A disease shaped by history

Breast cancer, like all cancers, is a highly complex disease.  The combination of genetic mutations, environmental pressures and lifestyle choices make it difficult to pin down causation.  Plus the fact that each cancer is a product of self adds a level of individuality that only impairs classification.  New research out this week exposes the complexity of breast cancer and also highlights a strange correlation between race and risk.

The use of hormone replacement therapy (HRT) to reduce the symptoms associated with menopause has long been associated with an increased risk of breast cancer.  The study published this week shows for the first time how other factors combine with HRT use to affect breast cancer risk.  Amongst other things they discovered that factors like body mass index and breast tissue density determined the level of risk a women was at from using HRT.  The researchers also looked at any correlation with race and found that there was at least a 20% increased risk from HRT use amongst white and Hispanic but not black women.

The statistics on ethnicity and breast cancer are complex.  In the US, white women have the highest overall risk of breast cancer, while black women are much more likely to die of the disease.  There is a higher incidence of BRCA mutations amongst Eastern European Jewish (Ashkenazi) women, thus they have an increased risk of hereditary breast cancer.  Women of African ancestry seem to be at an increased risk of developing more aggressive forms of the disease such as triple negative breast cancer (TNBC).  Male breast cancer is also more prevalent amongst men of African ancestry than any other ethnicity.

But why is this?

Ashkenazi Jews can trace their roots back to a small Jewish community with origins to the ancient Israelites of the Middle East.  Generations of reproductive isolation following their movement into central and Eastern Europe may have contributed to specific genes becoming prevalent.  The general idea is that random changes to genes that confer a survival advantage will inevitably replicate within a population and come to dominate the genetic landscape by a process called adaptive evolution.  The problem with this theory is that BRCA mutations would have to confer a survival advantage, which as of yet, no one has managed to ascertain.

In depth studies into the statistics, genetics and variation in BRCA mutations amongst modern Ashkenazi Jews suggest that processes such as random genetic drift and the founder effect are more likely to be responsible.  These phenomena may have occurred due to a population bottleneck when a small portion of Ashkenazi Jews migrated to Europe.  If the majority of these migrants carried BRCA mutations then natural selection would not remove them from the population, rather they would remain dominant, creating a drift in Ashkenazi genetics that has remained in modern descendants.

So what about the fact that TNBC is much more common amongst women of African ancestry?

This is still a bit of a mystery but one recent study of breast cancer genes found several mutations that were more prevalent in the African American population.  Moreover, these mutations were strongly associated with triple negative breast cancer, suggesting that genetic predisposition may play a big part.  It turns out that BRCA mutations are also linked with triple negative breast cancer so it has been postulated that African ancestry might be associated with a hereditary disposition to TNBC.

Genetic and population history sets out a nice story explaining the relationship between racial history and diseases.  Of course it’s interesting to put the timeline of events together but the real benefit will come from knowing how to use it to improve prevention so that incidence and risk is not confounded by ethnicity.

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