Breast cancer prognosis associated with oncometabolite accumulation

The metabolic profile of cancer cells can be used to develop therapies and identify biomarkers associated with cancer outcome. New research has discovered an association between the oncometabolite 2-hydroxyglutarate (2-HG) levels, DNA methylation patterns, and breast cancer prognosis.

In this research, Stefan Ambs, PhD, MPH, and colleagues at the National Cancer Institute in Bethesda, Maryland, used the concept of metabolomics as a discovery tool. Recent research has found that breast and other cancers have essentially new metabolomic pathways for tumor growth. Changes in metabolism in cancer cells may define disease aggressiveness and its response to therapy.

The research team examined metabolite signatures in breast cancer and how these differed between African-American and European-American patients. They identified a breast cancer subtype with high levels of 2-HG, and a distinct DNA methylation pattern that was associated with reduced survival. Their study was published in the Journal of Clinical Investigation (2013; doi:10.1172/JCI71180).

The breast tumors with elevated 2-HG were predominantly estrogen receptor-negative and had poor clinical outcomes. The breast tumors with high 2-HG had a hypermethylated phenotype, and they were a DNA methylation-defined molecular subgroup. This subgroup is called subgroup III, and it has a stem cell-like gene expression signature. The accumulation of 2-HG was frequent in tumors and cell lines of the basal-like/mesenchymal subtype.

The authors could not use metabolomics to separate the tumors into subtypes that have been described based on distinct gene expression profiles. They found that the luminal-A subtype was well distinguished, but that the human epidermal growth factor receptor 2-positive and -negative subtypes were not adequately separated.

The characteristics of patient age, body mass, socioeconomic status, and menopausal status were not found to be associated with the tumor metabolome. The research team stated that this finding suggests “that breast tumors have a robust intrinsic metabolome signature that predominates over the influence of these factors.”

The breast cancer subtype with high levels of 2-HG was common in African-American breast cancer patients who, as a group, have a high prevalence of aggressive breast cancers. This study indicates that evaluation of 2-HG along with DNA methylation may be a useful biomarker for breast cancer diagnosis and prognosis.

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