Preclinical Study

Breast Cancer Research and Treatment

, Volume 134, Issue 3, pp 1103-1114

First online:

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

  • Anneke Q. van HoeselAffiliated withDepartment of Molecular Oncology, John Wayne Cancer Institute (JWCI) at St. John’s Health CenterDepartment of Surgery, Leiden University Medical Center (LUMC)
  • , Cornelis J. H. van de VeldeAffiliated withDepartment of Surgery, Leiden University Medical Center (LUMC)
  • , Peter J. K. KuppenAffiliated withDepartment of Surgery, Leiden University Medical Center (LUMC)
  • , Gerrit Jan LiefersAffiliated withDepartment of Surgery, Leiden University Medical Center (LUMC)
  • , Hein PutterAffiliated withDepartment of Medical Statistics and Bioinformatics, Leiden University Medical Center (LUMC)
  • , Yusuke SatoAffiliated withDepartment of Molecular Oncology, John Wayne Cancer Institute (JWCI) at St. John’s Health Center
  • , David A. ElashoffAffiliated withDepartment of Medicine, Statistics Core, University of California
  • , Roderick R. TurnerAffiliated withDepartment of Pathology, John Wayne Cancer Institute (JWCI) at St. John’s Health Center
  • , Jaime M. ShamonkiAffiliated withDepartment of Pathology, John Wayne Cancer Institute (JWCI) at St. John’s Health Center
    • , Esther M. de KruijfAffiliated withDepartment of Surgery, Leiden University Medical Center (LUMC)
    • , Johanna G. H. van NesAffiliated withDepartment of Surgery, Leiden University Medical Center (LUMC)
    • , Armando E. GiulianoAffiliated withDivision of Surgical Oncology, John Wayne Cancer Institute (JWCI) at St. John’s Health Center
    • , Dave S. B. HoonAffiliated withDepartment of Molecular Oncology, John Wayne Cancer Institute (JWCI) at St. John’s Health Center Email author 

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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

Age Breast cancer LINE-1 Methylation Prognosis