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.

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In the beginning … 

You may have noticed that the American actress Angelina Jolie, who is now employed as a  Special Envoy  for the  United Nations High Commissioner for Refugees, has re-surfaced in the pages of the science media. She first hit the nerdy headlines by announcing in The New York Times that she had had a preventive double mastectomy (in 2013) and a preventive oophorectomy (in 2015).

We described the molecular biology that prompted her actions in A Taxing Inheritance. The essential facts were that she had a family history of breast and ovarian cancer: genetic testing revealed that she carried a mutation in the BRCA1 gene giving her a 87% risk of breast cancer and a 50% chance of getting ovarian cancer.

A star returns

BRCA1 and breast cancer are back in the news as a result of a paper by Jane Visvader, Geoffrey Lindeman and colleagues in Melbourne that asked a very simple question: which type of cell is driven to proliferate abnormally and give rise to a tumour by mutant BRCA1 protein? That is, pre-cancerous breast tissue contains a mixture of cell types: does cancer develop from one in particular –  and, if you blocked proliferation of that type of cell, could you prevent tumours forming?

Simple question but their paper summarises about 10 years of work to come up with a clear answer.

And the villain is …

The mature mammary gland is made up of lots of small sacs (alveoli) lined with cells that produce milk – called luminal cells. Groups of alveoli are known as lobules, linked by ducts that carry milk to the nipple. Most breast cancers start in the lobular or duct cells.

Breast fig copy

Left: Normal breast lobule showing alveoli lined with milk-producing luminal cells connected to duct leading to the nipple. Right: Normal milk sac, non-invasive cancer, invasive cancer.

Things are complicated by there being more than one type of progenitor cell but the Melbourne group were able to show that, in mice carrying mutated BRCA1, one subtype stood out in terms of its cancerous potential. These cells carried a protein on their surface called RANK (which is member of the tumour necrosis factor family). They had gross defects in their DNA repair systems (so they can’t fix genetic damage) and they’re highly proliferative. Luminal progenitors that don’t express RANK behave normally.

Slide1 copy

Scheme representing normal and abnormal cell development. The basic idea is that different types of cells evolve from a common ancestor. The Australian work identified one type of luminal progenitor cell that carries a protein called RANK on its surface (pink cell) as being a prime source of tumours. RANK+ cells have defective DNA repair systems so they accumulate mutations (red cells) more rapidly than normal cells, a feature of tumour cells.

In mice with mutant BRCA1 a monoclonal antibody (denosumab) that blocks RANK signalling markedly slowed tumour development. In a small pilot study blockade of RANK inhibited cell proliferation in breast tissue from human BRCA1-mutation carriers.

Next?

How effective blocking the activation of RANK signalling will be in preventing breast cancer is anyone’s guess but the idea behind the work of the Australian group cannot be faulted. Being able to prevent the ‘starter’ cells from launching themselves on the pathway to cancer driven by mutation in BRCA1 would mean that women in Angelina Jolie’s position would not have to contemplate the drastic course of surgery. The question is: will the preliminary mouse results lead to something that works in humans and, moreover, does so with high efficiency. As ever in cancer, watch this space – but don’t hold your breath!

References

Nolan, E. et al. (2016). RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers.

 

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.

Lethal Lifesaver

Almost exactly three years ago (goodness me, it seems like a couple of months!) I wrote a piece about one of the novel approaches to cancer therapy being tried around the world. This exploits an effect called synthetic lethality that refers to the death of a cell as a result of a combination of mutations in two or more genes whilst mutation in either of these genes alone leaves the cell perfectly functional. The example involved two distinct pathways that repair damaged DNA – recall that our genetic material is being continuously assaulted in a variety of ways and that we’ve evolved very effective repair strategies. One of these involves a pair of familiar ‘cancer genes’, BRCA1 and BRCA2, mutated forms of which can be inherited to give rise to several types of cancer. The other requires an enzyme called PARP (for poly (ADP-ribose) polymerase). So the idea is that if BRCA mutations block that route the cell becomes dependent on PARP. Stop PARP functioning and the cell accumulates genetic damage that it is eventually unable to live with. Result: death of a cancer cell.

Blog fig

Synthetic lethality. If there are two distinct signaling pathways in a cell, each of which can be blocked without harming the cell but when both are inhibited simultaneously the cell dies, the effect is called synthetic lethality. The enzyme PARP (poly (ADP-ribose) polymerase 1) normally repairs single-strand DNA breaks. When this pathway is blocked by PARP inhibitors single-strand DNA breaks accumulate together with double-strand DNA breaks. If cells have normal BRCA, the double-strand breaks are repaired by a second pathway involving BRCA and the cell survives. However, in cancer cells with mutant BRCA this pathway is impaired. The use of PARP inhibitors means that neither pathway can work and the inhibitors, in effect, selectively target and kill cancer cells with BRCA mutations.

‘Three cancers for the price of one’ summarized small-scale clinical trials of several related PARP inhibitors, including one called olaparib, treating breast, ovarian and prostate cancers (BRCA mutations cause about 5% of breast cancers and 10% of ovarian cancers and they can also give rise to prostate cancer). The drugs showed effects on all three tumour types but in a subsequent trial there was no significant survival benefit for breast cancer patients.

Whilst that was a set-back I was sufficiently prescient to comment that ‘the PARP story is far from over’ and indeed further trials have shown significant effects on ovarian cancer, olaparib prolonging progression free survival from 4.3 months to 11.2 months. On this basis  Lynparza (aka Olaparib) was approved in December 2014 in both Europe and the USA for the treatment of advanced ovarian cancer with mutated BRCA.

This is only one more small step along the road to equipping us with a comprehensive anti-cancer drug cabinet but it is, of course, good news for the patient group who should benefit. For my colleague Steve Jackson and his team who developed this approach it must be a wonderful moment and they can look forward to following the success of the drug, now being marketed by Astra-Zeneca.

A Taxing Inheritance

The centenary of the beginning of the First World War prompted me, as perhaps many others, to reflect on how successive generations have done since then in terms of what they’ve bequeathed to their offspring. I didn’t need to think for too long though, to find myself muttering ‘Thank heavens for science’—because most of the rest is a pretty dismal chronicle. I know, not all technological advances in the past one hundred years have been a cause of unrestrained joy but many of them transformed life in the most wonderful ways. Would that we could point to such success in other fields.

Our best defence may be to aver: “Man cannot control the current of events. He can only float with them and steer”, a saying attributed to Otto von Bismarck. If the ‘Iron Chancellor’ actually did utter those words it seems to me he was being coy beyond belief. He is, after all, generally credited with unifying Germany, seeing off the last French monarch (Napoleon III) and establishing the peaceful domination of Europe by the German Empire that lasted until long after his death—and setting up the first welfare state along the way. “The main thing is to make history, not to write it” sounds much more like Bismarck in full and frank mode.

Nature and Nurture

One form of history that we do write but indeed we cannot control comes in the form of the genetic material that we pass to the next generation. We’re all familiar with some of this legacy because we literally see it in physical resemblances and other attributes between parents and children (“He’s got his Mum’s eyes”) or shared by siblings (“Jack and Jill are wonderful musicians”). They’re shared because large chunks of the genetic code (i.e. DNA) are identical between the individuals concerned. But if conserved DNA makes for similarities, what of the differences—the fact that our parents and brothers look different to all the seven thousand million other people on the planet? Our unique features come from variations in the genetic code—odd changes in the units (bases) of DNA scattered through our genome. Called SNPs (pronounced ‘snips’ for single nucleotide polymorphisms), they’re what make the differences between us. In other words, a SNP is a difference in a single nucleotide—A, T, C or G—within a stretch of DNA sequence that is otherwise identical between two individuals. For example, you have AAGCCTA whereas I have AAGCTTA. These genetic variations that make individuals different are the basis of DNA fingerprinting.

There’s about three million SNPs scattered throughout the human genome (so, on average, you’d come across one in every 1,000 bases if you scanned your DNA from beginning to end) and they’re what makes each of us unique. Within ethnic groups common patterns of such variants confer characteristics (dark skin/light skin, tall/short, etc) and, with that in mind, you might guess that there will also be variants that make such groups more (or less) susceptible to diseases.

Of course, there’s an endless debate about the border between our genetic inheritance and how the world we experience makes us what we are—how much of Jack and Jill’s precocious talent is because Mum and Dad made them practice twelve hours a day from age five? Fortunately we can ignore nurture here and stick to genes because we’re trying to pin down the good and the bad of our genetic legacy.

What’s all this got to do with cancer?

A good bit is that we’re distinct from everyone else but still share family features. However, our genetic baggage may also contain some unwanted freebies—the most potent of which can give a helping hand to a variety of diseases, including cancers. Cancers are caused by damage to DNA—a build-up of changes, i.e. mutations, that affect the activity of proteins critically involved in controlling cell growth. For most cancers (90%) these mutations accumulate over the lifetime of the individual—they’re called “somatic mutations”—so you can’t blame anyone but yourself and Lady Luck. But about 10% get a kind of head start when someone is born with a key mutation. That is, the mutated gene came from either egg or sperm (so it’s a germline mutation). This effect gives rise to cancers that “run in families”: a critical mutation is passed from generation to generation so that children who inherit it have a greatly increased risk of developing cancer. Two of the most common cancers that can come in hereditary form are those of the breast and bowel.

Steeplechase

A mutational steeplechase leads to cancer. Of the tens of thousands of mutations that accumulate over time in a cancer cell, a small number of distinct “drivers” make the cancer develop (four are shown as Xs). Almost all mutations arise after birth, but about one in every ten cancers start because a person is unfortunate enough to be born with a mutation: they are already one jump ahead and are much more likely to get cancer than those born with a normal set of genes. The rate at which mutations arise is increased by exposure to carcinogens, e.g., in tobacco smoke.

Breast cancer is about twice as common in first-degree relatives of women with the disease as it is in the general population (you’re a first degree relative if you’re someone’s parent, offspring, or sibling). About 5% of all female breast cancers (men get the disease too but very rarely—about 1% of all breast cancers) arise from inherited mutations. In the 1990s two genes were identified that can carry such mutations. These are BRCA1 and BRCA2 and their abnormal versions can increase the lifetime risk of the disease to over 50%, compared with an average of about 10%. Since then heritable mutations in some other genes have also been shown to increase the risk.

Angelina Jolie

Angelina Jolie

A star turn

Breast cancer genetics came under the spotlight with the much-publicised saga of Angelina Jolie, the American film actress. Jolie’s mother and maternal grandmother had died of ovarian cancer and her maternal aunt from breast cancer—a family history that persuaded Jolie to opt for genetic testing that indeed revealed she was carrying a mutation in BRCA1 (BRCA1 and BRCA2 mutations account for about 10% of breast cancers and 15% of ovarian cancers). For Jolie the associated lifetime risk of breast cancer was estimated as 87%, prompting her to have a preventative double mastectomy, thereby reducing her risk to less than 5%. The months after she revealed her story saw the “Angelina effect”, a doubling in the number of women being referred for genetic testing for breast cancer mutations.

What’s all this got to do with SNPs?

The story so far is of the one in ten cancers that get kicked off by a powerful, inherited mutation that changes the action of the affected protein—the BRCAs being the best-known examples. However, the BRCAs and other known mutated genes account for only about 25% of familial breast cancers, meaning that for three quarters of cases the genetic cause remains unknown. And yet we know there is an inherited (genetic) cause simply because of the generational thread. Which brings us back to those other, more subtle tweaks to DNA that we mentioned—SNPs—alterations that don’t directly affect proteins, so they’re often called variants to distinguish them from mutations.

It seems very likely that the missing culprits are indeed SNPs—lots of them. These DNA variants each make a contribution so small that on its own would have no detectable effect on the chances that the carrier will get cancer. Their impact comes from a cumulative effect. They’re like pieces of straw, individually easily bent or broken but put a dozen of them together and you have a rope. Thus combinations of individually insignificant SNPs can raise the risk of cancer by, say, 10%—not a massive increase but not negligible either. Twins who are genetically identical have similar risks of developing breast cancer, consistent with the idea that many variants, each having a very small effect, can combine to give a substantial increase in risk. Very slowly, by sequencing lots of genomes, these rare variants are being identified. Given that clusters of appropriate variants confer risk, people with the “other” variant have, in effect, a degree of protection against cancer.

And in our more distant relatives?

All this comes from the huge effort that has gone into finding genetic variants linked to one of the most common cancers but, unsurprisingly, almost all the attention has focused on European women. Not before time, someone has got round to looking for breast cancer variants in East Asians who, after all, make up over one fifth of all the people in the world. Cai Qiuyin and his colleagues at the Vanderbilt University School of Medicine compared the genomes of over 20,000 cancer cases from China, Japan and South Korea with a similar number of disease-free controls. After much selecting and comparing of sequences, three particular DNA variants consistently associated with significant cancer risk. The variants were much less common in European women, suggesting that as the DNA keyboard has been strummed by evolution, distinct patterns associated with breast cancer have emerged in diverse populations.

Just two problems then. First it’s a huge task to assemble the lists of runners (and as the Asian results show, they will differ between ethnic groups). But the real challenge is yet to come. Almost all of these variants (99.9%) don’t change the sequence of proteins (i.e. how the proteins work). What they do is exert subtle effects on, for example, how much RNA or protein is made from a DNA gene at any time. At the moment we have little understanding of how this works, yet alone ideas on how to intervene to change the outcome.

Although identifying the BRCA genes that help to drive breast and ovarian cancers was a giant breakthrough, we still have no effective therapy for countering their malign influences. The intervening twenty-five years of effort have brought us to a new era of revealing the more subtle effects of variants. But the price we pay for unveiling the complete picture is perceiving just how tough is the therapeutic challenge.

Reference

Qiuyin Cai, et al. (2014). Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nature Genetics 46, 886–890. doi:10.1038/ng.3041.

A Small Helping For Australia

There’s an awful lot of very good things in Australia. Australians for a start. They’re just so kind, open, welcoming and accommodating it makes touring round this vast land a joy. Not merely do they cheerfully find a way to fix anything you want but they’re so polite that no one’s drawn attention to my resemblance to a scientific version of those reconstructed geriatric pop groups (viz the Rolling Stones or whatever) staggering round the place on their Zimmer frames. And they say wonderful things about my talks – that’s how charming they are!!

Greater bilgy

Greater bilby

Of course, you could say of Australia what someone once said of America and Britain: two nations divided by a common language. In the case of Oz you could also add ‘and by a ferociously competitive obsession with sport.’ So it’s wonderfully not home. Even Easter’s different in that here you get chocolate Easter bilbies rather than rabbits. Bilbies, by the way, are a sort of marsupial desert rat related to bandicoots. The lesser version died out in the 1950s so only the greater bilby is left (up to 20 inches long + tail half as long again) and you have to go to the arid deserts to find those. Not the choccy versions obviously: they don’t do too well in the deserts but they’re all over Melbourne:

Easter bilby

Easter bilby

shops full of ’em – and a lot bigger than the real thing. So, together with the egg avalanche, there’s no limit to the number of calories you can consume in celebrating the resurrection of Christ. Coupled with the glorious fact that there’s scarcely any mention of wretched soccer, all these novelties mean you’re never going to be lulled into thinking you’re still in dear old Blighty (or back in the old country as they delightfully put it here).

Hors D’Oeuvres

Even so there are some marked similarities to make you feel at home. One of the least striking is that most people are overweight. That is, I scarcely notice it, coming from what I regard as the global fat capital, i.e. Cambridge. The stats say that that’s not true, of course. The USA does these things better than the UK. Of course it does. But there’s not much in it. More than two-thirds of American adults are overweight and one person in three is obese. For the UK the prediction is that one in three will be obese by 2020. Currently in Australia 63% of the adult population is overweight, a figure that includes 28% who are obese.

The essential point is that there’s stuff all difference between those countries and the really critical thing is that the rates go on soaring. In the U.S. between 1980 and 2000 obesity rates doubled among adults and since 1980 the number of overweight adolescents has tripled. By 2025 one Australian child in three will be in the overweight/obese category.

Main course

The meat in this piece is provided by a report written by a bunch of Australian heavyweights – all Profs from Sydney or wherever. It has the droll title ‘No Time To Weight’ – do I need to explain that or shall I merely apologise for the syntax? ‘Oh c’mon!’ I hear our Aussie readers protest. ‘We’re going to hell in a handcart and you’re wittering about grammar. Typical b***** academic.’ Quite so. Priorities and all that. So the boffins’ idea is to wake everyone up to obesity and get policy-makers and parliamentarians to do something effective.No Time to Weight report

Why is this so important? Probably unnecessary to explain but obesity causes a variety of disorders (diabetes, heart disease, age-related degenerative disease, sleep apnea, gallstones, etc.) but in particular it’s linked to a range of cancers. Avid followers of this BbN blog will recall obesity cropping up umpteen times already in our cancer-themed story (Rasher Than I Thought?/Biting the bitter bullet/Wake up at the back/Twenty winks/Obesity and Cancer/Isn’t Science Wonderful? Obesity Talks to Cancer) and that’s because it significantly promotes cancers of the bowel, kidney, liver, esophagus, pancreas, endometrium, gallbladder, ovaries and breast. The estimate is that if we all had a body mass index (BMI) of less than 25 (the overweight threshold) there would be 12,000 fewer UK cancers per year. Mostly the evidence is of the smoking gun variety: overweight/obese people get these cancers a lot more often than lesser folk but in Obesity Talks to Cancer we looked at recent evidence of a molecular link between obesity and breast cancer.

Entrée (à la French cuisine not North American as in Main course)

Or, as you might say, a side dish of genetics. The obvious question about obesity is ‘What causes it?’ The answer is both complicated and simple. The complexity comes from the gradual accumulation of evidence that there is a substantial genetic (i.e. inherited) component. Many people will have heard of the hormone leptin, a critical regulator of energy balance and therefore of body weight. Mutations in the leptin gene that reduce the level of the hormone cause a constant desire to eat with the predictable consequence. But only a very small number of families have been found who carry leptin mutations and, although other mutations can drive carriers to overeating, they are even rarer.

However, aside from mutations, everyone’s DNA is subtly different (see Policing DNA) – about 1 in every 1000 of the units (bases) that make up our genetic code differs between individuals. All told the guess is that in  90% of the population this type of genetic variation can contribute to their being overweight/obese.

Things are made more complicated by the fact that diet can cause changes in the DNA of pregnant mothers (what’s called an epigenetic effect). In short, if a pregnant woman is obese, diabetic, or consumes too many calories, the obesity trait is passed to her offspring. This DNA ‘imprinting’ activates hormone signaling to increase hunger and inhibit satiety, thereby passing the problem on to the child.Preg Ob

So the genetics is quite complex. But what is simple is the fact that since 1985 the proportion of obese Australians has gone up by over 10-fold. That’s not due to genes misbehaving. As David Katz, the director of Yale University’s Prevention Research Center puts it: ‘What has changed while obesity has gone from rare to pandemic is not within, but all around us. We are drowning in calories engineered to be irresistible.’

Desserts

We might hope that everyone gets theirs but for obesity that’s not the way it works. The boffos’ report estimates that in 2008 obesity and all its works cost Australia a staggering $58.2 billion. Which means, of course, that every man, woman and child is paying a small fortune as the epidemic continues on its unchecked way. The report talks formulaically of promoting ‘Australia-wide action to harmonise and complement efforts in prevention’ and of supporting treatment. It’s also keen that Australia should follow the American Medical Association’s 2013 decision to class obesity as a disease, the idea being that this will help ‘reduce the stigma associated with obesity i.e. that it is not purely a lifestyle choice as a result of eating habits or levels of physical activity.’ Unfortunately this very p.c. stance ignores that fact that obesity is very largely the result of eating habits coupled to levels of physical activity. The best way to lose weight is to eat less, eat more wisely and exercise more.

In 2008 Australian government sources forked out $932.7 million over 9 years for preventative health initiatives, including obesity. This latest report represents another effort in this drive. Everyone should read it but, clear and well written though it is, it looks like a government report, runs to 34 pages and almost no one will give it the time of day.

The problem is that in Australia, as in the UK and the USA, all the well-intentioned propaganda simply isn’t working. As with tobacco, car seat belts and alcohol driving limits, the only solution is legislation, vastly unpopular though that always is – until most folk see sense. Start with the two most obvious targets: ban the sale of foods with excessive sugar levels (especially soft drinks) and make everyone have a BMI measurement at regular intervals, say biannually. Then fine anyone over 25 in successive tests who isn’t receiving some sort of medical treatment.

Amuse bouche

I know: I’ll never get in on that manifesto. But two cheers for ‘No Time To Weight’ and I trust the luminaries who complied it appreciate my puny helping hand from Cambridge. In the meantime, not anticipating any progress on a national front, I’m going to start my own campaign – it’s going to be a bit labour-intensive, one target at a time, but here goes!

The other evening I had dinner in a splendid Italian restaurant (The Yak in Melbourne: very good!). And delightful it would have been had I not shared with two local girls at the next table. One was your archetypal tall, slender, blonde, 25-ish Aussie female – the sort you almost feel could do with a square meal. Her companion of similar age was one of the dirigible models. (You’ll understand I wasn’t looking at them at all: I was with my life’s companion so no chance of that – but I do have very good peripheral vision. Comes from playing a lot of rugby). Each had one of the splendid pasta dishes on offer – but, bizarrely, they also ordered a very large bowl of chips. No prizes for guessing who ate all the fries. Miss Slim didn’t have one – not a single one! (OK, by now I was counting). Her outsize friend had the lot. How could she do that with a shining example of gastronomic sanity sitting opposite?

So c’mon Miss Aussie Airship: you know who you are. Let’s have no more of it. Obesity is not a personal ‘issue.’ Regardless of your calorie intake in one meal, your disgraceful behavior ruined a delightful dining experience for me, and quite possibly several other folk within eyeshot, upset the charming waitress and insulted The Yak’s excellent chef. Just think in future: there’s a place in life for chips – but it’s not with everything.

Reference

“Obesity: A National Epidemic and its Impact on Australia”

Twenty winks

Not now obviously but after you’ve read the first episode of this absorbing tale you may feel a nap is in order, despite the fact that in Wake up at the back we noted that snoring can give you cancer.

Setting aside that hazard, the general finding is that most people require seven or eight hours of sleep to function optimally. Fall short of that, to less than six hours even for one night, and we all know that the consequences may include a degree of grumpiness helped along by a tendency to clumsiness and generally heightened incompetence. If you happen to suffer from hypertension you could measure another result because your blood pressure will be even higher than usual for the rest of the day. However, these are all reversible states, so that real problems only come with more extended sleep deprivation and there is much evidence that this can profoundly affect memory, creativity and emotional stability, as well as leading to heart disease, diabetes and obesity. The molecular drive for the latter is that folk who are short of sleep have lower levels of the hormone leptin (which tells the brain you’ve had enough to eat) but higher levels of ghrelin (appetite stimulant). One week of only four hours nightly kip converts healthy young men to pre-diabetics in terms of their insulin and blood sugar levels.

The cancer link

To all of which must be added the dribble of reports over many years that disrupted sleep patterns, such as result from shift-work, may increase the risk of a variety of cancers (these include breast, prostate, bowel and endometrial cancers and also non-Hodgkin’s lymphoma). The effects are moderate (that is, the risk rise is small – typically up to 20%), making these findings suggestive rather than conclusive, although they are bolstered by a considerable number of studies on animals. So sleep, or rather lack of it, is yet another of these things that seems to affect cancer but for which really hard evidence is lacking. It’s not a9f5f190difficult to see why. You can’t put a number on ‘a good night’s sleep’ (though you can now get phone apps that record your every snort and contortion) nor do we understand the biological consequences of sleep disruption, and then there are the perpetual problems that everyone’s different and cancers take years to show themselves. However, you can put a figure on how you feel about sleep: our friends at the wonderful Karolinska Institute in Stockholm have come up with a Sleepiness Scale (1 = very alert, 9 = very sleepy, great effort to keep awake) – which could replace the traditional grunt when asked ‘How are you?’ ‘Oh, much as usual, about eight on the Karolinska Scale.’

Sleeping Off Breast Cancer

Trawling the literature it seems that the majority of cancer/sleep studies focus on the breast and a word about two of the most recent will suffice to paint the picture. In a large group of Japanese ladies over the age of 40 those who said they slept for less than six hours were markedly more likely to develop breast cancer than those who slept longer. Over nine hours a night (sleep that is) even appeared to give a degree of protection.

The main culprit for the breast cancer/sleep link is shift work, illustrated by the Danish military where women working night-shifts are more prone to breast cancer than those with normal sleep patterns and there is an upward trend in risk with years of night-shift work.

An association with ovarian cancer has also been reported although, somewhat perplexingly, that study didn’t show that the risk got bigger the longer night-shifts were worked. This rather confusing picture may reflect individual variation. As we all know, some folk are ‘larks’ – up at the crack of dawn – my lady wife is one – whereas others are ‘owls’ who perform better the later it is (no prize for guessing what kind of bird I am – bit of domestic incompatibility there!). It may be that ‘owls’ suffer less from night-shift perturbation and they may therefore be more likely to opt for that mode of work – and indeed the Danish study found that ‘larks’ on night-shifts were more likely to get breast cancer. As if that’s not enough, irregular shift patterns make it more difficult for women to conceive and working only nights increases the chances of miscarrying.

Similar results have been found for other cancers, notably of the bowel – 50% more likely to occur in those who sleep an average of less than six hours a night than those who zzzz for over seven. Put another way, the less than six hours risk is about the same as having a first degree relative with the disease or eating lots of red meat – and similar to that for breast cancer.

Mu Treadmill

th-2

th-1

Mice Sleep Too

It’s not a bad idea to keep in mind that we are very similar to mice – we’ve got more or less the same number of genes and exercising (on a treadmill for example) helps to keep at least some cancers at bay. Another similarity is that sleep deprivation upsets the works so that, for example, in models of colon cancer it reverses the beneficial effects of moderate exercise.

So insomnia is no laughing matter, however it comes about, and next time we’ll put two and two together by looking at the molecular story – after which you really may need forty winks.

 References

Kakizaki, M. et al. (2008).  Sleep duration and the risk of breast cancer: the Ohsaki Cohort Study. Br J Cancer  99, 1502–1505.

Hansen, J. and Lassen, C.F. (2012). Nested case-control study of night shift work and breast cancer risk among women in the Danish military. Occup Environ Med., 69, 551–556.

Bhatti, P. et al. (2012). Nightshift work and risk of ovarian cancer. Occup Environ Med., 0:1–7. doi:10.1136/oemed-2012-101146.

Thompson, C.L. et al. (2011). Short Duration of Sleep Increases Risk of Colorectal Adenoma. Cancer 117, 841–847.

Zielinski, M.R. et al. (2012). Influence of chronic moderate sleep restriction and exercise on inflammation and carcinogenesis in mice. Brain, Behavior, and Immunity 26, 672–679.

Spray Painting Cancer

I’m pretty certain that anyone reading this will be fully aware that one of the biggest problems in cancer is spotting the blighters. We have, of course, X-ray detection (as in mammography), CTs and MRI scans, all so familiar we need not bother to define them, and there’s also a variety of sampling methods for specific cancers (e.g., the Pap test for cervical cancer). But, useful though all these are, the plain fact of the matter is that none are ideal and in particular the pictures created by imaging methods are very limited in sensitivity. Put another way, they won’t pick something up until it is quite large – a centimeter in diameter – meaning that the abnormal growth is already quite advanced.

Cunning Chemistry

Needless to say, much inspiration and perspiration is being applied to this matter and what has been really exciting over the last ten years or so is the way very smart chemists are collaborating with clinicians to come up with new ways of looking at the problem. One of these clever tactics is being developed in the University of Tokyo using a different type of imaging ‘reporter’ that signals its presence by fluorescing. Fluorescence occurs when a molecule absorbs light and becomes ‘excited’ before relaxing back to its ‘ground state’ by giving off a photon. Fluorescent molecules (fluorophores) are much used in biology because the background signal is often very low so the high signal-to-noise ratio gives excellent sensitivity.

Spray Paint scheme

The cell-surface enzyme GGT converts the small molecule  gGlu-HMRG to a fluorescent form (HMRG) that is then taken up by the cell. GGT is only found on tumor cells so they light up and normal cells do not

Fortunately we don’t need to know how the chemists did it – merely to say that Yasuteru Urano and his colleagues came up with a small molecule (called gGlu-HMRG for short) that does not give off light until a small fragment is chopped off its end, whereupon it changes shape: this flips the switch that turns on fluorescence. The cutting step needs an enzyme that is found on the surface of various cancer cells but not in normal tissue (GGT for short).

Joining Forces

To show that there was real mileage in their idea they followed the time-honored blue-print of cancer research, showing first that it works on tumor cells grown in the lab (and, equally important, that it doesn’t highlight normal cells), before moving to mouse models of ovarian tumors. The later is where chemists meet clinicians because an endoscope is required (quite a small one) – a flexible tube for looking inside the body – devices now so sophisticated that they can incorporate a fluorescence camera.

In the final synthetic step the cunning chemists formulated a spray-on version of their probe molecule so that it can be dispensed during endoscopy or surgery – a bit like an underarm deodorant. Now it’s easy: find suspect tissue, give it a squirt of gGlu-HMRG, wait a few minutes and see if it lights up. The answer is, of course, that in their ovarian cancer model the spray-on graffiti lights up within 10 minutes of sticking to a tumor cell and can detect clumps of cells as small as 1 millimeter in diameter – a terrific advance in terms of sensitivity. The brief time taken for the signal to be visible after the probe has been applied means that within the same procedure it could be used to guide surgeons in removing small tumor masses.

The Tokyo system is not the only one under development. My colleague Andre Neves at the Cambridge Cancer Centre, another of these fiendishly clever chemists, is working on a parallel line using different fluorophores that can be topically applied to the lining of the intestine. The goal here is, of course, the early detection of colon tumors. Yet other approaches use molecules that accumulate preferentially in tumor cells and respond to light in the near-infrared region of the spectrum (800 nm to 2500 nm wavelength, compared to just under 500 nm for gGlu-HMRG), giving an even better signal-to-noise ratio.

This is, as Mr. Churchill might have pointed out, not even the beginning of the end of this story. But it is one more small and innovative step forward. Not all cancers even of the same type will be detectable by a given probe because they vary so much in the genes they express but the ingenuity of the chemists gives hope that a substantial panel of ever more sensitive reporters will emerge. It is also true that endoscopy is unlikely to gain widespread popularity as a routine screening method. However, these advances, moving us to detection at ever earlier stages may become very powerful as a follow-up test, combined with the capacity for simultaneous treatment, when tumor cells have been detected in more comfortable screens, for example as circulating cells in small blood samples, an immensely exciting prospect to which we will return in a later episode.

 References

Urano, Y., Masayo Sakabe, Nobuyuki Kosaka, Mikako Ogawa, Makoto Mitsunaga, Daisuke Asanuma, Mako Kamiya, Matthew R. Young, Tetsuo Nagano, Peter L. Choyke, and Kobayashi, H. (2011). Rapid Cancer Detection by Topically Spraying a γ-Glutamyltranspeptidase–Activated Fluorescent Probe. Science Translational Medicine 3, 110ra119.

http://www.ncbi.nlm.nih.gov/pubmed/22116934

Shi, C. (2012). Comment on “Rapid Cancer Detection by Topically Spraying a γ-Glutamyltranspeptidase–Activated Fluorescent Probe. Science Translational Medicine 4, 121le1.

http://stm.sciencemag.org/content/4/121/121le1.long

Powdering Your Nose and Other Parts

If you were asked ‘What is the worst thing about being a research scientist?’ you might well come up with ‘Feeling stupid every day’ – especially if you’d read Martin Schwartz’s wonderfully funny and incisive essay ‘The importance of stupidity in scientific research’ pointing out that research means battling with the unknown. Bad though that is, I can tell you, on the basis of collecting absolutely no data whatsoever, that 100% of scientists would answer ‘Literature’ – or to be slightly more expansive ‘Keeping up with published research.’ To give the rest of mankind a feel for their problem, suppose you work on a gene called MYC which is one of the most powerful cancer drivers: the Web of Knowledge database lists 3,839 hits for MYC as a topic and 468 with it in the title (which means you really ought to read those papers!). So far this year! That’s six months  worth!!

Dusting down the literature

Broadly speaking, scientific literature comes in two categories: a huge one that you might call worthy but dull and a tiny one to which you ought to say ‘Wow!’, that is, there’s some amazing revelation about the way life works, a brilliantly clever method or some stunning insight. But there are two other small classes of which we rarely speak. One is, of course, stuff that is poor (or worse still plagiarized) and should never have been published. The other is perfectly OK – indeed you might even say ‘good someone’s done it’ – it’s just that your heart sinks when you see the title because you know what’s in store.

talc-powder

My latest heart-sinker is a zippy little thing called Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls and it has that effect because the title tells all. They’ve tackled a question that’s been around for 30 years, namely whether applying talcum powder to the nether regions can cause cancer of the ovaries, by pulling together data from separate studies with mixed conclusions, so that a kind of average emerged from the haze as a modest increased risk.’

What’s my problem?

Being certain that such a title will be picked up by the press and reported in a misleading and over-hyped fashion. Step forward the MailOnline (Women who regularly use talcum powder to keep fresh raise their risk of ovarian cancer by almost a quarter SHOCK HORROR!!). OK, I added the last two words but they were there by implication. It has to be admitted that the scientists didn’t help by calculating Odds Ratios (the ratio of the odds of an event occurring in one group to the odds of it occurring in another group), with the inevitable result that they were interpreted as ratios of risks, which overestimates the effect. However, if journalists actually bothered to read the papers they latch on to, it might occur to them that a balanced picture might be conveyed by quoting what the scientists themselves said. In this case the odds ratio was 1.24 which they summarized as ‘Genital powder use was associated with a modest increased risk of epithelial ovarian cancer.’ It would also help the non-scientist reader to put things into context by, in this case, noting that for ovarian cancer the average lifetime risk is about 1.4%. Thus even if you did have an increase of one quarter, the risk is still less than 1.8%.

The ordinary reader might also appreciate a comment on some of the problems faced by such studies. Not the least of these is that they are retrospective (i.e. they asked folk to recall what they used, when and how). It’s not difficult to be skeptical about the precision of the responses, especially when you’re tiptoeing around in what might be called delicate areas, and that’s before you mention the different wording in each study of questions that were pretty convoluted anyway. It’s also worth noting that the analysis showed no increase in risk with prolonged use, which is a little odd (recall that for smoking the more you do it the higher your chances of lung cancer).

Anything else worth adding?

Talcum powder, for this is what we’re talking about, is made from talc which is mostly magnesium, silicon and oxygen and the powder is, of course, widely used because it absorbs moisture and reduces friction, helping to keep skin dry and rash-free. Asbestos, another silicate, occurs together with talc in nature, and it causes the form of lung cancer called mesothelioma. Before 1976, talcum powder was commonly contaminated with asbestos but since the 1970s talcum products have been asbestos-free. There is evidence both in humans and rodents that talc particles can travel up through the genital tract and alight on the surface of the ovaries. Such particles can cause inflammation, one way in which cancer development can be set off, but there is no evidence that talc does promote ovarian cancer in this way.

Ideally in looking for cause and effect, scientists like to get a handle on mechanism. Somewhat surprisingly, for an effect that is modest at most, there is the glimmering of a lead. It comes in the form of a family of enzymes that can detoxify carcinogens (they’re glutathione S-transferases) but the genes encoding two of them, GSTM1 and GSTT1, are missing in about 50% and 20% of Caucasians respectively – so, of course, their activity is lost. There is one study showing that women with GSTM1-present and GSTT1-missing have a stronger association between talc use and ovarian cancer risk. The number of cases is small and it is possible that the effect is not real. It’s also not at all clear how the actions of this combo might interact with the effects of talc. Nevertheless, it is striking that it’s the only pairing of these two genes that shows an association.

What’s a girl to do?

1. Don’t read anything by a journalist that talks about Odds Ratios because the odds are they won’t have a clue what they’re on about.

2. Do read Thou Shalt Not Report Odds Ratios’, Mark Liberman’s witty but brutal evisceration of two ‘science editors’, Mark Henderson of the London Times and Steve Connor of the Independent newspaper.

3. Note that the authors of this study say that genital powder exposure is associated with a ‘small-to-moderate increased risk.’ – nothing stronger than that.

4. Remember that there’s no evidence that talcum powder applied anywhere other than the genital area can cause any problems and that includes the lungs. Even rats forced to inhale talc for 6 hours a day, five days a week for over two years were reluctant to get lung cancer although the incidence did increase in females (maybe they were just trying to escape the Dickensian smog ‘Strewth guvnor, I ’ardly get to see the nippers these days: may as well end it all by getting lung cancer’).

5. Bear in mind that the International Agency for Research on Cancer (IARC) classifies talc-based body powder as a class 2b carcinogen “possibly carcinogenic to human beings.”

6. Be aware that the major factors increasing the risk of ovarian cancer are (1) increasing age, (2) family history of breast or ovarian cancer, (3) being overweight and (4) hormone replacement therapy, whilst having children and breastfeeding them as well as taking the pill reduce the risk.

7. Finally, if the possibility of a slight increase in a small risk really spooks you, avoid orifice powdering and let nature take care of things. Or, if you’re really desperate for friction-free movement, use cornstarch powder: it’s a carbohydrate and there’s absolutely no evidence that it is a risk factor for ovarian cancer.

References

Terry, K.L., Karageorgi, S., Shvetsov, Y.B. et al. (2013). Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls. Cancer Prevention Research Published OnlineFirst June 12, 2013.

http://www.dailymail.co.uk/health/article-2343974/Women-regularly-use-talcum-powder-increase-risk-ovarian-cancer-24.html

Gates, M.A., Tworoger, S.S., Terry, K.L. et al. (2008). Talc use, variants of the GSTM1, GSTT1, and NAT2 genes, and risk of epithelial ovarian cancer. Cancer Epidemiology Biomarkers & Prevention 17, 2436-2444.

http://itre.cis.upenn.edu/~myl/languagelog/archives/004767.html

Signs of Resistance

In Beware of Greeks … we noted that in one sort of leukemia at least, tumour cells have come up with an extraordinary way of escaping from the bone marrow where they start life into the circulation where they cause trouble – by releasing pieces of their own DNA that then break down the retaining barrier.

Keeping track of tumors

Curious behaviour though it may be, there’s nothing new about the idea of cells shedding bits of their genetic code – that was first shown to happen over 60 years ago. What is novel is the evidence that not only does this happen in a variety of cancer cells but that modern methods enable those fragments to be isolated from just a teaspoonful of blood: the sequence of the DNA can then be determined – which gives the mutational signature of the original tumour. A remarkable development has now shown that repeating these steps over a period of time can reveal the response of secondary tumours (metastases) to drug treatment (chemotherapy).

Untitled

One great advantage of this blood sampling method is that it is as near as makes no difference ‘non-invasive’. That is, it uses only a (small) blood sample and there’s no need for painful excavations to dig out tumour samples. The study, largely funded by Cancer Research UK, looked at three major cancers (breast, ovarian and lung) and identified specific mutations caused by drugs over a period of one to two years. For good measure they also took tumour samples to show that the mutation patterns found in circulating DNA did indeed represent what had gone on in the tumour itself. In other words, they had established what scientists like to call ‘proof of principle’ – i.e. we can do it!

There’s another more subtle advantage of this approach in that it gets round a problem we described in Molecular Mosaics: tumours are a mixture and the mutational signature differs depending on which bit you sample and sequence. The cell-free DNA fragments collected from blood are a gemisch – an averaged signature if you like – that may therefore give a better picture of the target for drug cocktails at any given time during tumour evolution.

Why is this so important?

There are two main reasons why it’s difficult to exaggerate the potential important of this step. The first is that metastasis accounts for over 90% of cancer deaths, the second that the fiendish ingenuity with which tumours negate chemotherapy, i.e. develop drug resistance, is one of the biggest challenges to successful treatment. So, the sooner changes that enable tumours to become insensitive to drugs can be detected the better in terms of adjusting the treatment regime. Even more exciting, however, is that notion that the DNA shed by cancers into the circulation may permit detection years or even decades earlier than is possible with any of the current methods (e.g., mammography) – with screening being carried put routinely from blood samples. Being even more optimistic, very early stage tumours may be particularly susceptible to appropriate drug combos, so that we might look forward to the day when chemotherapy replaces surgery as the first line of treatment for most cancers.

Reference

Murtaza, M. et al., (2013). Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112.