Barron’s Medical Journal Reporting From Boston At Harvard University Beth Israel Medical Center
How Susan G. Komen And Personalized Medicine--Genomics Is A Breast Cancer Game Changer
Boston MA ( AP )Barron’s Medical Journal investigative report on breast cancer fundraising series starts with The Susan G Komen March. With only fifteen percent of the research dollars spent on Personalized Medicine, Barron's wants to make all of the new patient’s that is going to get to go the Doctors now that they have Affordable Health Care Act ( Obama Care )BMJ want to make sure that patients are asking about genomics for breast cancer. DNA methylation patterns can discover three hundred times faster than a mammogram can breast cancer. Breast cancer is one of the most prevalent human malignancies and is a major cause of cancer-related morbidity and mortality. Invasive ductal carcinoma (IDC) of the breast is a phenotypically diverse disease, consisting of tumors with varying pathologic and molecular characteristics. The primary biological subtypes of IDC include estrogen receptor (ER)– and progesterone receptor (PR)–positive tumors (luminal A and B), tumors that are human epidermal growth factor receptor 2 (HER2)–enriched, and tumors that are ER/PR-negative (basal-like). These molecular determinants have significant effects on metastatic behavior and clinical outcome. For example, ER/PR+tumors are generally associated with better clinical prognosis, whereas basal-like (ER/PR− and HER2−, triple-negative) tumors are associated with higher rates of metastasis and death The genomic alterations, including both genetic and epigenetic aberrations, underlying these differing metastatic potentials are ill-defined.
Significant effort has been undertaken to more accurately define the molecular alterations underlying breast cancer. For example, it has been shown that hormone receptor (HR) status is prognostic for clinical outcome. Mutations in genes such asBRCA1, PTEN, and PIK3CA help promote breast cancer oncogenesis and are enriched in specific subgroups of IDC in breast cancers). These data demonstrate that there exists substantial biological heterogeneity between and within the ER/PR+ and ER/PR− subgroups for which the molecular foundations remain obscure In addition, gene expression classifiers have been developed to help predict metastatic risk). Despite their increasing use in the clinic, the genomic root causes of the transcriptome differences that underlie metastatic potential are unclear.
Genome-wide sequencing surveys have been performed to identify the scope of mutations
It is well established that widespread changes in DNA methylation patterns occur during oncogenesis and tumor progression Cancer-specific changes in DNA methylation can alter genetic stability, genomic structure, and gene expression). Promoter CpG island methylation can result in transcriptional silencing and plays an important role in the oncogenic process A CpG island methylator phenotype (CIMP), which is associated with a strong tendency to hypermethylate specific loci, has been described in a subset of colorectal cancers, and recently in a subgroup of gliomas Aberrations in DNA methylation have been reported in human breast cancer, but the impact of the methylome on metastasis and the presence of a B-CIMP have remained elusive To resolve these questions, we conducted a systematic, genome-wide characterization of the breast cancer methylome in breast cancers with diverse metastatic behavior.
Cancer cells undergo massive alterations to their DNA methylation patterns that result in aberrant gene expression and malignant phenotypes. However, the mechanisms that underlie methylome changes are not well understood nor is the genomic distribution of DNA methylation changes well characterized.
Here, we performed methylated DNA immunoprecipitation combined with high-throughput sequencing (MeDIP-seq) to obtain whole-genome DNA methylation profiles for eight human breast cancer cell (BCC) lines and for normal human mammary epithelial cells (HMEC). The MeDIP-seq analysis generated non-biased DNA methylation maps by covering almost the entire genome with sufficient depth and resolution. The most prominent feature of the BCC lines compared to HMEC was a massively reduced methylation level particularly in CpG-poor regions. While hypomethylation did not appear to be associated with particular genomic features, hypermethylation preferentially occurred at CpG-rich gene-related regions independently of the distance from transcription start sites. We also investigated methylome alterations during epithelial-to-mesenchymal transition (EMT) in MCF7 cells. EMT induction was associated with specific alterations to the methylation patterns of gene-related CpG-rich regions, although overall methylation levels were not significantly altered. Moreover, approximately 40% of the epithelial cell-specific methylation patterns in gene-related regions were altered to those typical of mesenchymal cells, suggesting a cell-type specific regulation
of DNA methylation. Cancer-specific alterations in DNA methylation are hallmarks of human malignancies; however, the nature of the breast cancer epigenome and its effects on metastatic behavior remain obscure. To address this issue, we used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Groups of breast tumors were characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating a breast CpG island methylator phenotype (B-CIMP).
The B-CIMP provided a distinct epigenomic profile and was a strong determinant of metastatic potential. Specifically, the presence of the B-CIMP in tumors was associated with low metastatic risk and survival, and the absence of the B-CIMP was associated with high metastatic risk and death. B-CIMP loci were highly enriched for genes that make up the metastasis transcriptome. Methylation at B-CIMP genes accounted for much of the transcriptomal diversity between breast cancers of varying prognosis, indicating a fundamental
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