Epigenomic alterations in breast carcinoma from primary tumor to locoregional recurrences

PLoS One. 2014 Aug 6;9(8):e103986. doi: 10.1371/journal.pone.0103986. eCollection 2014.

Abstract

Introduction: Epigenetic modifications such as aberrant DNA methylation has long been associated with tumorogenesis. Little is known, however, about how these modifications appear in cancer progression. Comparing the methylome of breast carcinomas and locoregional evolutions could shed light on this process.

Methods: The methylome profiles of 48 primary breast carcinomas (PT) and their matched axillary metastases (PT/AM pairs, 20 cases), local recurrences (PT/LR pairs, 17 cases) or contralateral breast carcinomas (PT/CL pairs, 11 cases) were analyzed. Univariate and multivariate analyzes were performed to determine differentially methylated probes (DMPs), and a similarity score was defined to compare methylation profiles. Correlation with copy-number based score was calculated and metastatic-free survival was compared between methods.

Results: 49 DMPs were found for the PT/AM set, but none for the others (FDR < 5%). Hierarchical clustering clustered 75% of the PT/AM, 47% of the PT/LR, and none of the PT/CL pairs together. A methylation-based score (MS) was defined as a clonality measure. The PT/AM set contained a high proportion of clonal pairs while PT/LR pairs were evenly split between high and low MS score, suggesting two groups: true recurrences (TR) and new primary tumors (NP). CL were classified as new tumors. MS score was significantly correlated with copy-number based scores. There was no significant difference between the metastatic-free survival of groups of patients based on different classifications.

Conclusion: Epigenomic alterations are well suited to study clonality and track cancer progression. Methylation-based classification of TR and NP performed as well as clinical and copy-number based methods suggesting that these phenomenons are tightly linked.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / mortality
  • Breast Neoplasms* / pathology
  • DNA Methylation*
  • DNA, Neoplasm* / genetics
  • DNA, Neoplasm* / metabolism
  • Disease-Free Survival
  • Epigenesis, Genetic*
  • Epigenomics
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local* / genetics
  • Neoplasm Recurrence, Local* / metabolism
  • Neoplasm Recurrence, Local* / mortality
  • Neoplasm Recurrence, Local* / pathology
  • Survival Rate

Substances

  • DNA, Neoplasm

Associated data

  • GEO/GSE44870

Grants and funding

MM was supported by the French league against cancer (www.ligue-cancer.net). JPV was supported by the European Research Council (SMAC-ERC-280032, url: erc.europa.eu). AF was supported by the hospital program for clinical research (AOM 06 149, url: http://www.sante.gouv.fr/le-programme-hospitalier-de-recherche-clinique-phrc.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.