title: Aging impacts transcriptomes but not genomes of hormone-dependent breast cancers.
abstract: BACKGROUND
  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 <or= 45 years) or older (age >or= 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.
  
  
  CONCLUSIONS
  These findings suggest that epigenetic transcriptome changes, more than genotypic variation, account for age-associated differences in sporadic breast cancer incidence and prognosis.
authors.affiliation: Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Yau
authors.forename: Vita
authors.initials: V
authors.lastname: Fedele
authors.forename: Ritu
authors.initials: R
authors.lastname: Roydasgupta
authors.forename: Jane
authors.initials: J
authors.lastname: Fridlyand
authors.forename: Alan
authors.initials: A
authors.lastname: Hubbard
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Karen
authors.initials: K
authors.lastname: Chew
authors.forename: Shanaz H
authors.initials: SH
authors.lastname: Dairkee
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Francesco
authors.initials: F
authors.lastname: Schittulli
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Donna G
authors.initials: DG
authors.lastname: Albertson
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Benz
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen