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

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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.

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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

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Acknowledgments

We thank the clinical and pathological department staff at Saint John’s Health Center and LUMC for their support, and staff at Department of Molecular Oncology for technical support. This study was supported by funding from Susan G. Komen Breast Cancer Foundation Grant# BCTR0707528 (DSBH), the Leslie and Susan Gonda (Goldschmied) Foundation (DSBH, Los Angeles, CA), Ruth and Martin H. Weil Fund (DSBH, Los Angeles, CA), Associates for Breast and Prostate Cancer (ABC) Studies, Fashion Footwear Association of New York (FFANY), and California Breast Cancer Research Program #16IB-0076 (DSBH).

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Authors and Affiliations

  1. Department of Molecular Oncology, John Wayne Cancer Institute (JWCI) at St. John’s Health Center, 2200 Santa Monica Blvd., Santa Monica, CA, 90404, USA

    Anneke Q. van Hoesel, Yusuke Sato & Dave S. B. Hoon

  2. Department of Surgery, Leiden University Medical Center (LUMC), Leiden, The Netherlands

    Anneke Q. van Hoesel, Cornelis J. H. van de Velde, Peter J. K. Kuppen, Gerrit Jan Liefers, Esther M. de Kruijf & Johanna G. H. van Nes

  3. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center (LUMC), Leiden, The Netherlands

    Hein Putter

  4. Department of Medicine, Statistics Core, University of California, Los Angeles, CA, USA

    David A. Elashoff

  5. Department of Pathology, John Wayne Cancer Institute (JWCI) at St. John’s Health Center, 2200 Santa Monica Blvd., Santa Monica, CA, USA

    Roderick R. Turner & Jaime M. Shamonki

  6. Division of Surgical Oncology, John Wayne Cancer Institute (JWCI) at St. John’s Health Center, 2200 Santa Monica Blvd., Santa Monica, CA, USA

    Armando E. Giuliano

Authors
  1. Anneke Q. van Hoesel
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  2. Cornelis J. H. van de Velde
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  3. Peter J. K. Kuppen
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  4. Gerrit Jan Liefers
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  5. Hein Putter
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  6. Yusuke Sato
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  7. David A. Elashoff
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  9. Jaime M. Shamonki
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  10. Esther M. de Kruijf
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  11. Johanna G. H. van Nes
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  13. Dave S. B. Hoon
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Correspondence to Dave S. B. Hoon.

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van Hoesel, A.Q., van de Velde, C.J.H., Kuppen, P.J.K. et al. Hypomethylation of LINE-1 in primary tumor has poor prognosis in young breast cancer patients: a retrospective cohort study. Breast Cancer Res Treat 134, 1103–1114 (2012). https://doi.org/10.1007/s10549-012-2038-0

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  • DOI: https://doi.org/10.1007/s10549-012-2038-0

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