title: Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue.
abstract: Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure (p < 0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA. hannah.oh@nih.gov.
authors.forename: Hannah
authors.identifier: 0000-0002-8368-3032
authors.initials: H
authors.lastname: Oh
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Bodelon
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Palakal
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.|Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Linville
authors.affiliation: The University of Vermont, Burlington, VT, USA.
authors.forename: Berta M
authors.initials: BM
authors.lastname: Geller
authors.affiliation: The University of Vermont, Burlington, VT, USA.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Vacek
authors.affiliation: The University of Vermont, Burlington, VT, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Weaver
authors.affiliation: The University of Vermont, Burlington, VT, USA.
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Chicoine
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Daphne
authors.initials: D
authors.lastname: Papathomas
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Deesha A
authors.initials: DA
authors.lastname: Patel
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Jackie
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Clare
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Genomic Health, Inc., Redwood City, CA, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Mies
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Brinton
authors.affiliation: Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Anna Maria V
authors.initials: AM
authors.lastname: Storniolo
authors.affiliation: Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.|Indiana University Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: He
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Gierach
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.|Usher Institute of Population Health Sciences and Informatics, Institute of Genomics and Molecular Medicine, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: Jonine D
authors.initials: JD
authors.lastname: Figueroa
mesh_terms: D000328:Adult; D000367:Age Factors; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D042361:Mammary Glands, Human / Q000033:anatomy & histology* / Q000473:pathology; D008572:Menarche / Q000235:genetics*; D008593:Menopause; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
keywords: Breast histology; Lobular involution; Menarche; Menopause; SNP; TDLU