Methylation-Based Biological Age and Breast Cancer Risk

Abstract Background Age is one of the strongest predictors of cancer, chronic disease, and mortality, but biological responses to aging differ among people. Epigenetic DNA modifications have been used to estimate “biological age,” which may be a useful predictor of disease risk. We tested this hypothesis for breast cancer. Methods Using a case-cohort approach, we measured baseline blood DNA methylation of 2764 women enrolled in the Sister Study, 1566 of whom subsequently developed breast cancer after an average of 6 years. Using three previously established methylation-based “clocks” (Hannum, Horvath, and Levine), we defined biological age acceleration for each woman by comparing her estimated biological age with her chronological age. Hazard ratios and 95% confidence intervals for breast cancer risk were estimated using Cox regression models. All statistical tests were two-sided. Results Each of the three clocks showed that biological age acceleration was statistically significantly associated with increased risk of developing breast cancer (5-year age acceleration, Hannum’s clock: hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.00 to 1.21, P = .04; Horvath’s clock: HR = 1.08, 95% CI = 1.00 to 1.17, P = .04; Levine’s clock: HR = 1.15, 95% CI = 1.07 to 1.23, P < .001). For Levine’s clock, each 5-year acceleration in biological age corresponded with a 15% increase in breast cancer risk. Although biological age may accelerate with menopausal transition, age acceleration in premenopausal women independently predicted breast cancer. Case-only analysis suggested that, among women who develop breast cancer, increased age acceleration is associated with invasive cancer (odds ratio for invasive = 1.09, 95% CI = 0.98 to 1.22, P = .10). Conclusions DNA methylation-based measures of biological age may be important predictors of breast cancer risk.

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DNA methylation-based biological age, genome-wide average DNA methylation, and conventional breast cancer risk factors

Scientific Reports ◽

10.1038/s41598-019-51475-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Minyuan Chen ◽

Ee Ming Wong ◽

Tuong L. Nguyen ◽

Gillian S. Dite ◽

Jennifer Stone ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Dna Methylation ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Biological Age ◽

Age At Menarche ◽

Cancer Risk Factors ◽

Genome Wide ◽

Breast Cancer Risk Factors

Abstract DNA methylation-based biological age (DNAm age), as well as genome-wide average DNA methylation, have been reported to predict breast cancer risk. We aimed to investigate the associations between these DNA methylation-based risk factors and 18 conventional breast cancer risk factors for disease-free women. A sample of 479 individuals from the Australian Mammographic Density Twins and Sisters was used for discovery, a sample of 3354 individuals from the Melbourne Collaborative Cohort Study was used for replication, and meta-analyses pooling results from the two studies were conducted. DNAm age based on three epigenetic clocks (Hannum, Horvath and Levine) and genome-wide average DNA methylation were calculated using the HumanMethylation 450 K BeadChip assay data. The DNAm age measures were positively associated with body mass index (BMI), smoking, alcohol drinking and age at menarche (all nominal P < 0.05). Genome-wide average DNA methylation was negatively associated with smoking and number of live births, and positively associated with age at first live birth (all nominal P < 0.05). The association of DNAm age with BMI was also evident in within-twin-pair analyses that control for familial factors. This study suggests that some lifestyle and hormonal risk factors are associated with these DNA methylation-based breast cancer risk factors, and the observed associations are unlikely to be due to familial confounding but are likely causal. DNA methylation-based risk factors could interplay with conventional risk factors in modifying breast cancer risk.

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Nutrient-wide association study of 92 foods and nutrients and breast cancer risk

Proceedings of The Nutrition Society ◽

10.1017/s0029665120001275 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Alicia Heath ◽

David Muller ◽

Piet van den Brandt ◽

Nikos Papadimitriou ◽

Elena Critselis ◽

...

Keyword(s):

Breast Cancer ◽

Alcohol Consumption ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Association Study ◽

Cox Regression ◽

Dietary Factors ◽

Breast Cancers ◽

Study Approach ◽

Increased Risk

AbstractSeveral dietary factors have been extensively investigated for associations with risk of breast cancer, but to date unequivocal evidence only exists for alcohol consumption. We sought to systematically evaluate the association between 92 dietary factors and breast cancer risk using a nutrient-wide association study approach. Using data from 272,098 women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we assessed dietary intake of 92 foods and nutrients estimated by dietary questionnaires. Cox regression with age as the time scale and adjustment for potential confounders, was used to quantify the association between each food or nutrient and risk of breast cancer. A false discovery rate (FDR) of 0.05 was used to select the set of foods and nutrients to evaluate in the independent replication cohort, the Netherlands Cohort Study (NLCS). During a median follow-up time of 15 years, 10,979 incident invasive breast cancers were identified in the women from the EPIC study. Six foods and nutrients were associated with risk of breast cancer when controlling the FDR at 0.05. Higher intake of alcohol overall was associated with a higher risk of breast cancer (hazard ratio (HR) for a 1 SD increment in intake = 1.05, 95% confidence interval (CI) 1.03–1.07), as was beer/cider intake and wine intake (HRs per 1 SD increment = 1.05, 95% CI 1.03–1.06 and 1.04, 95% CI 1.02–1.06, respectively), whereas higher intakes of fibre, apple/pear, and carbohydrates were associated with a lower risk of breast cancer (HRs per 1 SD increment = 0.96, 95% CI 0.94–0.98; 0.96, 95% CI 0.94–0.99; and 0.96, 95% CI 0.95–0.98, respectively). When evaluated in the NLCS (2368 invasive breast cancer cases), estimates for each of these foods and nutrients were similar in magnitude and direction, with the exception of beer/cider intake, which was not associated with risk of breast cancer in the NLCS. Our findings confirm the well-established increased risk of breast cancer associated with alcohol consumption, and suggest that higher intake of dietary fibre, and possibly fruit and carbohydrates, might be associated with reduced breast cancer risk.

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Genetically Predicted Levels of DNA Methylation Biomarkers and Breast Cancer Risk: Data From 228 951 Women of European Descent

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djz109 ◽

2019 ◽

Vol 112 (3) ◽

pp. 295-304 ◽

Cited By ~ 10

Author(s):

Yaohua Yang ◽

Lang Wu ◽

Xiao-Ou Shu ◽

Qiuyin Cai ◽

Xiang Shu ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Statistical Power ◽

Prediction Models ◽

Statistical Tests ◽

Critical Role ◽

White Blood Cells ◽

Cpg Sites

Abstract Background DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. Methods Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women’s Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. Results Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10–7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. Conclusion Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.

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СONTRIBUTION OF POLYMORPHIC VARIATION OF ТP53 AND XRCC1 GENES TO THE SUSCEPTIBILITY TO BREAST CANCER FOR WOMEN OF KYRGYZ AND BELARUSIAN NATIONALITY - A COMPARATIVE STUDY ON MULTIFACTOR DIMENSIONALITY REDUCTION METHODS

Problems in oncology ◽

10.37469/0507-3758-2018-64-1-95-101 ◽

2018 ◽

Vol 64 (1) ◽

pp. 95-101

Author(s):

Nazira Aldasheva ◽

Vyacheslav Kipen ◽

Zhaynagul Isakova ◽

Sergey Melnov ◽

Raisa Smolyakova ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Dimensionality Reduction ◽

Multifactor Dimensionality Reduction ◽

Rflp Analysis ◽

Kyrgyz Republic ◽

Increased Risk ◽

Polymorphic Variants ◽

The Republic

Basing on Multifactor Dimensionality Reduction method we showed that polymorphic variants p.Q399R (rs25487, XRCC1) and p.P72R (rs1042522, TP53) correlated with increased risk of breast cancer for women from the Kyrgyz Republic and the Republic of Belarus. Cohort for investigation included patients with clinically verified breast cancer: 117 women from the Kyrgyz Republic (nationality - Kyrgyz) and 169 - of the Republic of Belarus (nationality - Belarusians). Group for comparison included (healthy patients without history of cancer pathology at the time of blood sampling) 102 patients from the Kyrgyz Republic, 185 - from the Republic of Belarus. Respectively genotyping of polymorphic variants p.Q399R (rs25487, XRCC1) and p.P72R (rs1042522, TP53) was done by PCR-RFLP. Analysis of the intergenic interactions conducted with MDR 3.0.2 software. Both ethnic groups showed an increase of breast cancer risk in the presence of alleles for SNPs Gln p.Q399R (XRCC1) in the heterozygous state: for the group “Kyrgyz” - OR=2,78 (95% CI=[1,60-4,82]), p=0,001; for the group “Belarusians” - OR=1,85 (95% СІ=[1Д1-2,82], p=0,004. Carriers with combination of alleles Gln (p.Q399R, XRCC1) and Pro (p.P72R, TP53) showed statistically significance increases of breast cancer risk as for patients from the Kyrgyz Republic (OR=2,89, 95% CI=[1,33-6,31]), so as for patients from the Republic of Belarus (OR=3,01, 95% CI=[0,79-11,56]).

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Analysis of Italian BRCA1/2 Pathogenic Variants Identifies a Private Spectrum in the Population from the Bergamo Province in Northern Italy

Cancers ◽

10.3390/cancers13030532 ◽

2021 ◽

Vol 13 (3) ◽

pp. 532

Author(s):

Gisella Figlioli ◽

Arcangela De Nicolo ◽

Irene Catucci ◽

Siranoush Manoukian ◽

Bernard Peissel ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Disease Risk ◽

Northern Italy ◽

Genetic Isolate ◽

National Population ◽

Pathogenic Variants ◽

High Breast Cancer Risk

Germline pathogenic variants (PVs) in the BRCA1 or BRCA2 genes cause high breast cancer risk. Recurrent or founder PVs have been described worldwide including some in the Bergamo province in Northern Italy. The aim of this study was to compare the BRCA1/2 PV spectra of the Bergamo and of the general Italian populations. We retrospectively identified at five Italian centers 1019 BRCA1/2 PVs carrier individuals affected with breast cancer and representative of the heterogeneous national population. Each individual was assigned to the Bergamo or non-Bergamo cohort based on self-reported birthplace. Our data indicate that the Bergamo BRCA1/2 PV spectrum shows less heterogeneity with fewer different variants and an average higher frequency compared to that of the rest of Italy. Consistently, four PVs explained about 60% of all carriers. The majority of the Bergamo PVs originated locally with only two PVs clearly imported. The Bergamo BRCA1/2 PV spectrum appears to be private. Hence, the Bergamo population would be ideal to study the disease risk associated with local PVs in breast cancer and other disease-causing genes. Finally, our data suggest that the Bergamo population is a genetic isolate and further analyses are warranted to prove this notion.

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Transiently increased risk of breast cancer after childbirth: implications for fertility treatments and surrogacy

Human Reproduction ◽

10.1093/humrep/deaa102 ◽

2020 ◽

Vol 35 (6) ◽

pp. 1253-1255

Author(s):

Zeev Blumenfeld ◽

Norbert Gleicher ◽

Eli Y Adashi

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Meta Analysis ◽

Small Degree ◽

Short Term ◽

Benefit Ratio ◽

Professional Societies ◽

Fertility Treatments ◽

Increased Risk

Abstract Whereas longstanding dogma has purported that pregnancies protect women from breast cancer, a recent meta-analysis now mandates reconsideration since it reported an actual higher breast cancer risk for more than two decades after childbirth before the relative risk turns negative. Moreover, the risk of breast cancer appears higher for women having their first birth at an older age and with a family history and it is not reduced by breastfeeding. The process of obtaining informed consent for all fertility treatments, therefore, must make patients aware of the facts that every pregnancy, to a small degree, will increase the short-term breast cancer risk. This observation may be even more relevant in cases of surrogacy where women agree to conceive without deriving benefits of offspring from assuming the risk, thus creating a substantially different risk-benefit ratio. Consequently, it appears prudent for professional societies in the field to update recommendations regarding consent information for all fertility treatments but especially for treatments involving surrogacy.

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Endogenous hormones and risk of invasive breast cancer in pre- and post-menopausal women: findings from the UK Biobank

British Journal of Cancer ◽

10.1038/s41416-021-01392-z ◽

2021 ◽

Author(s):

Sandar Tin Tin ◽

Gillian K. Reeves ◽

Timothy J. Key

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Invasive Breast Cancer ◽

Cox Regression ◽

Menopausal Status ◽

Endogenous Hormones ◽

Uk Biobank ◽

Menopausal Women ◽

Post Menopausal

Abstract Background Some endogenous hormones have been associated with breast cancer risk, but the nature of these relationships is not fully understood. Methods UK Biobank was used. Hormone concentrations were measured in serum collected in 2006–2010, and in a repeat subsample (N ~ 5000) in 2012–13. Incident cancers were identified through data linkage. Cox regression models were used, and hazard ratios (HRs) corrected for regression dilution bias. Results Among 30,565 pre-menopausal and 133,294 post-menopausal women, 527 and 2,997, respectively, were diagnosed with invasive breast cancer during a median follow-up of 7.1 years. Cancer risk was positively associated with testosterone in post-menopausal women (HR per 0.5 nmol/L increment: 1.18; 95% CI: 1.14, 1.23) but not in pre-menopausal women (pheterogeneity = 0.03), and with IGF-1 (insulin-like growth factor-1) (HR per 5 nmol/L increment: 1.18; 1.02, 1.35 (pre-menopausal) and 1.07; 1.01, 1.12 (post-menopausal); pheterogeneity = 0.2), and inversely associated with SHBG (sex hormone-binding globulin) (HR per 30 nmol/L increment: 0.96; 0.79, 1.15 (pre-menopausal) and 0.89; 0.84, 0.94 (post-menopausal); pheterogeneity = 0.4). Oestradiol, assessed only in pre-menopausal women, was not associated with risk, but there were study limitations for this hormone. Conclusions This study confirms associations of testosterone, IGF-1 and SHBG with breast cancer risk, with heterogeneity by menopausal status for testosterone.

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Association of APC and MCC Polymorphisms with Increased Breast Cancer Risk in an Indian Population

The International Journal of Biological Markers ◽

10.5301/jbm.2011.6266 ◽

2011 ◽

Vol 26 (1) ◽

pp. 43-49 ◽

Cited By ~ 3

Author(s):

Nupur Mukherjee ◽

Nilanjana Bhattacharya ◽

Satyabrata Sinha ◽

Neyaz Alam ◽

Runu Chakravarti ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Minor Allele ◽

Nucleotide Polymorphisms ◽

Breast Cancer Patients ◽

Increased Risk ◽

Risk Of Cancer

The adenomatous polyposis coli (APC) and mutated in colorectal cancer (MCC) genes are key regulatory genes of the Wnt/β-catenin signaling pathway, which are independently involved in maintaining low levels of β-catenin in the cell. In addition to genetic and epigenetic alterations, some genetic polymorphisms in the genes associated with the Wnt signaling pathway have been reported to be associated with an increased risk of cancer, including breast cancer. In the present study we analyzed the association of genotype and haplotype status of two single nucleotide polymorphisms (SNPs), rs2229992 and rs11283943, in the APC and MCC genes, respectively, with an increased risk of breast carcinogenesis in a breast cancer and control population from eastern India. We observed a significant association of the rs11283943 SNP with increased breast cancer risk. Two specific haplotypes involving the minor allele of rs11283943 were found to be associated with an increased breast cancer risk. Kaplan-Meier curves showed a significant association of the 2–2 genotype (genotype homozygous for the rs11283943 minor allele) with decreased survival (p=0.045) of the breast cancer patients in our study, in particular patients with early-onset BC.

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