title: Hypomethylation of LINE-1 in primary tumor has poor prognosis in young breast cancer patients: a retrospective cohort study.
abstract: Long interspersed element 1 (LINE-1), a non-coding genomic repeat sequence, methylation status can influence tumor progression. In this study, the clinical significance of LINE-1 methylation status was assessed in primary breast cancer in young versus old breast cancer patients. LINE-1 methylation index (MI) was assessed by absolute quantitative assessment of methylated alleles (AQAMA) PCR assay. Initially, LINE-1 MI was assessed in a preliminary study of 235 tissues representing different stages of ductal breast cancer development. Next, an independent cohort of 379 primary ductal breast cancer patients (median follow-up 18.9 years) was studied. LINE-1 hypomethylation was shown to occur in DCIS and invasive breast cancer. In primary breast cancer it was associated with pathological tumor stage (p = 0.026), lymph node metastasis (p = 0.022), and higher age at diagnosis (>55, p < 0.001). In multivariate analysis, LINE-1 hypomethylation was associated with decreased OS (HR 2.19, 95 % CI 1.17-4.09, log-rank p = 0.014), DFS (HR 2.05, 95 % CI 1.14-3.67, log-rank p = 0.016) and increased DR (HR 2.83, 95 % CI 1.53-5.21, log-rank p = 0.001) in younger (≤55 years), but not older patients (>55 years). LINE-1 analysis of primary breast cancer demonstrated cancer-related age-dependent hypomethylation. In patients ≤55 years, LINE-1 hypomethylation portends a high-risk of DR.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute (JWCI) at St. John's Health Center, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA.
authors.forename: Anneke Q
authors.initials: AQ
authors.lastname: van Hoesel
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Liefers
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.forename: David A
authors.initials: DA
authors.lastname: Elashoff
authors.forename: Roderick R
authors.initials: RR
authors.lastname: Turner
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Shamonki
authors.forename: Esther M
authors.initials: EM
authors.lastname: de Kruijf
authors.forename: Johanna G H
authors.initials: JG
authors.lastname: van Nes
authors.forename: Armando E
authors.initials: AE
authors.lastname: Giuliano
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D000328:Adult; D000367:Age Factors; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D055815:Young Adult