Age at menarche, age at natural menopause and risk of rheumatoid arthritis – a Mendelian randomization study

Abstract Background Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM) and age at first birth (AFB) with the risk of RA.Methods We collected summary statistics from the hitherto largest GWAS conducted in AAM (N=329,345), ANM (N=69,360), AFB (N=251,151) and RA (Ncase=14,361, Ncontrol=43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted-median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions.Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM=1.06 [0.98-1.15]; ORper-SD increment in ANM=1.05 [0.98-1.11], OR per-SD increment in AFB=0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM=1.06 [0.97-1.15], ORper-SD increment in ANM=1.05 [0.98-1.13], ORper-SD increment in AFB=0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM=1.03 [0.94-1.12], ORper-SD increment in ANM=1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis.Conclusions Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

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Age at Menarche, Age at Natural Menopause and Risk of Rheumatoid Arthritis – A Mendelian Randomization Study

10.21203/rs.3.rs-95577/v1 ◽

2020 ◽

Author(s):

Jingjing Zhu ◽

Zheng Niu ◽

Lars Alfredsson ◽

Lars Klareskog ◽

Leonid Padyukov ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mendelian Randomization ◽

Reproductive Factors ◽

European Ancestry ◽

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Natural Menopause ◽

Menarche Age ◽

Mr Study

Abstract Background Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM) and age at first birth (AFB), with the risk of RA.Methods We collected summary statistics from the hitherto largest GWAS conducted in AAM (N=329,345), ANM (N=69,360), AFB (N=251,151) and RA (Ncase=14,361 and Ncontrol=43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted-median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions.Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORAAM=1.06 [0.98-1.15], ORANM=1.05 [0.98-1.11], ORAFB=0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (ORAAM=1.06 [0.97-1.15], ORANM=1.05 [0.98-1.13], ORAFB=0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (ORAAM=1.03 [0.94-1.12], ORANM=1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis.Conclusions Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

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Age at menarche, age at natural menopause, and risk of rheumatoid arthritis — a Mendelian randomization study

Arthritis Research & Therapy ◽

10.1186/s13075-021-02495-x ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Jingjing Zhu ◽

Zheng Niu ◽

Lars Alfredsson ◽

Lars Klareskog ◽

Leonid Padyukov ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mendelian Randomization ◽

Reproductive Factors ◽

European Ancestry ◽

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Natural Menopause ◽

Menarche Age ◽

Mr Study

Abstract Background Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA. Methods We collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (Ncase = 14,361, Ncontrol = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions. Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM = 1.06 [0.98–1.15]; ORper-SD increment in ANM = 1.05 [0.98–1.11], OR per-SD increment in AFB = 0.85 [0.65–1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM = 1.06 [0.97–1.15], ORper-SD increment in ANM = 1.05 [0.98–1.13], ORper-SD increment in AFB = 0.81 [0.61–1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM = 1.03 [0.94–1.12], ORper-SD increment in ANM = 1.04 [0.95–1.14]). No outlying instrument was identified through the leave-one-out analysis. Conclusions Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

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The relationships between women’s reproductive factors: a Mendelian randomization analysis

10.1101/2021.09.29.21264251 ◽

2021 ◽

Author(s):

Claire Prince ◽

Gemma C Sharp ◽

Laura D Howe ◽

Abigail Fraser ◽

Rebecca C Richmond

Keyword(s):

Mendelian Randomization ◽

Reproductive Factors ◽

Sexual Partners ◽

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Age At Menopause ◽

Lifetime Number ◽

Number Of Sexual Partners ◽

Number Of Births

AbstractBackgroundWomen’s reproductive factors include their age at menarche and menopause, the age at which they start and stop having children, and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors.MethodsWe used data from the UK Biobank and genetic consortia with data available for the following reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age at first sex and lifetime number of sexual partners. Linkage disequilibrium score regression (LDSC) was performed to investigate the genetic correlation between reproductive factors. We then applied Mendelian randomization (MR) methods to estimate the causal relationships between these factors. Sensitivity analyses were used to investigate directionality of the effects, test for evidence of pleiotropy and account for sample overlap.ResultsLDSC indicated that most reproductive factors are genetically correlated (rg range: |0.06 – 0.94|), though there was little evidence for genetic correlations between lifetime number of sexual partners and age at last birth, number of births and ever being parous (rg < 0.01). MR revealed potential causal relationships between many reproductive factors, including later age at menarche (1 SD increase) leading to a later age at first sexual intercourse (Beta (B)=0.09 SD, 95% confidence intervals (CI)=0.06,0.11), age at first birth (B=0.07 SD, CI=0.04,0.10), age at last birth (B=0.06 SD, CI=0.04,0.09) and age at menopause (B=0.06 SD, CI=0.03,0.10). Later age at first birth was found to lead to a later age at menopause (B=0.21 SD, CI=0.13,0.29), age at last birth (B=0.72 SD, CI=0.67,0.77) and a lower number of births (B=-0.38 SD, CI=-0.44,-0.32).ConclusionThis study presents evidence that women’s reproductive factors are genetically correlated and causally related. Future studies examining the health sequelae of reproductive factors should consider a woman’s entire reproductive history, including the causal interplay between reproductive factors.

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Variations in reproductive events across life: a pooled analysis of data from 505 147 women across 10 countries

Human Reproduction ◽

10.1093/humrep/dez015 ◽

2019 ◽

Vol 34 (5) ◽

pp. 881-893 ◽

Cited By ~ 11

Author(s):

Keyword(s):

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Natural Menopause ◽

Individual Level ◽

Level Data ◽

Education Levels ◽

Reproductive Events ◽

Racial Ethnic ◽

Reproductive Indices

Abstract STUDY QUESTION How has the timing of women’s reproductive events (including ages at menarche, first birth, and natural menopause, and the number of children) changed across birth years, racial/ethnic groups and educational levels? SUMMARY ANSWER Women who were born in recent generations (1970–84 vs before 1930) or those who with higher education levels had menarche a year earlier, experienced a higher prevalence of nulliparity and had their first child at a later age. WHAT IS KNOWN ALREADY The timing of key reproductive events, such as menarche and menopause, is not only indicative of current health status but is linked to the risk of adverse hormone-related health outcomes in later life. Variations of reproductive indices across different birth years, race/ethnicity and socioeconomic positions have not been described comprehensively. STUDY DESIGN, SIZE, DURATION Individual-level data from 23 observational studies that contributed to the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) consortium were included. PARTICIPANTS/MATERIALS, SETTING, METHODS Altogether 505 147 women were included. Overall estimates for reproductive indices were obtained using a two-stage process: individual-level data from each study were analysed separately using generalised linear models. These estimates were then combined using random-effects meta-analyses. MAIN RESULTS AND THE ROLE OF CHANCE Mean ages were 12.9 years at menarche, 25.7 years at first birth, and 50.5 years at natural menopause, with significant between-study heterogeneity (I2 > 99%). A linear trend was observed across birth year for mean age at menarche, with women born from 1970 to 1984 having menarche one year earlier (12.6 years) than women born before 1930 (13.5 years) (P for trend = 0.0014). The prevalence of nulliparity rose progressively from 14% of women born from 1940–49 to 22% of women born 1970–84 (P = 0.003); similarly, the mean age at first birth rose from 24.8 to 27.3 years (P = 0.0016). Women with higher education levels had fewer children, later first birth, and later menopause than women with lower education levels. After adjusting for birth year and education level, substantial variation was present for all reproductive events across racial/ethnic/regional groups (all P values < 0.005). LIMITATIONS, REASONS FOR CAUTION Variations of study design, data collection methods, and sample selection across studies, as well as retrospectively reported age at menarche, age at first birth may cause some bias. WIDER IMPLICATIONS OF THE FINDINGS This global consortium study found robust evidence on variations in reproductive indices for women born in the 20th century that appear to have both biological and social origins. STUDY FUNDING/COMPETING INTEREST(S) InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by the Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844).

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A prospective study of reproductive factors in relation to risk of systemic lupus erythematosus among black women

Lupus ◽

10.1177/0961203320973074 ◽

2020 ◽

pp. 096120332097307

Author(s):

Yvette C Cozier ◽

Medha Barbhaiya ◽

Nelsy Castro-Webb ◽

Karen H Costenbader ◽

Lynn Rosenberg

Keyword(s):

Systemic Lupus Erythematosus ◽

Black Women ◽

Breast Feeding ◽

Lupus Erythematosus ◽

Reproductive Factors ◽

European Ancestry ◽

Age At Menarche ◽

Age At First Birth ◽

Systemic Lupus ◽

Incident Cases

Objective Systemic lupus erythematosus (SLE) occurs most commonly among reproductive age women, compatible with a potential role of reproductive factors, although past studies including women of mainly European ancestry have yielded conflicting results. We assessed relationships of reproductive factors to SLE risk among black women. Methods We followed 58,243 participants in the Black Women’s Health Study (BWHS) from 1995 – 2015 using biennial health questionnaires, on which participants reported reproductive and other factors. Self-reported incident SLE cases were confirmed as meeting 1997 American College of Rheumatology SLE classification criteria by medical record review. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for SLE for several reproductive factors, controlling for potential confounders. Results During 954,476 person-years of follow-up, 125 incident cases of SLE were confirmed. Later age at menarche and longer duration of breast feeding were associated with increased risk of SLE. The multivariable HRs were 2.31 (95% CI, 1.30–4.11) for age at menarche ≥15 relative to age 12, and 1.73 (95% CI, 1.01–2.94) for breast feeding ≥6 months relative to none. There were no clear associations with parity, age at first birth, menopausal status, hysterectomy, age at menopause, or history of endometriosis. Conclusion Our results suggest that later menarchal age and breastfeeding of infants for ≥6 months vs. none may be associated with increased SLE risk among black women, while other reproductive factors did not appear related. The biological mechanisms underlying these potential associations should be pursued.

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Reproductive characteristics are associated with gene-specific promoter methylation status in breast cancer

BMC Cancer ◽

10.1186/s12885-019-6120-4 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Lauren E. McCullough ◽

Lindsay J. Collin ◽

Kathleen Conway ◽

Alexandra J. White ◽

Yoon Hee Cho ◽

...

Keyword(s):

Breast Cancer ◽

Promoter Methylation ◽

Tumor Tissue ◽

Methylation Status ◽

Reproductive Factors ◽

Gene Promoter ◽

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Reproductive Characteristics

Abstract Background Reproductive characteristics are well-established risk factors for breast cancer, but the underlying mechanisms are not fully resolved. We hypothesized that altered DNA methylation, measured in tumor tissue, could act in concert with reproductive factors to impact breast carcinogenesis. Methods Among a population-based sample of women newly diagnosed with first primary breast cancer, reproductive history was assessed using a life-course calendar approach in an interviewer-administered questionnaire. Methylation-specific polymerase chain reaction and Methyl Light assays were used to assess gene promotor methylation status (methylated vs. unmethylated) for 13 breast cancer-related genes in archived breast tumor tissue. We used case-case unconditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations with age at menarche and parity (among 855 women), and age at first birth and lactation (among a subset of 736 parous women) in association with methylation status. Results Age at first birth > 27 years, compared with < 23 years, was associated with lower odds of methylation of CDH1 (OR = 0.44, 95% CI = 0.20–0.99) and TWIST1 (OR = 0.48, 95% CI = 0.28–0.82), and higher odds of methylation of BRCA1 (OR = 1.63, 95% CI = 1.14–2.35). Any vs. no lactation was associated with higher odds of methylation of the PGR gene promoter (OR = 1.59, 95% CI = 1.01–2.49). No associations were noted for parity and methylation in any of the genes assayed. Conclusions Our findings indicate that age at first birth, lactation and, perhaps age at menarche, are associated with gene promoter methylation in breast cancer, and should be confirmed in larger studies with robust gene coverage.

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Influence of Selected Reproductive Factors and Smoking on Age at Menopause

The Journal of South Asian Federation of Menopause Societies ◽

10.5005/jsafoms-3-2-64 ◽

2015 ◽

Vol 3 (2) ◽

pp. 64-66 ◽

Cited By ~ 1

Author(s):

B Rumianowski ◽

I Rotter ◽

A Brodowska ◽

G Adler ◽

J Kowalski ◽

...

Keyword(s):

Hormone Replacement ◽

Reproductive Factors ◽

Age At Menarche ◽

First Birth ◽

Natural Menopause ◽

Age At Menopause ◽

The Difference ◽

Surrounding Areas ◽

Effect Of Age

ABSTRACT Introduction Early menopause may be associated with serious health risks resulting from, e.g. decreased estrogen levels. This may occur despite hormone replacement therapy. Aim The aim of this study was the determination of the effect of selected reproductive factors and smoking on age at the onset of menopause in women from Szczecin and surrounding areas. Materials and methods Three hundred and five women after natural menopause were asked to complete a questionnaire, and blood samples were collected from them to test for the levels of follicle stimulating hormone (FSH) andoestradiol (E2). Results Smoking women experienced menopause on average more than a year earlier than non-smokers, but this difference was not statistically significant. There was no statistically significant effect of age at menarche or first birth on age at the last menstrual period. Conclusion Age at menarche and first birth were not related to age at menopause. In smoking women, menopause occurred earlier but the difference was not statistically significant.

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Pregnancy and the Risk of Rheumatoid Arthritis in a Highly Predisposed North American Native Population

The Journal of Rheumatology ◽

10.3899/jrheum.120269 ◽

2012 ◽

Vol 39 (12) ◽

pp. 2253-2260 ◽

Cited By ~ 24

Author(s):

CHRISTINE A. PESCHKEN ◽

DAVID B. ROBINSON ◽

CAROL A. HITCHON ◽

IRENE SMOLIK ◽

DONNA HART ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

North American ◽

Shared Epitope ◽

Reproductive History ◽

Early Age ◽

Age At First Birth ◽

Native Population ◽

First Birth ◽

Pregnancy Smoking ◽

First Time

Objective.To examine reproductive history and rheumatoid arthritis (RA) risk in a highly predisposed population of North American Natives (NAN) with unique fertility characteristics.Methods.The effect of pregnancy on the risk of RA was examined by comparing women enrolled in 2 studies: a study of RA in NAN patients and their unaffected relatives; and NAN patients with RA and unrelated healthy NAN controls enrolled in a study of autoimmunity. All participants completed questionnaires detailing their reproductive history.Results.Patients with RA (n = 168) and controls (n = 400) were similar overall in age, education, shared epitope frequency, number of pregnancies, age at first pregnancy, smoking, and breastfeeding history. In multivariate analysis, for women who had ≥ 6 births the OR for developing RA was 0.43 (95% CI 0.21–0.87) compared with women who had 1–2 births (p = 0.046); for women who gave birth for the first time after age 20 the OR for developing RA was 0.33 (95% CI 0.16–0.66) compared with women whose first birth occurred at age ≤ 17 (p = 0.001). The highest risk of developing RA was in the first postpartum year (OR 3.8; 95% CI 1.45–9.93) compared with subsequent years (p = 0.004).Conclusion.In this unique population, greater parity significantly reduced the odds of RA; an early age at first birth increased the odds, and the postpartum period was confirmed as high risk for RA onset. The protective effect of repeated exposure to the ameliorating hormonal and immunological changes of pregnancy may counterbalance the effect of early exposure to the postpartum reversal of these changes.

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Reproductive period and risk of dementia in a diverse cohort of health care members

Neurology ◽

10.1212/wnl.0000000000007326 ◽

2019 ◽

Vol 92 (17) ◽

pp. e2005-e2014 ◽

Cited By ~ 15

Author(s):

Paola Gilsanz ◽

Catherine Lee ◽

Maria M. Corrada ◽

Claudia H. Kawas ◽

Charles P. Quesenberry ◽

...

Keyword(s):

Life Course ◽

Health Indicators ◽

Reproductive Period ◽

Age At Menarche ◽

Natural Menopause ◽

Estrogen Exposure ◽

Dementia Risk ◽

Life Course Health ◽

Large Prospective Cohort Study ◽

Menarche Age

ObjectiveWomen have >50% greater lifetime risk of dementia than men but the role of female-specific endocrine milieu is not well-understood. This study evaluates associations between indicators of estrogen exposure from women's reproductive period and dementia risk in a large diverse population.MethodsWe evaluated 15,754 female members (29.9% nonwhite) of Kaiser Permanente with clinical examinations and health survey data from 1964 to 1973 and were members as of January 1, 1996. In midlife (mean age 51.1 years), women reported age at menarche and menopause and hysterectomy status. Reproductive span was calculated as menopause age minus menarche age. Dementia diagnoses were abstracted from January 1, 1996 to September 30, 2017 medical records (mean age at start of dementia follow-up 76.5 years). Cox proportional hazard models evaluated associations between aspects of reproductive span and dementia risk adjusting for demographics and life course health indicators.ResultsForty-two percent of women developed dementia. Compared to menarche at age 13.0 (mean menarche age), menarche at ≥16 was associated with 23% greater dementia risk (adjusted hazard ratio [HR] 1.23; 95% confidence interval [CI] 1.01–1.50) adjusting for demographics and life course health indicators. Natural menopause at age <47.4 (mean menopause age) was associated with 19% elevated dementia risk (HR 1.19; 95% CI 1.07–1.31). Reproductive spans <34.4 years (mean duration) were associated with 20% elevated dementia risk (HR 1.20; 95% CI 1.08–1.32). Hysterectomies were associated with 8% elevated dementia risk (HR 1.08; 95% CI 1.01–1.16).ConclusionIn this large prospective cohort study, endocrine events signaling less estradiol exposure (i.e., later age at menarche, younger age at menopause, shorter reproductive span, and hysterectomies) were associated with elevated risk of dementia.

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Diet, menopause and the risk of ovarian, endometrial and breast cancer

Proceedings of The Nutrition Society ◽

10.1017/s0029665118002884 ◽

2019 ◽

Vol 78 (3) ◽

pp. 438-448 ◽

Cited By ~ 3

Author(s):

Yashvee Dunneram ◽

Darren C. Greenwood ◽

Janet E. Cade

Keyword(s):

Breast Cancer ◽

Health Outcomes ◽

Reproductive Factors ◽

Dietary Factors ◽

Current Evidence ◽

Age At Menarche ◽

Dietary Intakes ◽

Future Health ◽

Natural Menopause ◽

Increased Risk

Menopause, the permanent cessation of the menstrual cycle, marks the end of a woman's reproductive lifespan. In addition to changes in sex hormone levels associated with menopause, its timing is another predictor of future health outcomes such as duration of the presence of vasomotor symptoms (VMS) and the risk of hormone-related cancers. With ageing of the population, it is estimated that worldwide 1·2 billion women will be menopausal by the year 2030. Previously the effects of reproductive factors (e.g. parity, age at menarche, pregnancy) and socio-demographic factors on intermediate and long-term health outcomes of menopause have been widely documented. However, little is known about whether diet could have an impact on these. Therefore, we review current evidence on the associations of diet with menopause, presence of VMS and the risk of hormone-related cancers such as ovarian, endometrial and breast cancer. Dietary factors could influence the lifespan of the ovaries and sex-hormones levels, hence the timing of natural menopause. Few studies reported an association between diet, in particular soya consumption, and a reduced risk of VMS. Sustained oestrogen exposure has been associated with a higher risk of hormone-related cancers and thus high-fat and meat diets have been linked with an increased risk of these cancers. However, to better understand the mechanistic pathways involved and to make stronger conclusions for these relationships, further studies investigating the associations of dietary intakes and dietary patterns with menopause, presence of VMS and the risk of hormone-related cancers are required.

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