Desperately SEEKing …

These days few can be unaware that cancers kill one in three of us. That proportion has crept up over time as life expectancy has gone up — cancers are (mainly) diseases of old age. Even so, they plagued the ancients as Egyptian scrolls dating from 1600 BC record and as their mummified bodies bear witness. Understandably, progress in getting to grips with the problem was slow. It took until the nineteenth century before two great French physicians, Laënnec and Récamier, first noted that tumours could spread from their initial site to other locations where they could grow as ‘secondary tumours’. Munich-born Karl Thiersch showed that ‘metastasis’ occurs when cells leave the primary site and spread through the body. That was in 1865 and it gradually led to the realisation that metastasis was a key problem: many tumours could be dealt with by surgery, if carried out before secondary tumours had formed, but once metastasis had taken hold … With this in mind the gifted American surgeon William Halsted applied ever more radical surgery to breast cancers, removing tissues to which these tumors often spread, with the aim of preventing secondary tumour formation.

Early warning systems

Photos of Halsted’s handiwork are too grim to show here but his logic could not be faulted for metastasis remains the cause of over 90% of cancer deaths. Mercifully, rather than removing more and more tissue targets, the emphasis today has shifted to tumour detection. How can they be picked up before they have spread?

To this end several methods have become familiar — X-rays, PET (positron emission tomography, etc) — but, useful though these are in clinical practice, they suffer from being unable to ‘see’ small tumours (less that 1 cm diameter). For early detection something completely different was needed.

The New World

The first full sequence of human DNA (the genome), completed in 2003, opened a new era and, arguably, the burgeoning science of genomics has already made a greater impact on biology than any previous advance.

Tumour detection is a brilliant example for it is now possible to pull tumour cell DNA out of the gemisch that is circulating blood. All you need is a teaspoonful (of blood) and the right bit of kit (silicon chip technology and short bits of artificial DNA as bait) to get your hands on the DNA which can then be sequenced. We described how this ‘liquid biopsy’ can be used to track responses to cancer treatment in a quick and non–invasive way in Seeing the Invisible: A Cancer Early Warning System?

If it’s brilliant why the question mark?

Two problems really: (1) Some cancers have proved difficult to pick up in liquid biopsies and (2) the method didn’t tell you where the tumour was (i.e. in which tissue).

The next step, in 2017, added epigenetics to DNA sequencing. That is, a programme called CancerLocator profiled the chemical tags (methyl groups) attached to DNA in a set of lung, liver and breast tumours. In Cancer GPS? we described this as a big step forward, not least because it detected 80% of early stage cancers.

There’s still a pesky question mark?

Rather than shrugging their shoulders and saying “that’s science for you” Joshua Cohen and colleagues at Johns Hopkins University School of Medicine in Baltimore and a host of others rolled their sleeves up and made another step forward in the shape of CancerSEEK, described in the January 18 (2018) issue of Science.

This added two new tweaks: (1) for DNA sequencing they selected a panel of 16 known ‘cancer genes’ and screened just those for specific mutations and (2) they included proteins in their analysis by measuring the circulating levels of 10 established biomarkers. Of these perhaps the most familiar is cancer antigen 125 (CA-125) which has been used as an indicator of ovarian cancer.

Sensitivity of CancerSEEK by tumour type. Error bars represent 95% confidence intervals (from Cohen et al., 2018).

The figure shows a detection rate of about 70% for eight cancer types in 1005 patients whose tumours had not spread. CancerSEEK performed best for five types (ovary, liver, stomach, pancreas and esophagus) that are difficult to detect early.

Is there still a question mark?

Of course there is! It’s biology — and cancer biology at that. The sensitivity is quite low for some of the cancers and it remains to be seen how high the false positive rate goes in larger populations than 1005 of this preliminary study.

So let’s leave the last cautious word to my colleague Paul Pharoah: “I do not think that this new test has really moved the field of early detection very far forward … It remains a promising, but yet to be proven technology.”

Reference

D. Cohen et al. (2018). Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 10.1126/science.aar3247.

Bigger is Better

“Nonsense!” most males would cry, quite logically, given that we spend much of our time trying to persuade the opposite sex that size doesn’t matter. But we want to have it both ways: in the macho world of rugby one of the oldest adages is that ‘a good big ’un will always beat a good little ’un’.  Beethoven doubtless had a view about size – albeit unrecorded by history – but after he’d written his Eroica symphony, perhaps the greatest revolutionary musical composition of all, his next offering in the genre was the magical Fourth – scored for the smallest orchestra used in any of his symphonies. And on the theme of small can be good, the British Medical Journal, no less, has just told us that if we cut the size of food portions and put ’em on smaller plates we’ll eat less and not get fat!

Is bigger better?

Is bigger better?

All of which suggests that whether bigger is better depends on what you have in mind. Needless to say, in these pages what we have in mind is ‘Does it apply to cancer?’ – that is, because cancers arise from the accumulation in cells of DNA damage (mutations), it would seem obvious that the bigger an animal (i.e. the more cells it has) and the longer it lives the more likely it will be to get cancer.

Obvious but, this being cancer, also wrong.

Peto’s Paradox

The first person to put his finger on this point was Sir Richard Peto, most famous for his work with Sir Richard Doll on cancer epidemiology. It was Doll, together with Austin Bradford Hill, who produced statistical proof (in the British Doctors’ Study published in 1956) that tobacco smoking increased the risk of lung cancer. Peto joined forces with Doll in 1971 and they went on to show that tobacco, infections and diet between them cause three quarters of all cancers.

Whenever this topic comes up I’m tempted to give a plug to the unfortunate Fritz Lickint – long forgotten German physician – who was actually the first to publish evidence that linked smoking and lung cancer and who coined the term ‘passive smoking’ – all some 30 years before the Doll study. Lickint’s findings were avidly taken up by the Nazi party as they promoted Draconian anti-smoking measures – presumably driven by the fact that their leader, Gröfaz (to use the derogatory acronym by which he became known in Germany as the war progressed – from Größter Feldherr aller ZeitenGreatest Field Commander of all Time) was a confirmed non-smoker. Despite his usefulness, Lickint’s political views didn’t fit the ideology of the times. He lost his job, was conscripted, survived the war as a medical orderly and only then was able to resume his life as a doctor – albeit never receiving the credit he deserved.

Returning to Richard Peto, it was he who in 1975 pointed out that across different species the incidence of cancer doesn’t appear to be linked to the number of cells in animal – i.e. its size.   He based his notion on the comparison of mice with men – we have about 1000 times the number of cells in a mouse and typically live 30 times as long. So we should be about a million times more likely to get cancer – but in fact cancer incidence is another of those things where we’re pretty similar to our little furry friends. That’s Peto’s Paradox.

It doesn’t seem to apply within members of the same species, a number of surveys having shown that cancer incidence increases with height both for men and women. The Women’s Health Initiative found that a four inch increase in height raised overall cancer risk by 13% although for some forms (kidney, rectum, thyroid and blood) the risk went up by about 25%. A later study found a similar association for ovarian cancer: women who are 5ft 6in tall have a 23% greater risk than those who only make it to 5 feet. A similar risk links ovarian cancer to obesity (i.e. a rise in body mass index from 20 (slim) to 30 (slightly overweight) puts the risk up by 23%). Statistically sound though these results appear to be, it’s worth nothing that, as my colleague Paul Pharoah has pointed out, these risk changes are small. For example, the ovarian cancer finding translates to a lifetime risk of about 16-in-a-1000 for shorter women going up to 20-in-a-1000 as they rise by 6 inches.

It’s true that there may be a contribution from larger animals having bigger cells (whale red blood cells are about twice as big as those of the mouse) that divide more slowly but at most that effect seems small and doesn’t fully account for the fact that across species the association of size and age with cancer breaks down: Peto’s Paradox rules – humans are much more likely to get cancer than whales.

What did we know?

Well, since Peto picked up the problem, almost nothing about underlying causes. The ‘almost’ has been confined to the very small end of the scale and we’ve already met the star of the show – the naked mole rat – a rather shy chap with a very long lifespan (up to 30 years) but who never seems to get cancer. In that piece we described the glimmerings of an explanation but, thanks to Xiao Tian and colleagues of the University of Rochester, New York we now know that these bald burrowers make an extraordinarily large version of a polysaccharide (a polymer of sugars). These long strings of glucose-like molecules (called hyaluronan) form part of the extracellular matrix and regulate cell proliferation and migration. They’re enormous molecules with tens of thousands of sugars linked together but the naked mole rat makes versions about four times larger than those of mice or humans – and it seems that these extra-large sugar strings restrict cell behaviour and block the development of tumours.

Going up!

Our ignorance has just been further lifted with two heavyweight studies, one from Lisa Abegglen, Joshua Schiffman and chums from the University of Utah School of Medicine who went to the zoo (San Diego Zoo, in fact) and looked at 36 different mammalian species, ranging in size from the striped grass mouse (weighing in at 50 grams) to the elephant – at 4,800 kilogram nearly 100,000 times larger. They found no relationship between body size and cancer incidence, a result that conforms to Peto’s paradox. Comparing cancer mortality rates it transpires that the figure for elephants is less than 5% compared with the human range of 11% to 25%.

107 final pic

Cancer incidence across species by body size and lifespan. A selection of 20 of the 36 species studied is shown. Sizes range from the striped grass mouse to the elephant. As the risk of cancer depends on both the number of cells in the body and the number of years over which those cells can accumulate mutations, cancer incidence is plotted as a function of size (i.e. mass in grams × life span, years: y axis: log scale). Each species is represented by at least 10 animals (from Abegglen et al., 2015).

It can be seen at a glance that cancer incidence is not associated with mass and life span.

The Tasmanian devil stands out as a remarkable example of susceptibility to cancer through its transmission by biting and licking.

How does Jumbo do it?

In a different approach to Peto’s Paradox, Michael Sulak, Vincent Lynch and colleagues at the University of Chicago looked mainly at elephants – more specifically they used DNA sequencing to get at how the largest extant land mammal manages to be super-resistant to cancer. In particular they focused on the tumor suppressor gene P53 (aka TP53) because its expression is exquisitely sensitive to DNA damage and when it’s switched on the actions of the P53 protein buy time for the cell to repair the damage or, failing that, bring about the death of the cell. That’s as good an anti-cancer defence as you can imagine – hence P53’s appellation as the ‘guardian of the genome’. It turned out that elephants have no fewer than 20 copies of P53 in their genome, whereas humans and other mammals have only one (i.e. one copy per set of (23) chromosomes). DNA from frozen mammoths had 14 copies of P53 but manatees and the small furry hyraxes, the elephant’s closest living relatives, like humans have only one.

The Utah group confirmed that elephants have, in addition to one normal P53 gene, 19 extra P53 genes (they’re actually retrogenes – one type of the pseudogenes that we met in the preceding post) that have been acquired as the animals have expanded in size during evolution. Several of these extra versions of P53 were shown to be switched on (transcribed) and translated into proteins.

Consistent with their extra P53 fire-power, elephant cells committed P53-dependent suicide (programmed cell death, aka apoptosis) more frequently than human cells when exposed to DNA-damaging radiation. This suggests that elephant cells are rather better than human cells when it comes to killing themselves to avoid the risk of uncontrolled growth arising from defective DNA.

More genes anyone?

Those keen on jumping on technological bandwagons may wish to sign up for an extra P53 gene or two, courtesy of genetic engineering, so that bingo! – they’ll be free of cancers. Aside from the elephant, they may be encouraged by ‘super P53’ mice that were genetically altered to express one extra version of P53 that indeed significantly protected from cancer when compared with normal mice – and did so without any evident ill-effects.

We do not wish to dampen your enthusiasm but would be in dereliction of our duty is we did not add a serious health warning. We now know a lot about P53 – for example, that the P53 gene encodes at least 15 different proteins (isoforms), some of which do indeed protect against cancer – but there are some that appear to act as tumour promoters. In other words we know enough about P53 to realize that we simply haven’t a clue. So we really would be playing with fire if we started tinkering with our P53 gene complement – and to emphasise practicalities, as Mel Greaves has put it, we just don’t know how well the elephants’ defences would stack up if they smoked.

Nevertheless, on the bright side, light is at long last beginning to be shed on Peto’s Paradox and who knows where that will eventually lead us. Meanwhile Richard Peto’s activities have evolved in a different direction and he now helps to run a Thai restaurant in Oxford, a cuisine known for small things that pack a prodigious punch. Bit like Beethoven’s Fourth you could say.

a-gem-of-a-find-in-oxford

References

Peto, R. et al. (1975). Cancer and ageing in mice and men. British Journal of Cancer 32, 411-426.

Doll, R. and Peto, R. (1976). Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J. 2(6051):1525–36.

Maciak, S. and Michalak, P. (2015). “Cell size and cancer: A new solution to Peto’s paradox?”. Evolutionary Applications 8: 2.

Doll, R. and Hill, A.B. (1954). “The mortality of doctors in relation to their smoking habits”. BMJ 328 (7455): 1529.

Doll, R. and Hill, A.B. (November 1956). “Lung cancer and other causes of death in relation to smoking; a second report on the mortality of British doctors”. British Medical Journal 2 (5001): 1071–1081.

Tian, X. et al. (2013). High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346-349.

Abegglen, L.M., Schiffman, J.D. et al. (2015). Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. doi:10.1001/jama.2015.13134.

Sulak, M., Lindsey Fong, Katelyn Mika, Sravanthi Chigurupati, Lisa Yon, Nigel P. Mongan, Richard D. Emes, Vincent J. Lynch, V.J. (2015). TP53 copy number expansion correlates with the evolution of increased body size and an enhanced DNA damage response in elephants. doi: http://dx.doi.org/10.1101/028522.

García-Cao, I. et al. (2002). ‘Super p53’ mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO Journal 21, 6225–6235.

Whose side are you on?

Writing this blog – intended to be on current cancer-related topics – has been very good for me, if no one else, because it makes me read things I wouldn’t otherwise bother with. So I’m wiser than I would have been – but here’s a shocking admission: I’m becoming increasingly sympathetic to those who wish that scientists would just go away – or at least shut up sometimes. Of course I’m being jolly unfair: it’s not so much fellow boffins I’m miffed with as the ‘media’ – the BBC and the leading newspapers. They’re the ones who bring ‘stuff’ to my attention. Do you think I spend my time reading a journal called Alcohol and Alcoholism?!

Thanks to the medja, in just the last couple of weeks I’ve read that women’s height is linked to ovarian cancer  (BBC), breast cancer screening results in ‘unnecessary treatment’ (Telegraph), and a glass of wine carries a breast cancer warning (The Independent), – oh, and I should take an take an aspirin a day to cut cancer risk (Guardian). Just a month or two ago there was a similar stampede of ‘beef is bad’. This week the University of Gothenburg weighed in by discovering that some people are so ‘addicted’ to Facebook that they open it the moment they switch on their computers! And getting hooked (to Facebook, that is) makes women unhappy. Thank heavens they didn’t get round to emails or prostate cancer in Gothenburg or I might be needing something stronger than aspirin for my depression.

If you’d looked at all these important scientific surveys you’d have spotted that they have one thing in common: they never mention fun. Not one of them. Ever. Not a smile, nary a joyous feeling – and as for anything orgasmic …

Salvation is at hand

The good news is that some relieving guidance has popped up in the midst of all this ‘thou shalt not’, ‘it’s too late’ and ‘now look what you’ve done’. The absolutely astonishing thing is its source – ‘provenance’ as the antiques freaks like to put it. You aren’t going to believe this but it’s to the good old Church of England that we turn in the shape of a vicar from Hove (go on then …). This blessed man has revealed that not only is it a ‘good thing’ but it’s almost a moral duty, perhaps even a religious obligation, to spend Easter Sunday in bed, eating chocolate and having sex – and, by implication, doing anything else that feels as though it should be in the ‘naughty but nice’ statistical bracket. Well – who would have thought you’d read it here – praise be for the C of E!            Photograph by Hemera/Thinkstock

Here comes another of them scientists

Having let the grumpies have their say, shall we do as we preach and have a balanced, non-inflammatory comment on behalf of beleaguered boffins? Oh alright. Should the studies I listed have been done? Yes (apart from the Scandi one, obviously). They’re by excellent groups and they add another brick to the wall, even if it’s only reaffirming what we knew. The ovarian/height link paper makes a good case by pointing out that the evidence so far published on whether height, weight and body mass index (BMI) have any link with the risk of getting ovarian cancer has not given a very clear picture. They were thus prompted to put together 47 of these studies (a meta analysis) – and what emerged was that the risk increases with height and, for women who have never used hormone therapy, with BMI. However, the important point is that although the increases are statistically significant, they are very small. My colleague Paul Pharoah has helpfully estimated that they show that being 5ft 6in rather than 5ft tall raises the lifetime risk of ovarian cancer from about 16 in 1000 to 20 in 1000.

So these reports are good, though not seismic, stuff. And yes, it’s great that the media pick up on what science produces and bring it to the attention of the wider world. It would just be nice if they were less keen on eye-catching, doomy, headlines. How about taking a lead from The Sun, an organ not previously mentioned in this column, that headlined the C of E story with Easter Sinday. What might they do? Aspirin v. Expirin? I came up with a cracker for the ovarian study but a problem with talking and writing about cancer is the ease with which jokes (mine anyway!) teeter into what some would consider to be the realms of bad taste. So a green light for The Sun then!

Final thought for the day: am I now (1) religiously taking aspirin OR (2) opting for Nick the Vic’s life support strategy? I think you know the answer to that one.

References

Collaborative Group on Epidemiological Studies of Ovarian Cancer (2012) Ovarian Cancer and Body Size: Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies. PLoS Med 9(4): e1001200. doi:10.1371/journal.pmed.1001200

Kalager, M., Adami, H.O., Bretthauer, M. and Tamimi, R.M. (2012). Overdiagnosis of Invasive Breast Cancer Due to 491 Mammography Screening: Results From the Norwegian Screening Program. Annals of Internal Medicine 156, 491-499.

Rothwell, P.M., Wilson, M., Price. J.F., Belch, J.F.F., Meade, T.W. and Mehta, Z. (2012). Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. The Lancet, Early Online Publication, 21 March 2012 doi:10.1016/S0140-6736(12)60209-8Cite or Link Using DOI