Breast and Ovarian Cancer Screening

I am sometimes troubled by the concept of risk. I mean how can we possibly decide whether or not a risk is acceptable? No matter the statistics, if the issue under consideration doesn’t happen, then the risk assumed was acceptable. So far, so good. But of course the converse is also true: no matter how low the risk, if it does occur, well…

Ours is a culture of prediction. Statistics. Guessing. I rationalize buying a lottery ticket by convincing myself that if I don’t buy it, I won’t win -no matter how low the odds, no matter how unreasonable it would be to assume that I would be the one in –what?- ten million who wins the jackpot. Or anything, for that matter…  And no matter that without a year of such profligate spending, I could treat myself to a sumptuous dinner at a good restaurant.

Of course, we all live in hope, and if the lottery ticket funds some worthwhile government project, then it is an almost enjoyable form of indirect taxation. Assimilable because it is freely chosen. Optional.

It is a different proposition entirely if the risk is one to which we do not wish to subscribe but have no choice: genetic defects in a developing pregnancy, cancers, diseases, to name but a few. It is likely to our advantage to interrogate these, if possible. Of course, the question then becomes who should undergo the screening. Only those at the highest risk –those with a family member with the condition, say- or everybody? Just in case.

Screening always seems to be bathed in a soft, warm glow. If you can test, then why not? Just pop in to your local lab and get that PSA; find out if your prostate is betraying you. Demand yearly mammograms as soon as you feel concerned. As soon as a friend or even a friend-once-removed has a cancer scare. And at any age, because you never know…

If only screening was that good; if only all negative tests were reliable –and, for that matter, didn’t have to be repeated at intervals to keep pace with the ravages of Time wreaking its not so subtle havoc on our aging bodies.

Screening for specific inherited genetic mutations for breast and ovarian cancers are the relatively new species of Wunderkind: BRCA1 and BRCA2. These are tumour suppressor genes broadly speaking; we all have them, and they are located on chromosomes 17 (BRCA1) and 13 (BRCA2). But if they contain defects -mutations- they may no longer function efficiently and so be unable to winnow out mistakes such as tumours from proliferating. The mutations are inherited in an autosomal dominant manner and women with these particular mutated genes have a lifetime breast cancer risk of 50-85%. .

So why not screen all women for these genes? Indeed, a recent study published in the Proceedings of the National Academy of Sciences (USA) suggested just that: http://www.pnas.org/content/111/39/14205.abstract

On first reading, it sounds like a reasonable approach. But I’m not so sure. First of all let’s put the whole issue into context. Less than 10% of breast cancers (and <15% of ovarian cancers) seem to be associated with BRCA1 or BRCA2 mutations. And, although even less common, there are hereditary breast cancers associated with other genes, so there might be a false sense of security from testing only the BRCAs.

And then there’s the uncomfortable fact that there have been over a thousand different mutations in BRCA1 and 2 discovered so far. You’d have to know which one to look for. Of course, some populations have more prevalent mutations –so called Founder effects– which might simplify the search. Two per cent of Ashkenazi Jews, for example, carry specific mutations of BRCA1 or BRCA2. And there are other populations carrying unusual founder mutations that might facilitate searches in them as well: people from the Netherlands, Quebec, Iceland, to name a few. Or in still other groups -some families, for example- if the particular mutation resulting in their tumours has been identified, then the process is obviously easier.

The most successful screening is in people with identifiable risks, however. With breast cancer, such things as family history -especially a young age of developing the breast or ovarian cancers (the younger, the more chance there is a risk that can be  inherited), or a family history of so-called triple negative breast cancers –progesterone, estrogen and HER2 receptor negative. Males with breast cancer (yes it happens) are another, albeit infrequent clue to increased risk.

But screening everybody? Let’s get back to risk assimilability. Just what risk is acceptable? Less than 50%? Less than 25%? No risk at all..? Sometimes the answer is easy: a 50-85% lifetime risk of breast cancer if specific BRCA1 or 2 mutations are present is likely not tolerable. But what about the odds if only 2% of the population had that risk, as is the case for BRCA1 and 2 mutations in the Ashkenazim? Or if the chances of those mutations are even lower: 1/800-1/1000 as it is in the general population?

And what if you are not a member of a high risk population, or if there are no cases of breast or ovarian cancer in the family? Should you still be screened? And if so, with what? Remember there are many different mutations possible on the BRCAs -not all of which may result in an increased cancer risk. And there are other genes than BRCA that may play a similar role sometimes. So if you are just concerned that you might be at some risk, or worse, merely curious… Well, its best to remember that we are all exposed to dangers each day that we don’t even think about -and there’s no avoiding them: everything from tripping and falling down the stairs, to slipping on some ice; from having a heart attack, to getting hit by a car crossing the street to shop. We have to put things in perspective: life is a risk, and we are fragile creatures. Remember Shakespeare’s Hotspur in Henry IV:

‘Tis dangerous to take a
cold, to sleep, to drink; but I tell you, my lord fool, out of
this nettle, danger, we pluck this flower, safety.

So, if there is reason to believe there is a risk on the horizon, then it’s best to mitigate it. But don’t go looking for it in places it doesn’t exist.

 

 

 

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The Awe of BRCA

Awe: the word has been pasteurized, connotized almost beyond recognition. But I suppose that’s what happens to all really powerful words. There’s a life-span to language; a generation if you’re lucky; a year if social media gets hold of it –likes it… But I think the ship of awe and all of its elegance went down quickly -even before Facebook or Twitter could sink it. It’s a shame because I am sometimes filled with it.

Different things inspire it in me; there’s no formula, no recipe for the appeal. I am sometimes simply stopped in my tracks, occasionally accorded an audience with grandeur. Majesty. Awe: the ineffable sublimated and instilled wordlessly into my head.

Most recently it was occasioned by genetics -unsurpisingly, because I understand so little of it nowadays. Since the genetic code was cracked and genes in all their undress were unfurled from where they ruled unseen in their closet, I have been a stranger in an even stranger land. I sometimes feel as a child must, confronted with an explanation that has not lost any of its initial magic. Any of its mystery…

And it’s not merely the unravelling of the genetic puzzle that intrigues me. I am scarcely moved by the knowledge -no, not the knowledge, the words- that on the short arm of chromosome 3, position 21 (have I got that right?), there exists a gene that makes a chemokine (a what?) that has an important role in the resistance to infection. I suppose I should care more, but I don’t.

The gene that has captured my interest is the BRCA gene. ‘BRCA proteins are required for maintenance of chromosomal stability in mammalian cells and function in the biological response to DNA damage’ -that from the Journal of Cell Science. In other words, they make sure that the DNA is okay, and deal with it if it is not… They repair damage and keep the cell growing normally. They suppress tumours; mutate the genes -cripple them- and the oversight is lost.

That much I knew, but what intrigued me was that the BRCA genes also occur in plants. They evolved about 1.5 billion years ago in whatever single-celled creature that was the common evolutionary ancestor to both animals and plants. The fact that these genes also exist in plants (most studied in a small flowering plant called arabidopsis, because in 1990 it was chosen by the National Science Foundation as the first plant that would have its genome sequenced) suggests they have an important and enduring function throughout the phyla and kingdoms. Plants, too, need to manage what happens to their DNA: they are rooted to a spot and can’t avoid recurring environmental stress factors that might damage it. As an example, some mutations in the arabidopsis BRCA allow certain cells to divide uncontrollably making the plant very sensitive to various forms of radiation. Sound familiar..?

Not all of the BRCA gene is the same in different organisms, of course: different domains, or portions, with different functions are preserved that seem to have an evolutionary importance relevent to each entity. Why re-invent the wheel? Nature fiddles with what it already has -what it knows. That mutations in this same gene should have such important effects on breasts and ovaries in humans is interesting, to say the least. All organs have DNA that is responsible for their growth and development; all DNA needs surveillance and repair; all organs have a cancer potential…  So was there a common ancestor somewhere whose BRCAs first assumed uber guardianship of breasts? Whose unintended mutations engendered these hereditary risks -a family, an individual..? Presumably stuff has to start somewhere.

And although arabidopsis doesn’t have analogous organs to humans, similar BRCA mutations do not seem to be as lethal, so I suspect that studying them may lead to some important insights. Maybe they already have: I can barely understand the way the studies are worded and find myself perusing only the Introduction and then skipping past the Results section to Conclusions where the authors discuss whatever ramifications they feel obtain from the experiment. I still read through a glass, darkly.

But somehow, the knowledge that we are in a sense all part of the same organism is epiphanous. Humbling… As Shakespeare (in Troilus and Cressida) has Ulysses say: “One touch of nature makes the whole world kin.”