Patients' DNA sequences predict future breast cancer characteristics

Researchers have discovered a potential mechanism underpinning why a person's genome might influence the subtype of breast cancer they develop. 

A person's risk of getting breast cancer is influenced by the DNA sequences on their genome. Two of the genetic variants that have been discovered to be associated with a much higher risk of breast cancer, BRCA1 and 2, are associated with cancers that are more likely to be triple negative or estrogen receptor positive. These characteristics, or subtypes, describe the receptors that are expressed on the cancer cells, and can be used to determine which cancer treatments will be most effective and how aggressive the cancer might be. Researchers from Stanford University in California have investigated why this could be. 

'We wanted to understand how inherited DNA might sculpt how a tumour evolves,' said Dr Kathleen Houlahan, a post-doctoral researcher at Stamford University and lead researcher of the paper published in Science.

T-cells are a part of the immune system that identifies and eliminates cancer cells by detecting tumour-associated antigens that are expressed on the surface of these cells. These antigens contain a region called the epitope which allows it to be recognised by the immune system. The DNA we are born with includes the genes that code for these epitopes, and some people have more than one copy of these genes, meaning that larger amounts of these epitopes are expressed. 

Researchers hypothesised that people with DNA that coded repeatedly for a specific type of tumour-associated antigen epitope, would develop breast cancer tumours that had evolved to evade a different immune pathway. 

To investigate this they looked at the genetic sequences of breast cancer tumours from 5529 women, along with the sequence of the DNA they were born with, as well as the genetic profiles of tumours from a further 341 patients with early breast cancer. 

They discovered that people who have a genetic sequence that means they repeatedly express the epitope of the tumour-associated antigen known as HER2 (human epidermal growth factor receptor 2), were less likely to develop HER2 positive breast cancer than other breast cancer subtypes. This finding was repeated for estrogen receptor positive breast cancers.

They also found that people who had early breast cancers, but had DNA that exhibited a number of repeats for the epitopes of tumour-associated antigens had a lower rate of recurrence. Meanwhile tumours that overcame this mechanism were more aggressive.

Researchers suggest their findings could mean there are hundreds of other genetic variants that could affect cancer risk and aggressiveness. 

'Our findings not only explain which subtype of breast cancer an individual is likely to develop', said Dr Houlahan, 'but they also hint at how aggressive and prone to metastasising that subtype will be. Beyond that, we speculate that these inherited variants may influence a person's risk of developing breast cancer. However, future studies will be needed to examine this.'