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

  • Anneke Q. van Hoesel
  • Cornelis J. H. van de Velde
  • Peter J. K. Kuppen
  • Gerrit Jan Liefers
  • Hein Putter
  • Yusuke Sato
  • David A. Elashoff
  • Roderick R. Turner
  • Jaime M. Shamonki
  • Esther M. de Kruijf
  • Johanna G. H. van Nes
  • Armando E. Giuliano
  • Dave S. B. Hoon
Preclinical Study


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.


Age Breast cancer LINE-1 Methylation Prognosis 



Absolute quantitative assessment of methylated alleles


Atypical ductal hyperplasia


Breast-conserving surgery




Disease-free survival


Distant recurrence


Ductal carcinoma in situ


Ductal hyperplasia


Endocrine therapy


Estrogen receptor


Hazard ratio


Human epidermal growth factor receptor 2


Laser capture microdissection


Locoregional recurrence


Long interspersed element 1






Methylation index


Overall survival


Paraffin-embedded archival tissues


Progesterone receptor






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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Anneke Q. van Hoesel
    • 1
    • 2
  • Cornelis J. H. van de Velde
    • 2
  • Peter J. K. Kuppen
    • 2
  • Gerrit Jan Liefers
    • 2
  • Hein Putter
    • 3
  • Yusuke Sato
    • 1
  • David A. Elashoff
    • 4
  • Roderick R. Turner
    • 5
  • Jaime M. Shamonki
    • 5
  • Esther M. de Kruijf
    • 2
  • Johanna G. H. van Nes
    • 2
  • Armando E. Giuliano
    • 6
  • Dave S. B. Hoon
    • 1
  1. 1.Department of Molecular OncologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health CenterSanta MonicaUSA
  2. 2.Department of SurgeryLeiden University Medical Center (LUMC)LeidenThe Netherlands
  3. 3.Department of Medical Statistics and BioinformaticsLeiden University Medical Center (LUMC)LeidenThe Netherlands
  4. 4.Department of Medicine, Statistics CoreUniversity of CaliforniaLos AngelesUSA
  5. 5.Department of PathologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health CenterSanta MonicaUSA
  6. 6.Division of Surgical OncologyJohn Wayne Cancer Institute (JWCI) at St. John’s Health CenterSanta MonicaUSA

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