Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns.
BACKGROUND
Five different molecular subtypes of breast cancer have been identified through gene expression profiling. Each subtype has a characteristic expression pattern suggested to partly depend on cellular origin. We aimed to investigate whether the molecular subtypes also display distinct methylation profiles.


METHODS
We analysed methylation status of 807 cancer-related genes in 189 fresh frozen primary breast tumours and four normal breast tissue samples using an array-based methylation assay.


RESULTS
Unsupervised analysis revealed three groups of breast cancer with characteristic methylation patterns. The three groups were associated with the luminal A, luminal B and basal-like molecular subtypes of breast cancer, respectively, whereas cancers of the HER2-enriched and normal-like subtypes were distributed among the three groups. The methylation frequencies were significantly different between subtypes, with luminal B and basal-like tumours being most and least frequently methylated, respectively. Moreover, targets of the polycomb repressor complex in breast cancer and embryonic stem cells were more methylated in luminal B tumours than in other tumours. BRCA2-mutated tumours had a particularly high degree of methylation. Finally, by utilizing gene expression data, we observed that a large fraction of genes reported as having subtype-specific expression patterns might be regulated through methylation.


CONCLUSIONS
We have found that breast cancers of the basal-like, luminal A and luminal B molecular subtypes harbour specific methylation profiles. Our results suggest that methylation may play an important role in the development of breast cancers.
Holm
Karolina
K
Department of Oncology, Clinical Sciences, Lund University, Barngatan 2B, Lund, Sweden. karolina.holm@med.lu.se
Hegardt
Cecilia
C
Staaf
Johan
J
Vallon-Christersson
Johan
J
Jönsson
Göran
G
Olsson
Håkan
H
Borg
Ake
A
Ringnér
Markus
M
D001940:Breast / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018295:Neoplasms, Basal Cell / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate
D004273:DNA, Neoplasm