Abstract
IntroductionBreast cancer in premenopausal women (preM) is frequently associated with worse prognosis compared to that in postmenopausal women (postM), and there is evidence that preM estrogen receptor-positive (ER+) tumors may respond poorly to endocrine therapy. There is, however, a paucity of studies characterizing molecular alterations in premenopausal tumors, a potential avenue for personalizing therapy for this group of women.MethodsUsing TCGA and METABRIC databases, we analyzed gene expression, copy number, methylation, somatic mutation, and reverse-phase protein array data in breast cancers from >2,500 preM and postM women.ResultsPreM tumors showed unique gene expression compared to postM tumors, however, this difference was limited to ER+ tumors. ER+ preM tumors showed unique DNA methylation, copy number and somatic mutations. Integrative pathway analysis revealed that preM tumors had elevated integrin/laminin and EGFR signaling, with enrichment for upstream TGFβ-regulation. Finally, preM tumors showed three different gene expression clusters with significantly different outcomes.ConclusionTogether these data suggest that ER+ preM tumors have distinct molecular characteristics compared to ER+ postM tumors, particularly with respect to integrin/laminin and EGFR signaling, which may represent therapeutic targets in this subgroup of breast cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0618-8) contains supplementary material, which is available to authorized users.
Highlights
Breast cancer in premenopausal women is frequently associated with worse prognosis compared to that in postmenopausal women, and there is evidence that preM estrogen receptor-positive (ER+) tumors may respond poorly to endocrine therapy
We show here that estrogen receptor-positive (ER+) preM breast cancer is molecularly distinct from ER+ postM breast cancer, including changes in gene expression, methylation, copy number, and somatic mutation patterns
Normal and tumor samples were separated by the first principal component (PC), while ER+ and ER− tumor samples were separated by the second PC (Fig. 1b, Additional file 13: Figure S2A)
Summary
Breast cancer in premenopausal women (preM) is frequently associated with worse prognosis compared to that in postmenopausal women (postM), and there is evidence that preM estrogen receptor-positive (ER+) tumors may respond poorly to endocrine therapy. The most notable study compared DNA copy number and messenger RNA (mRNA) gene expression data in preM and postM breast cancer and concluded that transcriptomic changes, more than genotypic variation, account for age-associated differences in sporadic breast cancer incidence and prognosis [9]. Anders et al analyzed microarray data from 784 early-stage breast cancers to discover gene sets able to distinguish breast tumors arising in younger women from tumors of older women [10].
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