Cancer’s biggest riddle

fingerprints, and some had at least six. That number had risen to around 50 by 2018. A portion of them come from things we already know can increase the risk of cancer, such as tobacco.

Other signatures implicated agents we had previously suspected to cause cancer, but some fingerprints signalled that cancer had been an inside job, a consequence of fundamental processes of life inside our cells.

But the causes of around half these fingerprints remain a mystery, left in the genomes of cancer cells by culprits that are still at large.

The endoscopy suite in Moi Teaching and Referral Hospital in Eldoret, western Kenya, is busy. Oesophageal cancer is one of the most common tumours here, and every day a stream of patients arrive in search of relief from the bulging blockages in their gullets. Most have not eaten properly for weeks, making them incredibly thin and frail.

All of them are desperate for help, and most are going to die within the next year.

I watch as little pink globs of cancer tissue are carefully popped into plastic pots and sent off to a freezer, waiting to be shipped to the IARC, then on to the Sanger Institute to be sequenced and analysed for any telltale signatures that might explain what is causing all these cancers.

Diana Menya is a Kenyan epidemiologist at the hospital.

“Some years ago, I noticed that there were quite a number of patients presenting with difficulty swallowing, and when the diagnosis was finally done it was squamous cell oesophageal cancer,” Menya explains. “We were seeing more and more patients.”

Her solution was to set up ESCCAPE (Oesophageal Squamous Cell Carcinoma African Prevention Research), a study that compares the environment and lifestyle of people who have oesophageal cancer to those who don’t.

Menya’s study has already found that tobacco and alcohol are two factors likely to be driving the surfeit of oesophageal cancers — not surprising, given that previous studies have linked them to squamous cell carcinoma.

But these two culprits can’t explain all the cases.

Heading into the rural community outside Iten feels like walking into a world of carcinogens.

For instance, the farmland may be lush and fertile, but it is also awash with pesticides and fertilisers that can leach into the water supply. Sprouting fields of collard greens are cooked into a dish known locally as sukuma wiki (lasts a week) that’s particularly high in nitrates, which the body may convert into carcinogenic nitrosamines when eaten.

We visit Emily in her kitchen; the unventilated room is coated with a thick layer of soot. The smoke from the fire is overpowering.

And where there’s smoke, there’s PAHs — polycyclic aromatic hydrocarbons, a carcinogen released when certain materials such as wood, maize cobs or cow dung burn.

Women, young girls and children are particularly exposed as they spend so much time in the kitchen, often sleeping there at night to keep warm and safe.

Maize is a common food and fuel source in this area and is often treated with fungicide to prevent the growth of toxic pink mould — which may itself cause cancer. Burning these chemicals along with the cobs could release further carcinogens into the unventilated atmosphere.

Although it’s easy to suspect all these things (and more) as being behind the high oesophageal cancer rates in Kenya, we don’t yet have enough data to link most of these risk factors with fingerprints left in the cancer genome. That means we don’t yet know which of them is the most dangerous, or how they might act together to cause disease.

Right now, we’re still in the opening pages of this detective story.

In June 2018, researchers from the Mutographs team shared preliminary data from the first handful of cancer genomes to make it through the project’s pipeline.

Intriguingly, the first few oesophageal tumours from Kenya don’t appear to show any traces of PAHs, potentially putting smoky rural kitchens like Emily’s in the clear, although it’s important to stress that only a small fraction of cases have been analysed so far.

Curiously, all the oesophageal cancers do have signs of damage caused by a family of DNA-altering proteins commonly referred to as APOBECs thought to be activated in response to viral infections.

There’s a lot of scientific hand-waving about the role that these might play in cancer but the discovery of their fingerprints at the biological scene of the crime is intriguing.

Although it’s too early to nail down any suspects for sure, it’s becoming clear from the cancer genomes that we’re not dealing with individual baddies but with a gang of miscreants, each of which administers a potentially fatal blow to the genome.

Each causes mayhem in its own way, but they can combine to bring about catastrophe.

And because every cancer genome is shot through with many thousands of mutations, it’s impossible to say which culprit delivered the coup de grâce. A cell may be riddled with mutations, accumulated from all sorts of processes over a lifetime, but if none of them hit the vital genes or control switches responsible for growth or death, then it will remain healthy.

But we should be able to build up a much better picture of the contributions of different factors — be they biological or environmental — to each individual person’s disease.

This research is coming too late to help Emily’s parents, lying in their hillside graves. But Diana Menya is hopeful that her work will save lives in the future.

“We have eradicated many conditions and especially infectious diseases, so can we not eradicate noncommunicable diseases like cancer?”