Epigenetic patterns differentiate triple-negative breast cancers

Australian researchers have identified a new method that could help tell the difference between highly aggressive and more benign forms of triple-negative breast cancer (TNBC).

TNBCs, which make up 15-20% of all breast cancers, lack any of the three receptors (oestrogen, progesterone or HER2) that would make them responsive to targeted drugs. Patients tend to have a higher risk of disease recurrence and shorter survival than those with other breast cancers.

TNBC patients tend to fall into two categories: those who succumb to their disease within 3-5 years, regardless of treatment; and those who remain disease-free for longer than the average non-TNBC patient (at least eight years post-diagnosis). But there is currently no reliable way to ‘stratify’ triple-negative cancers into these two sub-groups, with clinicians using tumour size, degree of spread and infiltration of lymph nodes to determine whether a patient falls into a high- or low-risk category.

“The information we have at the moment is based on statistics and probability, and we are forced to treat triple-negative breast cancer patients as a group, even though we know that they are not a uniform population,” said pathologist Dr Glenn Francis.

Writing in the journal Nature Communications, the researchers explained that epigenetic alterations in cancer methylome “are common in breast cancer and provide novel options for tumour stratification”. The methylome provides a picture of the genome and shows how it is epigenetically ‘decorated’ with methyl groups - a process known as DNA methylation.

Professor Susan Clark, Dr Clare Stirzaker and Dr Elena Zotenko, from Sydney’s Garvan Institute of Medical Research, performed whole-genome methylation capture sequencing on archival tissue samples from TNBC patients and matched normal samples. This was followed by next-generation sequencing to determine cancer-specific changes in DNA methylation.

“We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites,” the authors said in their study. “Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival.”

Dr Francis, who analysed the tissue samples for the study, said the results should “enable us to track selected groups of patients over time, monitoring how they respond to different treatments”, thus solving the problem of over-treatment. Professor Clark added that the findings warrant further investigation in larger breast cancer cohorts.

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