Fetal-maternal genetic interactions and the effects of maternal age at first pregnancy on breast cancer susceptibility

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A woman's age at first full-term pregnancy impacts on her life-long breast cancer risk: below the age of 20, there is aprotective effect; by 25, there is an increase in risk around childbirth before the protective effect starts; after 25 theprotective effect is reduced. Women who give birth at 35 have a higher breast cancer risk than nulliparous women.Early pregnancy induces a genomic expression profile that is still identifiable in post-menopausal breast tissue, andincludes transcription factors and genes encoding apoptosis- and DNA repair-related proteins. However, little isknown about the impact of fetus-driven placental growth factors on maternal mammary gland differentiation duringpregnancy, or the genetic interactions that regulate them. It is not known whether placental growth factor levels differwith maternal age.About 95 placental and fetal growth regulating factors are encoded by imprinted genes. This project will examineexpression levels of imprinted genes in placental tissue relative to endocrine growth hormone levels and insulinsignalling markers in maternal serum during different stages of pregnancy, in women of different age groupsexperiencing a first pregnancy.Placental tissue and matched maternal serum samples are available from BabyBioBank. Placenta samples will beassayed for imprinted DNA methylation and expression using pyrosequencing assays and targeted RNA sequencing.Matched maternal serum samples will be analysed by mass spectrometry to correlate placental imprinted geneexpression with serum growth factors and hormone levels. These data will be compared to gene expression profilesin normal and tumour tissues of breast cancer patients using publicly available data sets such as the METABRICproject. Samples from the breast cancer clinic at RUH will be used to validate expression of selected genes identifiedin the analysis.The results will provide valuable information on fetal-maternal gene circuits and their influence on m ammary glanddifferentiation. Future studies will examine whether these gene circuits confer protection against breast cancer. Thisis a particularly pertinent project when women are tending to delay childbearing: in 1970, the average age of firstpregnancy was 21.4 years; in 2013 it was 30.3 years. Between 2002-2004 and 2011-2013, female breast cancerincidence rates (age standardised) have increased by 6%. As women delay having children the risk for breast cancerwill increase, therefore this approach to understanding whether placental development influences risk by alteringmammary gene expression profiles would lead to improved maternal health outcome and lifelong health.The project falls within the MRC strategic research priorities of "improved health outcome" and "genetics approach tounderstand lifelong health". Pregnant women are a priority in public health screening programs to ensure improvedhealth outcome for the next generation.The project provides cross-disciplinary research training, including in experimental design and statistics to carry out apopulation study using the available placenta and maternal serum samples. It aligns with MRC DTP goals prioritisingcross-cutting skills areas such as quantitative skills and in vivo science. The supervising team matches the aim tosupport collaboration across the GW4 the partner institutions, and includes early career researchers