Methylation biomarkers for pleomorphic lobular breast cancer - a short report

Cell Oncol (Dordr). 2015 Oct;38(5):397-405. doi: 10.1007/s13402-015-0241-9. Epub 2015 Sep 21.


Background: Pleomorphic invasive lobular cancer (pleomorphic ILC) is a rare variant of ILC that is characterized by a classic ILC-like growth pattern combined with an infiltrative ductal cancer (IDC)-like high nuclear atypicality. There is an ongoing discussion whether pleomorphic ILC is a dedifferentiated form of ILC or in origin an IDC with a secondary loss of cohesion. Since gene promoter hypermethylation is an early event in breast carcinogenesis and thus may provide information on tumor progression, we set out to compare the methylation patterns of pleomorphic ILC, classic ILC and IDC. In addition, we aimed at analyzing the methylation status of pleomorphic ILC.

Methods: We performed promoter methylation profiling of 24 established and putative tumor suppressor genes by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) analysis in 20 classical ILC, 16 pleomorphic ILC and 20 IDC cases.

Results: We found that pleomorphic ILC showed relatively low TP73 and MLH1 methylation levels and relatively high RASSF1A methylation levels compared to classic ILC. Compared to IDC, pleomorphic ILC showed relatively low MLH1 and BRCA1 methylation levels. Hierarchical cluster analysis revealed a similar methylation pattern for pleomorphic ILC and IDC, while the methylation pattern of classic ILC was different.

Conclusion: This is the first report to identify TP73, RASSF1A, MLH1 and BRCA1 as possible biomarkers to distinguish pleomorphic ILC from classic ILC and IDC.

Keywords: DNA hypermethylation; Epigenetics; Lobular breast cancer; MS-MLPA; Pleomorphic lobular breast cancer; Sporadic breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Analysis of Variance
  • BRCA1 Protein / genetics
  • Biomarkers, Tumor / classification
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Carcinoma, Ductal, Breast / diagnosis
  • Carcinoma, Ductal, Breast / genetics*
  • Carcinoma, Lobular / diagnosis
  • Carcinoma, Lobular / genetics*
  • Cluster Analysis
  • DNA Methylation*
  • DNA-Binding Proteins / genetics
  • Diagnosis, Differential
  • Female
  • Humans
  • Logistic Models
  • Multiplex Polymerase Chain Reaction / methods
  • MutL Protein Homolog 1
  • Nuclear Proteins / genetics
  • Promoter Regions, Genetic / genetics
  • ROC Curve
  • Tumor Protein p73
  • Tumor Suppressor Proteins / classification
  • Tumor Suppressor Proteins / genetics


  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein
  • BRCA1 protein, human
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Nuclear Proteins
  • RASSF1 protein, human
  • TP73 protein, human
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • MutL Protein Homolog 1