Early-Life Body Adiposity and the Breast Tumor Transcriptome
Menée à partir de l'analyse de 835 échantillons tumoraux et de 663 échantillons de tissus adjacents normaux provenant de patientes atteintes d'un cancer du sein et incluses dans les cohortes "Nurses’ Health Studies", cette étude analyse, en fonction du statut des récepteurs aux estrogènes, la corrélation entre le niveau d'adiposité corporelle à l'adolescence (âge : entre 10 et 20 ans) et l'expression de plusieurs ensembles de gènes au niveau de la tumeur et des tissus adjacents
Cumulative epidemiologic evidence has shown that early-life adiposity is strongly inversely associated with breast cancer risk throughout life, independent of adult obesity. However, the molecular mechanisms remain poorly understood. We assessed the association of early-life adiposity, defined as self-reported body size during ages 10–20 years from a validated 9-level pictogram, with the transcriptome of breast tumor (N = 835) and tumor-adjacent histologically-normal tissue (N = 663) in the Nurses’ Health Studies. We conducted multivariable linear regression analysis to identify differentially expressed genes in tumor and tumor-adjacent tissue, respectively. Molecular pathway analysis using Hallmark gene sets (N = 50) was further performed to gain biological insights. Analysis was stratified by tumor estrogen receptor (ER) protein expression status (N = 673 for ER+ and 162 for ER- tumors). No gene was statistically significantly differentially expressed by early-life body size after multiple comparison adjustment. However, pathway analysis revealed several statistically significantly (FDR < 0.05) up or down regulated gene sets. In stratified analyses by tumor ER status, larger body size during ages 10–20 years was associated with decreased cellular proliferation pathways, including MYC target genes, in both ER+ and ER- tumors. In ER+ tumors, larger body size was also associated with upregulation in genes involved in TNFα/NFkB signaling. In ER- tumors, larger body size was additionally associated with downregulation in genes involved in IFNα and IFNγ immune response and PI3K/ATK/mTOR signaling; the INFγ response pathway was also downregulated in ER- tumor-adjacent tissue though at borderline statistical significance (FDR = 0.1).These findings provide new insights into the biological and pathological underpinnings of the early-life adiposity and breast cancer association.
Journal of the National Cancer Institute , résumé, 2019