Heritable clustering and pathway discovery in breast cancer integrating epigenetic and phenotypic data.
BACKGROUND
In order to recapitulate tumor progression pathways using epigenetic data, we developed novel clustering and pathway reconstruction algorithms, collectively referred to as heritable clustering. This approach generates a progression model of altered DNA methylation from tumor tissues diagnosed at different developmental stages. The samples act as surrogates for natural progression in breast cancer and allow the algorithm to uncover distinct epigenotypes that describe the molecular events underlying this process. Furthermore, our likelihood-based clustering algorithm has great flexibility, allowing for incomplete epigenotype or clinical phenotype data and also permitting dependencies among variables.


RESULTS
Using this heritable clustering approach, we analyzed methylation data obtained from 86 primary breast cancers to recapitulate pathways of breast tumor progression. Detailed annotation and interpretation are provided to the optimal pathway recapitulated. The result confirms the previous observation that aggressive tumors tend to exhibit higher levels of promoter hypermethylation.


CONCLUSIONS
Our results indicate that the proposed heritable clustering algorithms are a useful tool for stratifying both methylation and clinical variables of breast cancer. The application to the breast tumor data illustrates that this approach can select meaningful progression models which may aid the interpretation of pathways having biological and clinical significance. Furthermore, the framework allows for other types of biological data, such as microarray gene expression or array CGH data, to be integrated.
Wang
Zailong
Z
Mathematical Biosciences Institute, The Ohio State University, 231 W, 18th Avenue, Columbus, OH 43210, USA. zailong.wang@yahoo.com <zailong.wang@yahoo.com>
Yan
Pearlly
P
Potter
Dustin
D
Eng
Charis
C
Huang
Tim H-M
TH
Lin
Shili
S
D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D016000:Cluster Analysis; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D015398:Signal Transduction; D018511:Systems Integration
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins