Why we are closer to cracking
Like criminals at the scene of a crime, the substances that cause cancer leave their fingerprints behind. Now, the world may be closer than ever to unravelling the clues hidden in our DNA
Halfway up a hill overlooking the Great Rift Valley in western Kenya are two graves. One of them is a few years old now, bristling with bushy shrubs stretching bright-green leaves towards a cloudless sky. The other is a freshly dug bed of rough red dirt planted with a white wooden cross. They are the final resting places of Emily’s mother and father, who died within four years of each other.
Still a young woman, Emily now looks after her family’s rural home near Iten — a town famed for churning out long-distance runners and playing host to award-winning British-Somali marathoner Mo Farah’s training camps. We reach it by driving through urban sprawl and out into the hills, passing a seemingly endless stream of impossibly fit athletes pounding the roadside paths.
Emily is busy cooking lunch when we arrive. Her kitchen is a small straw-capped hut built in the traditional style, similar to the other buildings that make up the homestead, with smoke pouring out of the door from an open fire and chickens scratching in the dirt nearby.
It seems idyllic, but there’s a killer on the loose around here: squamous cell oesophageal carcinoma — one of the two main forms of oesophageal cancer.
Cases started piling up more than 60 years ago in South Africa, when a doctor working in the then Transkei noticed an unusually high number of people dying from the disease, which was almost unheardof before the 1940s. Since then, scientists have speculated that it might have to do with diet, including the possible contamination of homegrown maize with the rock-bound compound silica from stone mortars. But this has not been proven, a 2017 research review published in the International Journal of Cancer stresses.
Worldwide, an average of 5.9 people per 100 000 will develop oesophageal cancer each year. In Kenya specifically it’s 18 in 100000, and in Malawi it’s even higher — 24 in 100 000 — making oesophageal cancer one of the three most common cancers in these countries, a 2017 study in the journal Nature found.
East Africa isn’t the only place in the world where this is happening. The Golestan region of Iran has one of the world’s highest rates of the cancer, and there are pockets of the disease in areas as diverse as Henan province in north-central China and southern Brazil, although it’s relatively rare in neighbouring Colombia, the World Health Organisation’s (WHO’s) Global Cancer Observatory reveals.
Other parts of the world have their own problems: there are strangely high rates of bowel cancer in Slovakia and Denmark, although they have low rates of liver cancer. People in the Czech Republic are more likely to be stricken by kidney or pancreatic cancer than the populations of neighbouring Austria and Poland.
We still don’t really know what’s causing these hot spots. Do these differences lie in inherited genetic variations, in lifestyle or is there an unknown carcinogen lurking in the environment? Maybe it’s a bit of all three?
The wild differences in rates of cancer across the world are a mystery — but a crack team of detectives is on the case.
Leading this team is Mike Stratton, director of the Wellcome Sanger Institute near Cambridge, in the United Kingdom. The centre is one of the world’s largest specialising in DNA sequencing and analysis. Together with the International Agency for Research on Cancer (IARC) in Lyon, France — the WHO’s cancer research arm — and others, Stratton has assembled an impressive detective force in cancer research: a project known as Mutographs of Cancer.
By peering deep inside the DNA of cancer cells, Stratton and his team are hunting for the unique signatures or genetic fingerprints that different cancer-causing agents and processes leave behind.
The team is recruiting 5 000 people across five continents with five different types of cancer. From them, they’ll extract and analyse DNA from thousands of tumours to build up a massive database of mutational signatures — a bit like Interpol’s international fingerprint collection — so they can try to match causes to cancers around the world.
To do this, they will have to create a picture of the genetic mutations that might be associated with cancer. The programme’s name “mutograph” — a combination of “mutation” and “photograph” — is inspired by that mission, the institute’s media officer Samantha Wynne explains.
And their findings have the potential to save thousands of lives.
At its heart, cancer is a disease of DNA. The human genome contains 20 000 or so genes — the biological instructions that tell our cells when to grow and multiply, what job to do, and even when to die — encoded within long strands of DNA known as chromosomes.
DNA itself is made from four chemical building blocks, or bases, strung together in endlessly varied combinations. It’s the order of these bases — adenine (A), thymine (T), guanine (G) and cytosine (C) — that conveys information within a gene, like a molecular alphabet spelling out the recipes of life. Any changes to the letters in an important gene might cause a cell to start multiplying out of control. Further alterations in other vital genes, along with a cellular environment that allows unchecked growth, will eventually lead to a tumour being formed.
But if you can detect the DNA mutations that give way to cancer and work out what caused them, then you should have the solution to their biological whodunnit.
But to do that, you need to be able to read DNA.
In the late 1970s, biochemist Fred Sanger developed a method for reading the sequence of letters in a stretch of DNA. But Sanger’s technique was time-consuming, only allowing scientists to read a few hundred bases at best so researchers focused on just one gene, p53, which is faulty in the majority of human cancers.
By 1991, scientists had shown that different cancers had their own unique suite of mutations in p53, which were likely to have different causes, a study published in the journal Nature found.
Stratton was intrigued.
“Seminal papers suggested that, yes, mutagens that cause cancer left their mark on the genome,” he recalls. “That had a big impression on me as an opportunity. But it’s one that had to be put away in the locker for 15 years waiting for the technology.”
That technology was next-generation sequencing: DNA-reading machines that enable scientists to move from surveying hundreds of bases at a time to thousands or even millions.
Straight away, Stratton saw the potential for the technology to revolutionise our understanding of the genetic changes inside tumours.
By 2009, he and his team had produced the first whole cancer genome sequences. These were detailed maps showing all the genetic changes that had occurred within two individual cancers — a melanoma from the skin and a lung tumour, work that was published a year later in Nature.
These choices of cancer types were far from random: decades of epidemiology and lab studies had shown that UV light exposure is likely to be the strongest sole cause of mela-