DNA sequence

Flickr/shaury

If you’ve read the news recently, you may have stumbled acrossan ongoing debateabout whether cancer is caused by ‘bad luck’, or by the choices we make during our lives.

The reality, of course, is that两者都是。但是简单的问题“什么原因导致癌症？”的答案取决于您问的人。

Researchers from a branch of science called流行病学, who study disease trends across whole populations, would point to things likesmokingorobesity- 因为他们的研究表明，有些癌症在吸烟或肥胖的人中更为普遍。

And we now know that asmany as four in ten cancersare linked to what epidemiologists collectively call ‘exposures’ – either well-known things likechemical carcinogensin tobacco smoke, or more complex processes like ‘a poor diet’, which is much less well understood.

But if you ask the laboratory-based biologists, who study cells’ inner mysteries, they’d probably talk about things likeDNA，基因和突变。From this point of view, cancer is caused when the genetic programming in our cells gets corrupted.

显然，这两个答案都是正确的。多亏了数十年的研究，我们对细胞内部的机械在灾难性上如何误解了，我们对环境中的事物（所谓的致癌物）可以更有可能使它更有可能使其更有可能。

But there are some crucial missing pieces in this jigsaw puzzle.

On the one hand, we simply don’t know exactlyhowsome of these things cause cancer – particularly ‘lifestyle’ factors like obesity or excess alcohol consumption (although we do havedecent theories对于其中一些）。

在另一，large studies查看无数的患者的肿瘤DNA已经开始发现数十种模式 - 随着癌症的发展，我们的基因组留下的疤痕。除了一些值得注意的例外，其中大多数都是未知的起源。

So the third of our Grand Challenges is to try to make significant headway in uncovering vital new links between the processes in our cells and the way our environment affects them – both to better understand how cancers arise and, crucially, to prevent them in the first place.

‘Reverse epidemiology’

作为哈佛医学院的教授埃德·哈洛（Ed Harlow） - 我们的成员大挑战咨询小组– tells us: “Epidemiology typically starts by looking for patterns in the distribution of tumours – where they occur in the population – and then uses those patterns to do detective work to figure out what might be the cause.”

This conventional approach has resulted in some “spectacular” findings, he says, identifying many of the important causes of cancer, such as smoking or UV radiation.

“But over the last few decades – and particularly the last couple of years – we’ve seen the appearance of another type of approach, that focuses first on the characteristics of tumors themselves, and uses those as a clue to search for what the cause might be.”

“So the idea that you might be able to find new carcinogens by this method caught the Grand Challenge panel’s attention. We thought, ‘oh yeah, we’ve got to do that’.”

And Harlow thinks the approach has the potential to transform how cancer development is understood.

我们想，‘哦，是的，我们必须这样做”。
Professor Ed Harlow

他回忆说，要展示它的功能the story of aristolochic acid，在某些植物中发现了一种强大的致癌化学物质，包括在某些传统中药中使用的化学物质。

2012年，研究罕见形式的膀胱癌的研究人员找到了可疑的模式of mutations in tumors from those who’d taken these medicines – effectively a fingerprint of the damage the chemical in them had wreaked inside the patient’s cells.

但是研究人员随后找到the exact same fingerprint in the DNA of some patients’肝癌症s too – a form of the disease not previously linked to aristolochic acid exposure, and giving renewed urgency to efforts to enforce bans of medicines containing it.

So identifying these patterns can lead to clear ways to prevent cancer. Can we find more?

工作正在进行中

惠康信托基金会（Wellcome Trust）位于英国剑桥市的桑格学院（Sanger Institute）的实验室之一。随着世界各地的研究人员开始发表癌症DNA数据的流程，Sanger领导的团队Dr Serena Nik-Zainal一直在梳理它们的基本模式。

他们从2012年开始看乳腺癌她说：“已知的癌症类型没有明确的环境协会。”“我们想看看我们是否可以从大量样本中获得广阔的突变信息。”

“We were heartened by unearthing 5 signatures in this single cancer type alone.”

This led to深度学习, in more types of cancer. “We’ve now identified 30 signatures in around 40 different cancer types. Some are associated with environmental exposures like UV radiation or aristolochic acid. Others are associated with problems inside cells, like defective DNA repair pathways, or the action of certain enzymes.”

But the vast majority, she says, are of completely unknown origin.

Professor Laurence Pearl，从苏塞克斯大学的基因组损害和稳定中心，以及英国癌症研究leading expertsin understanding how cells repair damaged DNA, has been keenly following the Sanger team’s progress.

“You look at some of the patterns Serena’s team have discovered and think, oh, that’s clearly caused by faults in one or other of the processes we’ve known about for some time,” he says.

“但是对于其他人来说，我们都在挠头，试图思考失败或失败的序列可能导致他们。了解正在发生的事情使我们迄今为止。”

A broad coalition

As well as the obvious strategy of playing ‘match the pattern to the carcinogen’, the Grand Challenge panel is hoping to see these sorts of efforts scaled up considerably, and broadened in scope – Harlow says he’s keen to look beyond mistakes in the sequence of ‘letters’ in the cancer’s DNA, for even wider patterns in how entire chromosomes or even cell types are organised.

“There’s a general call in this Challenge to say ‘look for new patterns,’ patterns that are inherited from tumor cell to tumor cell,” says Harlow. “If they are unique, or different – or even just found much more commonly in certain types of tumors – then that must mean that there’s some reason. Let’s go back and see what it is.”

因此，仅仅寻找致癌化学物质的作用是“清晰，相对容易理解的第一步”，哈洛认为这也可能导致目前我们根本不了解的事情。

他说,这将需要从whol专长e range of different scientific traditions.

“Starting at the beginning, if you identify a carcinogen [by analysing DNA patterns] you’d want to know the steps between exposure and actual changes in the DNA.

“So you’d need biochemists, cell biologists and systems biologists to be part of that discovery process, to try and learn what that pathway is. Then, if you’re thinking about mechanisms of prevention, you might bring in whole other types of scientific expertise too.”

And ‘traditional’ epidemiology has a vital role to play too: “Having people who think about the actual incidence of disease might be an interesting group to add to mix too, to point out places where it would be more interesting to look,” he says.

Pearl and Nik-Zainal agree. “You need a team with the capability to track how these changes emerge in tumours over time,” says Pearl. “It needs a really broad set of skills – not just geneticists, although you need them too. It’ll be a fascinating challenge. It’s very, very difficult, but certainly not impossible.”

Nik-Zainal说，跨学科专家的这种结合“将允许系统的大规模研究，可以进一步推动对签名的理解。”

但是，与此相处也有一个地理角度。世界不同地区are affected by different types of cancer- 这可能是由于生活方式，环境和遗传学的差异所致。因此，Harlow渴望强调挑战也需要国际投入。

“整体构建数据库的癌症DNAsequences, the greater chance you have to find patterns of interest. So more groups, and more information, gives you a much broader starting point, but it also changes the kinds of exposure and the kinds of cancer-causing events that might be picked up,” he says.

病人的观点

– Peter, Grand Challenge patient panel member

Prevention is better

The ultimate aim of the Challenge, says Harlow, is to try to find ways to prevent people from developing cancer – whether it’s by identifying rare, potent carcinogens, or a better, deeper understanding of how our lives affect our genomes.

“我们可以从中得到一些非常有价值的'已知'，但是在我看来，发现更强大但未知的东西的机会似乎使这是一个非常令人兴奋的机会。

“There are all sorts of things about how we live our lives that we don’t understand in great molecular detail yet. And I can imagine there could be something out there that we could find that would be eye-opening and completely astonishing to all of us.

“而且我不知道这是否会发生 - 但这肯定应该是我们应该瞄准的事情。”

If you’re a researcher and want to build a team to take on this challenge,visit Cancer Research UK’s website to find out how you can apply。