伦敦癌症研究所 追踪肿瘤从起源到扩散过程的时间线
First timeline of a cancer tracks tumours from origin to spread
上图：一个结直肠癌，追踪癌症的转移可以为我们提供治疗癌症的线索
癌症诊断时很少有明显的线索。但是一名男子的疾病导致了癌症进化的第一次精确追踪。知道病人体内某一特定肿瘤发生的确切时间，科学家们就可以为他的癌症从几个细胞进化到最终导致他死亡的肿瘤形成时间设定一个时间表。
这项研究为一些癌症的快速转移提供了线索，并可能在未来帮助医生评估肿瘤对治疗的反应。
这项分析是在2008年对一名被诊断出患有肠癌的男子进行的，该男子后来转移，扩散到身体的其他部位。伦敦癌症研究所的Nicola Valeri在手术切除原发性癌症后，在该男子的肺部发现了一个结节。他怀疑这也可能是癌症，但决定在做进一步的手术之前密切关注它。
2011年，人们用一根针取出了一个结节，并对其进行了分析，结果发现它是一个继发肿瘤，随后被切除。
但活检留下了后遗症:当医生取出针头时，留下了肿瘤细胞的痕迹——这是一种不幸但罕见的副作用。这些细胞随后变成了患者胸壁的另一个继发肿瘤。
直到两年后的2013年，这个肿瘤才被发现。它占据了针插入的精确位置，所以一定是在活检那天开始的。
这一罕见的转变为瓦莱里和他的同事们提供了一种秒表——一个精确的时间点，当一些细胞开始两年进化成转移性肿瘤时。
他们利用这个时间戳，以及对死者生前所有肿瘤(包括原发性肠肿瘤)的基因分析，研究出癌症在他的一生中是如何发展的。
他们知道这种罕见的胸壁肿瘤的确切出生时间，在两年后重新检查时，他们可以研究它已经产生了多少突变。这给了他们关于改变速度的信息，然后他们可以推断并使用这些信息来追踪疾病的进展，直到它的起源。
回到过去
分析显示原发性结肠癌在确诊前5到8年就已经出现。在它出现大约一年后，这种原发性癌症转移到肺和甲状腺。甲状腺肿瘤最终在2012年被发现。患者于2015年死于肾脏的新转移。
瓦莱里说，分析得出的最大惊喜是，癌症从肠道迅速扩散到肺和甲状腺，但这三种肿瘤都保持休眠多年，而不是继续扩散和生长。他说:“这表明，有时候，有一个大的时间窗口可以及早诊断并阻断扩散性转移。”“这意味着可能会有几年的时间我们可以进行干预。”
英国癌症研究中心的高级科学信息官Justine Alford说:“活检针引起的转移很罕见，但在这种情况下，这意味着科学家可以利用这种情况来为这个病人的肠癌发展制定个人路线图。”“通过这一独特的研究旅程，这项研究揭示了有关肠癌转移时间的全新而令人惊讶的见解，表明了这种疾病的复杂性，并强调了还有很多东西有待发现。”
奇怪的事件
这一分析揭示了癌症转如此迅速的重要线索，然后在变得具有攻击性之前，这些线索又持续了数年。虽然一个已知的促进癌细胞扩散的基因在早期发生了突变，但这似乎并没有影响后续转移的发展。这些肿瘤也未能进化出使癌症最具侵袭性的巨大基因改变，比如复制或整个染色体的损失。
“让我惊讶的是，转移发生的速度有多快，在那之后又有多缓慢，”坦佩市亚利桑那州立大学(Arizona State University)的Carlo Maley说。“我通常认为转移是一个失控过程的开始，它会杀死我们。”
Maley说:“像这样的研究和他们使用的工具将在未来的癌症治疗中起到关键作用。”他说，这样的工具将使我们能够判断肿瘤发展的速度，并以此预测其对治疗的反应。
参考文献:肿瘤学年报，DOI: 10.1093/annonc/mdx074
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DAILY NEWS 11 May 2017
First timeline of a cancer tracks tumours from origin to spread
A colorectal cancer
Tracking cancer’s spread could give us clues about how to treat it
Steve Gschmeissner/Science Photo Library
By Andy Coghlan
There’s rarely a silver lining to a cancer diagnosis. But one man’s illness has led to the first precise tracing of a cancer’s evolution. Knowing the exact time at which a particular tumour developed in the patient’s body allowed scientists to create a timeline for how his cancer evolved from a few cells, all the way through to the tumours that caused his eventual death.
The study provides clues about what makes some cancers spread rapidly, and may in the future help doctors estimate how a tumour might respond to therapies.
The analysis was carried out on a man diagnosed with bowel cancer in 2008, which later metastasised, spreading into other areas of his body. When the primary cancer was surgically removed, Nicola Valeri at the Institute of Cancer Research in London, discovered a nodule in the man’s lung. He suspected this might also be cancerous but decided to keep an eye on it before performing any further surgery.
In 2011, a piece of the nodule was extracted using a needle and analysed, revealing that it was a secondary tumour, which was subsequently removed.
But the biopsy left a legacy: as doctors withdrew the needle, it left behind a trail of cells from the tumour – an unfortunate but rare side effect of the procedure. These cells subsequently turned into another secondary tumour in the patient’s chest wall
This tumour was not discovered until two years later, in 2013. It occupied the precise track from where the needle had been inserted, and so must have originated on the day of the biopsy.
This rare turn of events provided Valeri and his colleagues with a kind of stopwatch – an exact point in time when a few cells began their two year evolution into a metastatic tumour.
They used this timestamp, alongside a genetic analysis of all the tumours the man developed before dying – including the primary bowel tumour – to work out how the cancer had progressed over his lifetime.
Knowing the exact time when the rare chest wall tumour was born, they could study how many mutations it had developed by the time they re-examined it two years down the line. This gave them information about the rate of change, which they could then extrapolate and use to follow the progression of the disease back in time to its origins.
Back in time
The analysis showed that the primary colon cancer had actually emerged five to eight years before it was diagnosed. Around a year after it emerged, this primary cancer metastasised and travelled to the lung and the thyroid. The thyroid tumour was eventually discovered in 2012. The patient died in 2015 from new metastasis in his kidneys.
Valeri says that the biggest surprise from the analysis was that the cancer had spread so quickly from the bowel to the lung and thyroid, yet all three of these tumours remained dormant for many years, instead of continuing to spread and grow. “It suggests that sometimes, there’s a large time window to make diagnosis early and disrupt metastatic spread,” he says. “It means there might be periods of years where we could intervene.”
“Metastases caused by biopsy needles are rare, but in this case it meant the scientists could use the situation to develop a personal roadmap of this patient’s bowel cancer development,” says Justine Alford, senior science information officer at Cancer Research UK. “Through this unique research journey, the study reveals new and surprising insights into the timings of bowel cancer spread, demonstrating the disease’s complexity and highlighting how much more there is to discover.”
Strange turn of events
The analysis revealed important clues about why the cancer spread so fast, then settled for years before becoming aggressive. Although a mutation in a gene known to promote the spread of cancerous cells occurred early on, this did not appear to effect the development of the subsequent metastases. These tumours also failed to evolve the large genetic alterations that make cancers most aggressive – such as duplications or losses of entire chromosomes.
“The surprise for me was how fast metastasis happened, and then how indolent it was after that point,” says Carlo Maley of Arizona State University, in Tempe, who specialises in cancer evolution and who contributed to the analysis. “I usually think of metastasis as the start of a runaway process that kills us.”
“Studies like these and the tools they use will be critical in the future management of cancer,” says Maley. He says such tools will allow us to judge how fast a tumour is evolving and use that to predict its response to therapies.
Journal reference: Annals of Oncology, DOI: 10.1093/annonc/mdx074
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