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Accumulation of DNA mutations found in healthy liver leads to disease
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Accumulation of DNA mutations found in healthy liver leads to disease

Accumulation of DNA mutations found in healthy liver leads to disease

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 detail how the accumulation of  mutations over time evolves during the development of chronic liver disease and liver cancer. These 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  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.
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.”

(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)

(23 October 2019)

Accumulation of DNA mutations found in healthy liver leads to disease

Accumulation of DNA mutations found in healthy liver leads to disease

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 detail how the accumulation of  mutations over time evolves during the development of chronic liver disease and liver cancer. These 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  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.
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.”

(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)

(23 October 2019)

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Accumulation of DNA mutations found in healthy liver leads to disease

Image by mcmurryjulie from Pixabay300 million people living with a rare disease worldwide

An open-access article, written by Orphanet (coordinated by INSERM, the French National Institute of Health and Medical Research), EURORDISRare Diseases Europe and Orphanet Ireland (based at the National Rare Diseases Office, Mater Misericordiae University Hospital, Dublin, Ireland), confirms  the number of people living with a rare disease is estimated at 300 million worldwide. According to this paper published in the European Journal of Human Genetics, rare diseases currently affect at any point in time 3.5% – 5.9% of the worldwide population, equivalent to a conservative estimate of 300 million people worldwide (4% of the an estimated world population of 7.5 billion), the number used until now by EURORDIS and Rare Diseases International. The analysis shows that there are over 6,000 clinically defined rare diseases, 72% are genetic, and of those 70% of rare diseases start in childhood.

This is the first time that a robust analysis of the global prevalence of rare diseases has been conducted using the publicly available epidemiological data in the Orphanet (www.orpha.net) database. The figures presented in the paper are derived from data from 67.6% of the prevalent rare  diseases. As this analysis does not take into account rare cancers, nor rare diseases caused by rare  bacterial or viral infectious diseases and poisonings, the number of people affected by rare diseases is likely considerably higher. Ana Rath, co-author of the paper, Director of Orphanet, stated, “Even if these are the best figures we can obtain today, they likely underestimate the number of rare disease patients still not visible in healthcare and social care systems. Having a specific codification system for them in national systems will help obtain definitive figures and, more importantly, produce data needed to adapt healthcare systems”.
Yann Le Cam, co-author of the paper, Chief Executive Officer of EURORDIS and member of the Council of Rare Diseases International, commented, “Collectively rare diseases are not rare. The findings published in this paper support years of efforts from the rare disease community to advocate for the prioritisation of rare diseases as a public health priority that affects millions of people around the world, not just the few. No one can deny the significance of the global rare disease population  anymore, a critical mass of people who have been the health orphans so far, with acute needs for better healthcare, access to innovative treatments and a social system that supports their right to reach their highest potential of well-being”.

Findings presented in the paper, based on the analysis of the 67.6% of the prevalent diseases, include
that:
• 149 rare diseases analysed affect around 80% of the rare disease population. These diseases are the most prevalent among the diseases, with each affecting 100 – 500 people per 1 million.
• The next most prevalent 241 rare diseases analysed affect 10 – 100 people per 1 million  people.
• Collectively, these nearly 400 diseases affect at least 98% of the rare disease population with a prevalence of 10 – 500 people per 1 million people. They can be grouped by therapeutic areas and care services built around these therapeutic areas.
• The remaining diseases analysed are the less prevalent diseases as they affect less than 10 people per 1 million people.

Building on these important data, the analysis will be developed in the future to cover rare diseases caused by infectious agents, environmental factors, bacteria or viruses, poisoning and rare cancers; and to deepen the research for around 24 rare disease groupings (mirroring the grouping adopted for
the European Reference Networks), all with the aim to ultimately help inform health and social care planning for people living with a rare disease and their families and to streamline research on rare diseases. Future registry research and the implementation of rare disease codification in healthcare systems will further refine the estimates.

(Nguengang Wakap S, Lambert D M, Olry A, Rodwell C, Gueydan C, Lanneau V, Murphy D, Le Cam Y, Rath A. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. European Journal of Human Genetics, 2019

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