49 [166] (Range: 26 – 55)	Median = 48 [94] (Range: 26 – 55)	Median = 49 [72] (Range: 28 – 53)	Median = 53 [639] (Range: 18 – 53)	United States (California)
Collins et al., 2013[3]	NA	Median = 51.[445]	Median = 51 [374]	Median = 52 [559] Median = 51 [462]	Australia and New Zeland
Finch et al., 2013	Mean = 50.3 [207] (Range: 38 – 53)	Mean = 49.9 [109] (Range: 39 – 65)	Mean = 50.8 [95] (Range: 38 – 59)	Mean = 49.0 [242] (Range: 30 – 63) Mean = 48.8 [126][4] (Range: 30 – 57) Mean = 49.2 [113][5] (Range: 36 – 62)	Canada and United States
Tea et al., 2013[6]	NA	Mean = 40.7 [50]	Mean = 46.8 [49]	NA	Austria
van Tilborg et al., 2016	Median = 53 [1208] (Range: 28 – 59)	NA	NA	Median = 53 [2211] (Range: 35 – 62)	The Netherlands
Kępczyński et al., 2020 (this study)	Mean = 48.4 [7] (Range: 43 – 52)	Mean = 48.4 [7] (Range: 43 – 52)	NA[7]	Mean = 46.2 [9] (Range: 41 – 52)	Poland

[1] All cases were attributed to BRCA1 mutations

[2] Range derived from Figures 3 and 4

[3] No dispersion measure nor range was given – excluded from analysis

[4] Controls for BRCA1 positive group

[5] Controls for BRCA2 positive group

[6] Mean calculated as mean of menarche in whole group + mean reproductive lifespan, no actual data nor dispersion measure was given – excluded from analysis

[7] Only one family with BRCA2 mutation

 

Family	BRCA1 mutation	Age of natural menopause
	NM_007294.4	BRCA1/2(+) sister(s)	BRCA1/2(–) sister(s)
I	BRCA1: c.5266dupC	43	50
II	BRCA1: c.5266dupC	44	46
			42
III	BRCA1: c.5266dupC	50	41
IV	BRCA1: c.1687C>T	48	44
		52
V	BRCA1: c.181T>G	52	45
			48
Family	BRCA2 mutation
	NM_000059.3
VI	c.6982G>T	50	48
			52

 

Opublikowano: Menopause Review Przegląd Menopauzalny

https://www.termedia.pl/Age-of-natural-menopause-onset-in-BRCA1-2-carriers-systematic-review-r-nand-meta-analysis,4,42760,0,1.html

 

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