Tiny changes to the genetic code can increase a person’s risk of breast cancer. Scientists call these changes “single nucleotide polymorphisms” (SNPs) and they are an area of research receiving a lot of attention.  
Friday 6 February 2015      Research blog
It's a snip - searching for genetic causes of breast cancer

Here, we explain what these SNPs are and their importance to cancer research.

Spell check

Editing blog posts can be quite demanding. The hardest part can be correcting the tiny errors in spelling, grammar and punctuation. It’s an essential task though as the internet can be a cruel and unforgiving place.  Being human, we are inevitably going to make mistakes, but we do our best to rectify them before the words are sent out into cyberspace.  Modern technology has gifted us with automatic spell checkers and auto-correct software but these are still far from perfect.

The problem with the auto spell check built into the word processing software is that it often misses a typo if the word you accidently typed is still a word.  For example, if I go to type “cat” but mash a key nearby instead of the “c” I could end up with “fat”, “vat” or even “bat”.  This accidental variation of “cat” is similar to variation that exists in the human genetic code.

Everyone is an individual and that individuality is caused somewhat by variation in the genetic code.  This variation can be as small as a change in one letter of the code.  If the same one letter change occurs a lot in a population of people then that variant is called a “single nucleotide polymorphism” or SNP (pronounced “snip”). 

Snipping breast cancer genes

We talk a lot about research discovering new genes for breast cancer or new genetic markers for breast cancer risk.  Most of the time this is referring to SNPs.  For example, the Breakthrough Generations Study (our big prevention project), as part of a larger international collaboration, has uncovered over 40 SNPs that are associated with breast cancer risk.  This means that some people have a change in a specific part of the genetic code that puts them at a higher risk of breast cancer compared with the general population, or people with the “normal” code.

This is best explained with an example.  The code for the most famous breast cancer gene, BRCA1, contains a specific section that normally reads “GCG”.  In some people this section reads as “GAG” and as a result they are more likely to be at risk of breast cancer.  The remarkable thing is that this is only a one-letter change amongst the 82,000 letters making up the BRCA1 gene.  Although it’s unlikely that one SNP is going to impact risk that much, having many of them can cause the level of risk to start adding up.  That’s why the search goes on to build an ever-growing database of SNPs for breast cancer risk.

Accumulating data

A recent paper published by the international COGS study uncovered several new SNPs within genes involved in protecting DNA from potential cancer-causing mutations.  Interestingly, these SNPs are particularly associated with ER-negative breast cancer, a sub-type of the disease with a poorer outlook for patients.  Each of these SNPs was shown to increase a person’s risk of ER-negative breast cancer by 6%.  This means that if, for example, the average risk were 10% then the absolute risk of someone with one of these SNPs would be increased to 10.6% (6% of 10 is 0.6, so 10.6% represents an increase of 0.6%).

This may not seem like a big difference, and you would be right to think so, but if a person has multiple SNPs then it could lead to a significant increase in risk.  Bringing lots of SNPs together, in one tool, could be a key way to accurately determine an individual’s risk of breast cancer.

From “what?” to “why?”

We’ve mentioned before that many of the SNPs found to increase breast cancer risk don’t actually fall in regions of DNA containing genes.  Instead they appear in regions called “junk DNA”.  Knowing SNPs is good for identifying people who may be more at risk but it’s also important that we understand why and how these variations to the DNA code influence risk.

Dr Nick Orr, a Breakthrough-funded geneticist involved in the COGS study, said:

“Once we have identified SNPs it is very rare that they actually fall within part of a gene coding for a particular protein.  Instead, it’s thought that many SNPs influence how cells behave by controlling how much certain genes are turned on or off.  We can now use some sophisticated techniques that allow us to see how specific SNPs interact with genes associated with cancer.

"We recently published research that identified two previously unknown SNPs which increase a woman’s risk of oestrogen receptor positive breast cancer.  Studying the functional impact of these SNPs suggests that they affect a gene involved in the growth and survival of certain cancer cells.

“This type of information helps us understand more about the underlying biology of the disease which in turn can provide clues that are useful in understanding how to prevent it.”

The more we know

The more clues we can gather about genetic risk factors for breast cancer, the more we can do to try and prevent the disease.  By picking out tiny spelling mistakes in the genetic code, we can not only identify people at high-risk of breast cancer, but also begin to understand how these genetic changes cause the disease.  This will open up new and better approaches to preventing breast cancer, ultimately saving thousands of women and their families from having to face the disease.  

Dr Matthew Lam is Breakthrough Breast Cancer's Senior Research Officer