Somatic mutations and clonal dynamics in healthy and cirrhotic human liver
The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse...
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| Vydáno v: | Nature (London) Ročník 574; číslo 7779; s. 538 - 542 |
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| Hlavní autoři: | , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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London
Nature Publishing Group UK
01.10.2019
Nature Publishing Group |
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| ISSN: | 0028-0836, 1476-4687, 1476-4687 |
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| Abstract | The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes
1
–
7
. Stem cells from normal livers have a low mutational burden and limited diversity of signatures
8
, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100–500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1–5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others—arising from exogenous exposures—were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.
Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures. |
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| AbstractList | The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes.sup.1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures.sup.8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others--arising from exogenous exposures--were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes.sup.1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures.sup.8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others--arising from exogenous exposures--were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures. The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes. Stem cells from normal livers have a low mutational burden and limited diversity of signatures, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes . Stem cells from normal livers have a low mutational burden and limited diversity of signatures , which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. The commonest causes of chronic liver disease are excess alcohol intake, viral hepatitis or non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation through cirrhosis to liver failure or hepatocellular carcinoma. The hepatocellular carcinoma genome exhibits diverse mutational signatures, resulting in recurrent mutations across >20-30 cancer genes1–7. Stem cells from normal livers have low mutation burden and limited diversity of signatures8, suggesting that the complexity of hepatocellular carcinoma arises during progression to chronic liver disease and subsequent malignant transformation. We sequenced whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers. Compared to normal liver, cirrhotic liver had higher mutation burden. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, both point mutations and structural variants, affected 1-5% clones. Clonal expansions millimetres in diameter occurred in cirrhosis, sequestered by bands of fibrosis engirdling regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCC; some were substantially more active in HCC than chronic liver disease; and others, arising from exogenous exposures, were present in a subset of patients. Up to 10-fold within-patient variation in activity of exogenous signatures existed between adjacent cirrhotic nodules, arising from clone-specific and microenvironmental forces. Synchronous hepatocellular carcinomas exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes 1 – 7 . Stem cells from normal livers have a low mutational burden and limited diversity of signatures 8 , which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100–500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1–5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others—arising from exogenous exposures—were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures. |
| Audience | Academic |
| Author | Moore, Luiza Davies, Susan E. Sanders, Mathijs A. Brunner, Simon F. Hooks, Yvette Abascal, Federico Alder, Chris Ellis, Pete Wylie, Luke A. Campbell, Peter J. Roberts, Nicola D. Aitken, Sarah J. Martincorena, Inigo Hoare, Matthew Stratton, Michael R. |
| AuthorAffiliation | 3 Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK 5 Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK 6 Department of Haematology and Stem Cell Institute, University of Cambridge, Hills Rd, Cambridge CB2 0XY, UK 4 Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands 1 Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK 2 CRUK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK |
| AuthorAffiliation_xml | – name: 3 Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK – name: 6 Department of Haematology and Stem Cell Institute, University of Cambridge, Hills Rd, Cambridge CB2 0XY, UK – name: 2 CRUK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK – name: 4 Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands – name: 1 Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK – name: 5 Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK |
| Author_xml | – sequence: 1 givenname: Simon F. surname: Brunner fullname: Brunner, Simon F. organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 2 givenname: Nicola D. surname: Roberts fullname: Roberts, Nicola D. organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 3 givenname: Luke A. surname: Wylie fullname: Wylie, Luke A. organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 4 givenname: Luiza surname: Moore fullname: Moore, Luiza organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 5 givenname: Sarah J. surname: Aitken fullname: Aitken, Sarah J. organization: CRUK Cambridge Institute, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital – sequence: 6 givenname: Susan E. surname: Davies fullname: Davies, Susan E. organization: Department of Pathology, University of Cambridge, Addenbrooke’s Hospital – sequence: 7 givenname: Mathijs A. surname: Sanders fullname: Sanders, Mathijs A. organization: Cancer Genome Project, Wellcome Trust Sanger Institute, Department of Hematology, Erasmus University Medical Center – sequence: 8 givenname: Pete surname: Ellis fullname: Ellis, Pete organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 9 givenname: Chris surname: Alder fullname: Alder, Chris organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 10 givenname: Yvette surname: Hooks fullname: Hooks, Yvette organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 11 givenname: Federico surname: Abascal fullname: Abascal, Federico organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 12 givenname: Michael R. surname: Stratton fullname: Stratton, Michael R. organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 13 givenname: Inigo surname: Martincorena fullname: Martincorena, Inigo organization: Cancer Genome Project, Wellcome Trust Sanger Institute – sequence: 14 givenname: Matthew surname: Hoare fullname: Hoare, Matthew email: Matthew.Hoare@cruk.cam.ac.uk organization: CRUK Cambridge Institute, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital – sequence: 15 givenname: Peter J. surname: Campbell fullname: Campbell, Peter J. email: pc8@sanger.ac.uk organization: Cancer Genome Project, Wellcome Trust Sanger Institute, Department of Haematology and Stem Cell Institute, University of Cambridge |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31645727$$D View this record in MEDLINE/PubMed |
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| Title | Somatic mutations and clonal dynamics in healthy and cirrhotic human liver |
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