Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue

Hannah Oh, Clara Bodelon, Maya Palakal, Nilanjan Chatterjee, Mark E. Sherman, Laura Linville, Berta M. Geller, Pamela M. Vacek, Donald L. Weaver, Rachael E. Chicoine, Daphne Papathomas, Deesha A. Patel, Jackie Xiang, Susan E. Clare, Daniel W. Visscher, Carolyn Mies, Stephen M. Hewitt, Louise A. Brinton, Anna Maria V. Storniolo, Chunyan HeMontserrat Garcia-Closas, Stephen J. Chanock, Gretchen L. Gierach, Jonine D. Figueroa

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Pages (from-to)341-350
Number of pages10
JournalBreast Cancer Research and Treatment
Volume158
Issue number2
DOIs
StatePublished - Jul 1 2016

Bibliographical note

Publisher Copyright:
© 2016, Springer Science+Business Media New York (outside the USA).

Funding

This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. Breast Cancer Research Stamp Funds (M.E. Sherman, L.A. Brinton) and cooperative agreement U01CA70013 (B.M. Geller, P.M. Vacek, D.L. Weaver, R.E. Chicoine) from the National Cancer Institute funded some of the data collection for this study. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Participants provided written informed consent, and the studies were approved by the Institutional Review Board at the Indiana University and the NIH Office of Human Subjects Research for the KTB and by the Institutional Review Boards at the University of Vermont and the NCI for the BREAST Stamp Project.

FundersFunder number
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute
National Center for Advancing Translational Sciences (NCATS)UL1TR001108
University of Southern Indiana
University of Vermont
National Cancer Institute Division of Cancer Epidemiology and GeneticsU01CA70013

    Keywords

    • Breast histology
    • Lobular involution
    • Menarche
    • Menopause
    • SNP
    • TDLU

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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