{"doi":"10.1093/hmg/ddz301","title":"Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>Prior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis, we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts. DNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. Through an epigenome-wide association study we explored CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer using linear mixed effects models adjusted for history of breast biopsy, age, RefFreeCellMix cell estimates, time of delivery, array chip and subject as random effect. We identified 58 differentially methylated CpG sites associated with a subsequent breast cancer diagnosis (q-value &amp;lt;0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls. Breast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors and improving primary and secondary prevention of breast cancer.</jats:p>","journal":"Human Molecular Genetics","year":2020,"id":613170,"datarank":0.4566783656585135,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.0,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1579458,"name":"Sara N Lundgren","orcid":null,"position":1,"is_corresponding":false},{"id":1579459,"name":"Eva P Browne","orcid":null,"position":2,"is_corresponding":false},{"id":1579460,"name":"Elizabeth C Punska","orcid":null,"position":3,"is_corresponding":false},{"id":1579461,"name":"Douglas L Anderton","orcid":null,"position":4,"is_corresponding":false},{"id":1114133,"name":"Margaret R Karagas","orcid":null,"position":5,"is_corresponding":false},{"id":1579462,"name":"Kathleen F Arcaro","orcid":null,"position":6,"is_corresponding":false},{"id":1566998,"name":"Brock C Christensen","orcid":null,"position":7,"is_corresponding":false},{"id":1579457,"name":"Lucas A Salas","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>Prior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis, we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts. DNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. Through an epigenome-wide association study we explored CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer using linear mixed effects models adjusted for history of breast biopsy, age, RefFreeCellMix cell estimates, time of delivery, array chip and subject as random effect. We identified 58 differentially methylated CpG sites associated with a subsequent breast cancer diagnosis (q-value &amp;lt;0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls. Breast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors and improving primary and secondary prevention of breast cancer.</jats:p>","is_dataset_classified":null,"base_score":3.044522437723423,"endowment":3.044522437723423,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31943067","pmcid":"PMC7068171","openalex_id":"https://openalex.org/W2999179630","authors":[],"funders":[{"funder_name":"Center for Molecular Epidemiology at Dartmouth","grant_id":"P20GM104416","title":null},{"funder_name":"National Cancer Institute","grant_id":"R01CA216265","title":null},{"funder_name":"National Cancer Institute","grant_id":"R01CA230478-01A1","title":null},{"funder_name":"National Institute of Environmental Health Sciences","grant_id":"P01ES022832","title":null},{"funder_name":"Environmental Protection Agency","grant_id":"RD-83544201","title":null},{"funder_name":"Congressionally Directed Medical Research Programs","grant_id":"W81XWH-08-1-0721","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA230478","title":null},{"funder_name":"National Institutes of Health","grant_id":"5P20GM104416-10","title":"Center for Molecular Epidemiology"},{"funder_name":"National Institutes of Health","grant_id":"5R01CA230478-02","title":"Fruit and vegetable intervention in lactating women to reduce breast cancer risk: effects on breast cell DNA methylation, breast inflammation, and weight"},{"funder_name":"National Institutes of Health","grant_id":"3P01ES022832-03S1","title":"Administrative Core/Leadership"},{"funder_name":"National Institutes of Health","grant_id":"5R01CA216265-05","title":"(PQ3) Immune epigenetic biomarkers of bladder cancer outcomes"},{"funder_name":"National Institutes of Health","grant_id":"5P20GM104416-02","title":"Biorepository Core"},{"funder_name":"Centers of Biomedical Research Excellence","grant_id":"","title":null},{"funder_name":"National Institutes of General Medical Sciences","grant_id":"","title":null}],"total_grants":14,"fwci":0.6831,"citation_percentile":0.68314731,"influential_citations":0,"citation_trend":[{"year":2019,"count":1},{"year":2020,"count":1},{"year":2021,"count":2},{"year":2022,"count":5},{"year":2023,"count":4},{"year":2024,"count":3},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"hybrid","license":"cc-by-nc","oa_locations":[{"url":"https://academic.oup.com/hmg/article-pdf/29/4/662/32899318/ddz301.pdf","host_type":"journal"},{"url":"https://academic.oup.com/hmg/article-pdf/29/4/662/32899318/ddz301.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/hmg/advance-article-pdf/doi/10.1093/hmg/ddz301/32323547/ddz301.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/hmg/article-pdf/29/4/662/32899318/ddz301.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/hmg/ddz301","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31943067","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7068171","host_type":"repository"},{"url":"https://hdl.handle.net/20.500.14394/50424","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC7068171","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC7068171?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1101/19001925","host_type":""},{"url":"http://dx.doi.org/10.1093/hmg/ddz301","host_type":""},{"url":"https://dx.doi.org/10.1093/hmg/ddz301","host_type":""},{"url":"https://dx.doi.org/10.1101/19001925","host_type":""},{"url":"http://dx.doi.org/10.1101/19001925","host_type":""},{"url":"https://doi.org/https://doi.org/10.1093/hmg/ddz301","host_type":""}],"fields_of_study":["Epigenetics and DNA Methylation","Genetic Syndromes and Imprinting","0301 basic medicine","03 medical and health sciences","Adolescent","Adult","Breast Neoplasms","Case-Control Studies","DNA Methylation","Epigenesis, Genetic","Female","Gene Expression Regulation, Neoplastic","Humans","Middle Aged","Milk, Human","Prognosis","Prospective Studies","Young Adult"],"mesh_terms":["Adolescent","Adult","Breast Neoplasms","Female","Humans","Middle Aged","Milk, Human","Prognosis","Prospective Studies","Gene Expression Regulation, Neoplastic","Case-Control Studies","DNA Methylation","Epigenesis, Genetic","Young Adult"],"keywords":["Breast cancer","DNA methylation","Oncology","Epigenetics","Breast disease","Cancer","Biology","CpG site","Internal medicine","Methylation","Carcinogenesis","Cancer research","Medicine","Genetics","Gene","Gene expression","Adult","Adolescent","Milk, Human","610","Breast Neoplasms","Middle Aged","Prognosis","Epigenesis, Genetic","Gene Expression Regulation, Neoplastic","General Article One","Young Adult","Case-Control Studies","616","Humans","Female","Prospective Studies"],"sdg_mappings":[{"sdg_number":2,"sdg_label":"2. 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