Breast Cancer Research and Treatment

, Volume 134, Issue 3, pp 1103–1114

Hypomethylation of LINE-1 in primary tumor has poor prognosis in young breast cancer patients: a retrospective cohort study

Authors

  • Anneke Q. van Hoesel
    • Department of Molecular OncologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health Center
    • Department of SurgeryLeiden University Medical Center (LUMC)
  • Cornelis J. H. van de Velde
    • Department of SurgeryLeiden University Medical Center (LUMC)
  • Peter J. K. Kuppen
    • Department of SurgeryLeiden University Medical Center (LUMC)
  • Gerrit Jan Liefers
    • Department of SurgeryLeiden University Medical Center (LUMC)
  • Hein Putter
    • Department of Medical Statistics and BioinformaticsLeiden University Medical Center (LUMC)
  • Yusuke Sato
    • Department of Molecular OncologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health Center
  • David A. Elashoff
    • Department of Medicine, Statistics CoreUniversity of California
  • Roderick R. Turner
    • Department of PathologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health Center
  • Jaime M. Shamonki
    • Department of PathologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health Center
  • Esther M. de Kruijf
    • Department of SurgeryLeiden University Medical Center (LUMC)
  • Johanna G. H. van Nes
    • Department of SurgeryLeiden University Medical Center (LUMC)
  • Armando E. Giuliano
    • Division of Surgical OncologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health Center
    • Department of Molecular OncologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health Center
Preclinical Study

DOI: 10.1007/s10549-012-2038-0

Cite this article as:
van Hoesel, A.Q., van de Velde, C.J.H., Kuppen, P.J.K. et al. Breast Cancer Res Treat (2012) 134: 1103. doi:10.1007/s10549-012-2038-0

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.

Keywords

AgeBreast cancerLINE-1MethylationPrognosis

Abbreviations

AQAMA

Absolute quantitative assessment of methylated alleles

ADH

Atypical ductal hyperplasia

BCS

Breast-conserving surgery

CT

Chemotherapy

DFS

Disease-free survival

DR

Distant recurrence

DCIS

Ductal carcinoma in situ

DH

Ductal hyperplasia

ET

Endocrine therapy

ER

Estrogen receptor

HR

Hazard ratio

HER2

Human epidermal growth factor receptor 2

LCM

Laser capture microdissection

LRR

Locoregional recurrence

LINE-1

Long interspersed element 1

MST

Mastectomy

M

Methylated

MI

Methylation index

OS

Overall survival

PEAT

Paraffin-embedded archival tissues

PgR

Progesterone receptor

RT

Radiotherapy

U

Unmethylated

Copyright information

© Springer Science+Business Media, LLC. 2012