健康肝脏中发现的DNA突变积累会导致疾病

StephenW

         Accumulation of DNA mutations found in healthy liver leads to disease  
            

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            24-10-2019
  
            
  
            New insights into the journey from health to disease in the human liver have been made by scientists at the Wellcome Sanger Institute, Cancer Research UK Cambridge Institute, the University of Cambridge and their collaborators. In the largest study of its kind, the team documented in unprecedented detail how the accumulation of changes in our DNA over time, known as mutations, evolves during the development of chronic liver disease and liver cancer.

  
            Researchers discovered that these signatures of DNA mutations are also present in healthy and diseased liver, and that it is the accumulation of changes from these signatures that ultimately leads to serious health problems.
The study, published this week in Nature, is the largest study of the differences in genetic changes between healthy and diseased liver tissue, with a view to better understanding how liver disease and hepatocellular carcinoma (HCC) develop. These discoveries advance the possibility of one day using genomic data to predict the future risk of cancer in people suffering from chronic liver disease.
Chronic liver disease, which refers to conditions including cirrhosis, fatty liver disease and cancer, has risen by 400 per cent in the UK since 1970 to become the biggest cause of death among 35-49 year olds. The commonest causes in the UK are excessive alcohol intake and obesity. In 2016/17, almost 15,000 deaths were caused by liver disease in the UK*.
There has been a 162 per cent increase in cases of liver cancer in the UK since the 1990s, with around 5,900 new cases every year, and by 2035 the number of cases is predicted to rise by 38 per cent (from 2014 levels)**. The most common type of primary liver cancer is called hepatocellular carcinoma (HCC)***. HCC is rare in people with a normal liver, but commonly develops in people with chronic liver disease.
DNA mutations**** play a prominent role in many forms of cancer and can be caused by a large number of factors, including genetic factors and things we are exposed to during life such as chemicals found in food or the environment. Liver cancer arises from the effects of particular types of DNA damage, which cause specific signatures of mutations.
The common genetic events and patterns of DNA mutation associated with liver cancers were previously known, but it was unknown in what order these events occur, or why some people with chronic liver disease develop cancer but others develop failure of the liver to perform its normal function.
The new study is the most comprehensive use of genomic analysis to compare normal liver tissue with tissue affected by chronic liver disease, providing researchers with an unprecedented level of detail on how the accumulation of DNA mutations over time leads to liver disease and cancer.
Tissue samples from five normal and nine cirrhotic livers were collected by Addenbrooke’s hospital in Cambridge*****. From these samples, scientists at the Wellcome Sanger Institute created 482 whole genome sequences so the DNA of the tissues could be analysed.
The team observed a substantial increase in the number of mutations in chronic liver disease compared to normal liver. Cirrhotic liver tissue contained around twice the number of mutations as healthy liver and HCC tumour tissue had an even higher numbers of mutations. The variety in the type of mutations in diseased and cancerous tissue was also much greater than healthy liver, with mutations causing more damage to the overall integrity of the DNA.
Only a few mutations associated with HCC were discovered in the chronically diseased liver, suggesting that the increased risk of liver cancer arises because the substantial DNA damage seen in liver disease promotes the emergence of cells with the potential to eventually become cancers.
The study also highlighted the way our environment can influence the patterns of DNA damage in the liver. For example, 10-20 per cent of DNA mutations in samples from one patient indicated exposure to a toxin produced by Aspergillus moulds. These moulds often contaminate crops and are prevalent in arable farmers, which was the occupation of the patient.
The researchers say that many things can cause DNA mutations associated with cancer, particularly in the liver because it processes many of the chemicals that we are exposed to in our diet and the environment. As such, the richest diversity of DNA mutations are found in liver cancer.
Dr Matthew Hoare, a lead author of the study from the Cancer Research UK Cambridge Institute, said: “It’s incredibly compelling to be able to show how liver disease affects the DNA in our livers. We knew there was a link between chronic liver disease and liver cancer, so it was unexpected to find so few cancer-causing mutations among the DNA damage in liver disease. The next step will be to look for common patterns within this damage that might help us predict who is at a higher risk of cancer”.
People with chronic liver disease have a higher risk of HCC, but it is not clear why this cancer occurs in some of these people and not in others. For now the exact cause of HCC remains unknown, but understanding that the processes involved in chronic liver disease are the same as those involved in HCC opens up the possibility of one day being able to predict an individual’s risk of liver cancer.
Dr Peter Campbell, a lead author of the study and Senior Group Leader at the Wellcome Sanger Institute, said: “What’s interesting about the findings of this study is that we have been able to observe how excessive alcohol intake and obesity are linked to DNA mutations in chronic liver disease as well as liver cancer. Though it is early days, we can start thinking about ways to predict a person’s risk of liver cancer from the number and types of mutations in their DNA.”
Image: Cirrhosis_ Nephron, Wikimedia Commons
*The British Liver Trust has information on liver disease and the rise in incidence https://britishlivertrust.org.uk/about-us/media-centre/statistics/
**For statistics on liver cancer in the UK, see the Cancer Research UK website https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/liver-cancer
***HCC is more common in people with cirrhosis, a form of chronic liver disease where scarring forms as a result of damage to the liver. This can be caused by excess alcohol consumption, hepatitis B or hepatitis C. Cancer Research UK has more information on HCC and other liver cancers https://www.cancerresearchuk.org/about-cancer/liver-cancer/types
****DNA mutations are changes to a single letter of a person’s genetic code and occur naturally as we go through life. Many mutations do not significantly alter how our body functions or are repaired by our bodies before they can interfere with our health. But when a large number of mutations occur, it increases the chances of something going wrong. The Genetics Home Reference website has a library of information on genetics and health https://ghr.nlm.nih.gov/primer#mutationsanddisorders
******Patients recruited at Addenbrooke’s Hospital, Cambridge gave written informed consent with approval of the Local Research Ethics Committee (16/NI/0196). All tissue samples were snap-frozen in liquid nitrogen and stored at -80°C in the Human Research Tissue Bank of the Cambridge University Hospitals NHS Foundation Trust.
Publication:
Simon F Brunner, Nicola D Roberts and Luke A Wylie et al. (2019). Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature. DOI: 10.1038/s41586-019-1670-9
Funding:
This work was supported by Wellcome and a Cancer Research UK Grand Challenge Award. The Cambridge Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre.

  

StephenW

健康肝脏中发现的DNA突变积累会导致疾病
24-10-2019
肝硬化_ Nephron，维基共享资源

Wellcome Sanger研究所，英国癌症研究剑桥研究所，剑桥大学及其合作伙伴的科学家们对人肝从健康到疾病的旅程有了新的见解。在同类研究中规模最大的一项研究中，研究小组在《未表达的细节》中详细记录了DNA随时间的变化积累（称为突变）在慢性肝病和肝癌的发展过程中如何演变。

研究人员发现，DNA突变的这些特征也存在于健康和患病的肝脏中，这些特征的变化积累最终导致严重的健康问题。

这项研究于本周发表在《自然》杂志上，是对健康和患病肝脏组织之间遗传变化差异的最大研究，目的是更好地了解肝脏疾病和肝细胞癌（HCC）的发展。使用基因组数据来预测患有慢性肝病的人将来患癌症的风险。

慢性肝病是指包括肝硬化，脂肪肝和癌症在内的疾病，自1970年以来，英国的慢性肝病已上升400％，成为35-49岁人群中最大的死亡原因。在英国，最常见的原因是过量饮酒和肥胖。在2016/17年度，英国有近15,000人死于肝病*。

自1990年代以来，英国的肝癌病例增加了162％，每年约有5900例新病例，到2035年，预计病例数将增加38％（与2014年相比）**最常见的原发性肝癌类型称为肝细胞癌（HCC）***。肝癌在肝正常的人中很少见，但在慢性肝病的人中通常会发展。

DNA突变****在许多形式的癌症中起着重要作用，并且可能由多种因素引起，包括遗传因素以及我们一生中所暴露的事物，例如食物或环境中发现的化学物质。肝癌是由特定类型的DNA损伤的作用引起的，DNA损伤会引起特定的突变特征。

先前已知与肝癌相关的常见遗传事件和DNA突变的模式，或者这些事件的发生顺序是未知的，或者为什么某些患有慢性肝病的人会发展为癌症，而另一些人会导致肝脏无法正常发挥其功能。

这项新研究是基因组分析最全面的应用，可以将正常肝组织与受慢性肝病影响的组织进行比较，从而为研究人员提供了有关DNA突变随时间累积如何导致肝病和癌症的更详细的信息。

位于剑桥的阿登布鲁克医院收集了来自五个正常肝和九个肝硬化肝的组织样本*****。从这些样品中，惠康桑格研究所的科学家创建了482个全基因组序列，因此可以分析组织的DNA。

研究小组观察到，与正常肝脏相比，慢性肝脏疾病的突变数量大大增加。肝硬化肝组织的突变数约为健康肝和HCC肿瘤组织的突变数的两倍。患病和癌变组织中的突变也比健康肝脏大得多，突变对DNA的整体完整性造成更大的损害。

在慢性疾病的肝脏中仅发现了与HCC相关的少数突变，这表明发生肝癌的风险增加是因为在肝病中看到的大量DNA损伤促进了细胞的出现，并有可能最终成为癌症。

该研究还强调了我们的环境可以影响肝脏DNA损伤方式的方式。例如，一名患者的样本中10％至20％的DNA突变表明接触了曲霉霉菌产生的毒素。这些霉菌经常污染农作物，在可耕种农民中很普遍，这是患者的职业。

这些病原体说，很多事情都可能导致与癌症有关的DNA突变，特别是在肝脏中，因为它会处理我们饮食和环境中暴露的许多化学物质。这样，在肝癌中发现了最丰富的DNA突变。
英国剑桥癌症研究机构的这项研究的主要作者马修·霍尔说：“令人难以置信的是，能够证明肝脏疾病如何影响我们肝脏的DNA。我们知道慢性肝病和肝癌之间存在联系，因此出乎意料的是，在肝病的DNA损伤中发现如此少的致癌突变。下一步将是寻找这种损害中的常见模式，这可能有助于我们预测谁的癌症风险更高。”

患有慢性肝病的人罹患肝癌的风险更高，但尚不清楚为什么这种癌症发生在其中某些人中而不是其他人中。目前，尚不清楚HCC的确切病因，但了解到慢性肝病所涉及的过程与HCC所涉及的过程相同，便有可能在一天之内就能预测出个体患肝癌的风险。

这项研究的主要作者，惠康大学桑格研究所高级小组负责人彼得·坎贝尔博士说：“这项研究的发现有趣的是，我们已经能够观察到过量的酒精摄入和肥胖与DNA突变有何关系。在慢性肝病以及肝癌中。尽管还处于初期，但我们可以开始思考从DNA突变的数量和类型来预测一个人患肝癌的风险的方法。”

图片：肝硬化_ Nephron，维基共享资源

*英国肝脏基金会（British Liver Trust）提供了有关肝脏疾病和发病率上升的信息https://britishlivertrust.org.uk ... -centre/statistics/

**有关英国肝癌的统计信息，请参见英国癌症研究网站https://www.cancerresearchuk.org ... r-type/liver-cancer

***肝癌在肝硬化患者中更为常见，肝硬化是一种慢性肝病，由于肝脏受损而形成疤痕。这可能是由于过量饮酒，乙型肝炎或丙型肝炎引起的。英国癌症研究中心提供了有关肝癌和其他肝癌的更多信息https://www.cancerresearchuk.org/about-cancer/liver-cancer/types

**** DNA突变是对一个人的遗传密码的单个字母的更改，并且随着我们的一生而自然发生。许多突变不会显着改变我们的身体功能或被我们的身体修复，然后才可以干扰我们的健康。但是，当发生大量突变时，就会增加出现问题的机会。遗传学家庭参考网站上有一个关于遗传学和健康的信息库https://ghr.nlm.nih.gov/primer#mutationsanddisorders

******经当地研究伦理委员会（16 / NI / 0196）批准，在剑桥阿登布鲁克医院招募的患者签署了知情同意书。将所有组织样品在液氮中速冻，并在-80°C下储存在剑桥大学医院NHS基金会信托基金的人类研究组织银行中。

出版物：

Simon F Brunner，Nicola D Roberts和Luke A Wylie等。 （2019）。健康和肝硬化人类肝脏中的体细胞突变和克隆动力学。性质。 DOI：10.1038 / s41586-019-1670-9

资金：

这项工作得到了惠康和英国癌症研究大挑战奖的支持。剑桥人类研究组织库得到了NIHR剑桥生物医学研究中心的支持。