Research article

Aging impacts transcriptomes but not genomes of hormone-dependent breast cancers

Christina Yau¹ , Vita Fedele² , Ritu Roydasgupta² , Jane Fridlyand² , Alan Hubbard¹ , Joe W Gray² , Karen Chew² , Shanaz H Dairkee³ , Dan H Moore^2,3 , Francesco Schittulli⁴ , Stefania Tommasi⁴ , Angelo Paradiso⁴ , Donna G Albertson² and Christopher C Benz^1,2

¹  Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA

²  University of California Comprehensive Cancer Center, 2340 Sutter Street, University of California, San Francisco, CA 94143, USA

³  California Pacific Medical Center Research Institute, 475 Brannan Street, San Francisco, CA 94107, USA

⁴  National Cancer Institute – Bari, via Amendola 209, 70126 Bari, Italy

author email corresponding author email

Breast Cancer Research 2007, 9:R59doi:10.1186/bcr1765

Published:	12 September 2007

Abstract

Introduction

Age is one of the most important risk factors for human malignancies, including breast cancer; in addition, age at diagnosis has been shown to be an independent indicator of breast cancer prognosis. Except for inherited forms of breast cancer, however, there is little genetic or epigenetic understanding of the biological basis linking aging with sporadic breast cancer incidence and its clinical behavior.

Methods

DNA and RNA samples from matched estrogen receptor (ER)-positive sporadic breast cancers diagnosed in either younger (age ≤ 45 years) or older (age ≥ 70 years) Caucasian women were analyzed by array comparative genomic hybridization and by expression microarrays. Array comparative genomic hybridization data were analyzed using hierarchical clustering and supervised age cohort comparisons. Expression microarray data were analyzed using hierarchical clustering and gene set enrichment analysis; differential gene expression was also determined by conditional permutation, and an age signature was derived using prediction analysis of microarrays.

Results

Hierarchical clustering of genome-wide copy-number changes in 71 ER-positive DNA samples (27 younger women, 44 older women) demonstrated two age-independent genotypes; one with few genomic changes other than 1q gain/16q loss, and another with amplifications and low-level gains/losses. Age cohort comparisons showed no significant differences in total or site-specific genomic breaks and amplicon frequencies. Hierarchical clustering of 5.1 K genes variably expressed in 101 ER-positive RNA samples (53 younger women, 48 older women) identified six transcriptome subtypes with an apparent age bias (P < 0.05). Samples with higher expression of a poor outcome-associated proliferation signature were predominantly (65%) younger cases. Supervised analysis identified cancer-associated genes differentially expressed between the cohorts; with younger cases expressing more cell cycle genes and more than threefold higher levels of the growth factor amphiregulin (AREG), and with older cases expressing higher levels of four different homeobox (HOX) genes in addition to ER (ESR1). An age signature validated against two other independent breast cancer datasets proved to have >80% accuracy in discerning younger from older ER-positive breast cancer cases with characteristic differences in AREG and ESR1 expression.

Conclusion

These findings suggest that epigenetic transcriptome changes, more than genotypic variation, account for age-associated differences in sporadic breast cancer incidence and prognosis.