DNA methylation of polycomb group target genes in cores taken from breast cancer centre and periphery.
We previously demonstrated that methylation of neugogenic differentiation 1 (NEUROD1) gene, a polycomb group target (PCGT) gene is a predictor of response to neoadjuvant chemotherapy in breast cancer. Here, we address the question whether NEUROD1 methylation provides clinical information independent from its expression level, and whether PCGT methylation is homogeneous in breast cancer. We examined: (1) NEUROD1 methylation and mRNA expression in 9 breast cancer cell lines and 63 tumour specimens, (2) DNA methylation in a training set of 55 PCGT genes taken from the centre (TUC) and periphery (TUP) of 15 breast cancer specimens, and compared this with 22 non neoplastic controls, and finally, (3) validated statistically significant genes in an independent set of 20 cases versus 18 controls. 8/9 cell lines demonstrated NEUROD1 methylation, whereas, there was only one cell-line that showed NEUROD1 expression. There was no association between methylation and expression in breast tumour specimens, with only 14% exhibiting NEUROD1 expression. Of the 55 PCGT genes analysed, 24% (13/55) were shown to be cancer specific (p < 0.05) with a receiver-operating-characteristic (ROC) area-under-the-curve (AUC) of >0.7 (range 0.71-0.95). DNA methylation accurately predicted the presence of cancer in both TUC and TUP. DNA methylation of PCGT genes predicts the presence of breast cancer and is not subject to tumour heterogeneity. Further work will reveal if methylation of PCGT genes will serve as a robust means for the clinical detection and assessment of breast cancer.
Department of Gynaecological Oncology, Institute for Women's Health, University College London, 1st Floor, Maple House, 149 Tottenham Court Road, London, W1T 7DN, UK.
Evangelia-Ourania
EO
Fourkala
Cornelia
C
Hauser-Kronberger
Sophia
S
Apostolidou
Matthew
M
Burnell
Allison
A
Jones
Johannes
J
Grall
Roland
R
Reitsamer
Heidi
H
Fiegl
Ian
I
Jacobs
Usha
U
Menon
Martin
M
Widschwendter
D019540:Area Under Curve; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger / Q000032:analysis; D012372:ROC Curve; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C093970:NEUROD1 protein, human