Intra-individual Gene Expression Variability of Histologically Normal Breast Tissue

Several studies have sought to identify novel transcriptional biomarkers in normal breast or breast microenvironment to predict tumor risk and prognosis. However, systematic efforts to evaluate intra-individual variability of gene expression within normal breast have not been reported. This study analyzed the microarray gene expression data of 288 samples from 170 women in the Normal Breast Study (NBS), wherein multiple histologically normal breast samples were collected from different block regions and different sections at a given region. Intra-individual differences in global gene expression and selected gene expression signatures were quantified and evaluated in association with other patient-level factors. We found that intra-individual reliability was relatively high in global gene expression, but differed by signatures, with composition-related signatures (i.e., stroma) having higher intra-individual variability and tumorigenesis-related signatures (i.e., proliferation) having lower intra-individual variability. Histological stroma composition was the only factor significantly associated with heterogeneous breast tissue (defined as > median intra-individual variation; high nuclear density, odds ratio [OR] = 3.42, 95% confidence interval [CI] = 1.15–10.15; low area, OR = 0.29, 95% CI = 0.10–0.86). Other factors suggestively influencing the variability included age, BMI, and adipose nuclear density. Our results underscore the importance of considering intra-individual variability in tissue-based biomarker development, and have important implications for normal breast research.