A dispatch from the genetic frontier
I never thought I had all that much in common with the glamorous film star Angelina Jolie – until May of this year, when she decided to tell the world about her family history of breast cancer, the results of genetic testing, and the decision it led her to take. She wrote poignantly and yet in a matter-of-fact way about the consequences of finding she does carry a BRCA1 mutation that predisposes her to breast and ovarian cancer and deciding to have major preventative surgery so as to reduce her risk of dying prematurely from the disease that killed her mother.
My personal story diverges from hers in one key respect, and I feel that this version of the tale is, for good clinical reasons, aired far less often by those who deal with the new frontiers of genetic / genomic and personalised medicine. So I decided to follow Jolie’s example and publish my own story, alongside the Perspective PLOS Biology published that considers the issues for those who receive a genetic diagnosis like Jolie’s and whether there is a case for population-level screening. I hope it is a useful contribution to the discussion of these issues, and that readers will forgive the appearance of self-indulgence.
Since I trained as a research biologist, I have known for a long time the implication for my own health of having a mother, maternal grandmother and great-aunt who died following diagnoses of breast cancer in their 40s and 50s. I was just making the transition from working in a lab to working in science publishing when the BRCA1 gene was cloned, and I continued to make the non-decision not to find out my own mutation status as BRCA2 was also cloned and as certain mutations in BRCA1 and BRCA2 were found to be prevalent in people of Ashkenazi Jewish descent (as I am).
But as my age crept closer to the age my mother was when diagnosed, I thought some more. I read the fascinating and well-researched book ‘Blood Matters: A Journey Along the Genetic Frontier’ by Masha Gessen, in which she took a similar decision to Jolie’s. I read research articles where I could get access to them – and incidentally increased my zeal for open access when they were hidden behind a subscription pay-wall. I spoke to friends and family. And finally I requested a referral from my general practitioner to a clinical geneticist who in due course asked for my family tree and medical history and then walked me through the implications.
He told me some harsh probabilities:
- ‘Anywoman’ in the UK: has a 1 in 9 lifetime chance of developing breast cancer
- With my family history: make that 1 in 3
- Add in Ashkenazi descent:extremely likely to be due to one of the small handful of mutations in BRCA1 or BRCA2 known to be specifically associated with this population
- And if you do have a BRCA1/2 mutation:a lifetime risk of 65-90% of developing breast cancer. And add in a significant risk of ovarian cancer, which is much harder to screen for or diagnose early
So, I decided that I would test for the known ‘Ashkenazi mutations’ (through the UK’s National Health Service), given that estimates suggest that more than 95% of BRCA mutations in the Ashkenazi population are due to these three variants. If I did carry a mutation I would continue breast screening and take the route of prophylactic oophorectomy, which – through surgery much less invasive than Jolie’s – would largely eliminate the excess ovarian cancer risk and would also reduce the breast cancer risk. (If anyone is trying to make a similar decision today, I strongly commend Stanford’s BRCA decision tool). But while busily preparing for future surgery and side-effects, and arming myself with data, I had failed to realistically consider an alternative outcome.
The result was negative. Apparently I was unusual in asking the geneticist when he gave me the negative result “Are you sure?”, rather than simply being relieved. In fact relief took some time to come, as I grappled with what this actually meant. At the risk of labouring a point to a well-informed audience: it didn’t negate the idea that my mother and grandmother carried an Ashkenazi-type BRCA1 or BRCA2 mutation, and hence that my nieces and cousins might do so. Because my affected relatives all died long before the BRCA genes were cloned, we do not know whether they had a particular mutation. And we will not know until or unless one or more members of my extended matrilineal family are told they carry a mutation. This result didn’t address the possibility of a different mutation in one of these genes or in another that might cause early-onset heritable breast cancer. In short, instead of a result that gave a terrible certainty, I had one that perpetuated much of the uncertainty that I had before I took the test.
And this seems to me the relatively under-explored side of the ‘new frontier’ of genetic medicine: what do we do when the results provide no clear message for the person concerned? In a time of squeezed healthcare budgets, I would not argue that much clinical time should be spent on the feelings of those of us who fail to receive expected bad news. But when we consider the possibilities of population-based screening, or indeed of sequencing all of our entire genomes for all possible variants predisposing to all diseases, it seems to me that we do need to consider carefully the effects beyond those who receive a clear message that requires clinical action.
Now that journalists and celebrities are having their full genomic information handed to them on a memory stick or iPad, they need to know how to understand all of it – the ‘good news’ as well as the bad. For myself, while my scientifically trained brain can understand a result of “negative for the 95%-most-likely cause of the disease that killed several members of your family,” another part of me carries the belief imbibed from my mother and from hers, that this is what kills women in our family. To date I have chosen not to pursue further the possibility of other genetic variants or of whole-genome sequencing or scanning. But I now believe I might live long enough for such analyses to be routine for those of us in the wealthy west and that we should plan more carefully what we will do with the resulting information when its personal meaning is uncertain.
The article was first published on PLOS blogs