Each pregnancy linearly changes immune gene expression in the blood of healthy women compared with breast cancer patients
Received 20 January 2018
Accepted for publication 30 April 2018
Published 6 August 2018 Volume 2018:10 Pages 931—940
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Amy Norman
Peer reviewer comments 2
Editor who approved publication: Professor Vera Ehrenstein
Eiliv Lund,1,2 Aurelie Nakamura,3,4 Igor Snapkov,1 Jean-Christophe Thalabard,5 Karina Standahl Olsen,1 Lars Holden,6 Marit Holden6
1Department of Community Medicine, UiT The Arctic University of Norway, Tromso, Norway; 2The Cancer Registry of Norway, Oslo, Norway; 3Department of Social Epidemiology, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, INSERM, Paris, France; 4French School of Public Health (EHESP), Doctoral Network, Rennes, France; 5MAP5, UMR CNRS 8145, Université Paris Descartes, Sorbonne Paris Cite, Paris, France; 6Norwegian Computing Center, Oslo, Norway
Background: There is a large body of evidence demonstrating long-lasting protective effect of each full-term pregnancy (FTP) on the development of breast cancer (BC) later in life, a phenomenon that could be related to both hormonal and immunological changes during pregnancies. In this work, we studied the pregnancy-associated differences in peripheral blood gene expression profiles between healthy women and women diagnosed with BC in a prospective design.
Methods: Using an integrated system epidemiology approach, we modeled BC incidence as a function of parity in the Norwegian Women and Cancer (NOWAC) cohort (165,000 women) and then tested the resulting mathematical model using gene expression profiles in blood in a nested case–control study (460 invasive case–control pairs) of women from the NOWAC postgenome cohort. Lastly, we undertook a gene set enrichment analysis for immunological gene sets.
Results: A linear trend fitted the dataset precisely showing an 8% decrease in risk of BC for each FTP, independent of stratification on other risk factors and lasting for decades after a woman’s last FTP. Women with six children demonstrated 48% reduction in the incidence of BC compared to nulliparous. When we looked at gene expression, we found that 756 genes showed linear trends in cancer-free controls (false discovery rate [FDR] 5%), but this was not the case for any of the genes in BC cases. Gene set enrichment analysis of immunologic gene sets (C7 collection in Molecular Signatures Database) revealed 215 significantly enriched human gene sets (FDR 5%).
Conclusion: We found marked differences in gene expression and enrichment profiles of immunologic gene sets between BC cases and healthy controls, suggesting an important protective effect of the immune system on BC risk.
Keywords: breast cancer, Norwegian Women and Cancer Study, gene expression, parity, semi-allograft, hormones, pregnancy
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