Abstract P4-05-03: Unique genetic, epigenetic, and transcriptomic changes in premenopausal breast cancer suggest novel strategies for therapy

Abstract

Abstract Breast cancer in premenopausal women (preM) is frequently associated with worse prognosis compared to that in postmenopausal women (postM) even when controlling for prognostic variables. In particular, preM ER+ tumors have a poor prognosis on endocrine therapy. There is, however, a paucity of studies characterizing molecular alterations in premenopausal tumors, a potential avenue for finding personalized therapies for this group of women. We analyzed gene expression, CNV, methylation, and somatic mutations in tumors from preM (≤45; ER+ n = 110, and ER- n = 39) and postM (≥55, ER+ n = 392, and ER- n = 102) women in The Cancer Genome Atlas (TCGA). Unbiased hierarchical clustering of 2,900 most variably expressed genes (using both RNA-seq and Agilent expression array data) in the whole dataset (n = 643) identified four major subtypes which correlated highly with the PAM50 defined subtypes LumA, LumB, Basal and HER2; however, there wasn't any separation between preM and postM samples. Similarly, principal component analysis using 10,000 genes with the highest inter-quartile range (IQR) demonstrated high similarity across preM and postM samples. Direct examination of gene expression differences between PreM and PostM ER+ tumors using unpaired t-test (5% FDR) identified 3,044 differentially expressed genes. The genes most upregulated in premenopausal tumors included AREG, TFPI2, MSMB, TCN1, and GLRA3. Ingenuity Pathway Analysis revealed a highly significant enrichment for TGFb (p<1.9E-16) pathway activity in preM tumors. Intriguingly, no significant gene expression differences between preM and postM ER- tumors were identified. We thus then focused on genetic and epigenetic alterations that may underlie these transcriptomic changes in ER+ preM tumors. Comparison of methylation (450K Illumina array) between preM and postM ER+ tumors showed a difference in 1% (n = 1,738) of the probes. Genes with the largest difference included ESR1, SIM2, and KLF6. Significant differences in DNA copy number variation (Affymetrix SNP 6.0 array) were also identified in ER+ preM tumors. A number of somatic mutations were significantly enriched in preM ER+ tumors including DSPP and GATA3. Integrated analysis also showed that approximately half of the observed differences in gene expression are driven by CNVs. Conclusion: Our in silico study has identified a number of genes and pathways which are significantly altered between preM and postM ER+ breast cancer. Distinct genetic and epigenetic differences suggest unique etiology for some preM tumors. Currently ongoing Paradigm analysis, and confirmatory studies using METABRIC data are expected to further identify pathways that could specifically be targeted in premenopausal breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-03.