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Cancer assessment by plasma nucleic acid analysis
ABSTRACTS
We hypothesised that liver-derived mRNA, such as albumin (ALB) mRNA, would be released into human plasma as a result of liver cell death. We genotyped the ALB mRNA molecules in plasma and whole blood of liver or bone marrow transplantation recipients by RNA-single nucleotide polymorphism analysis. The plasma and whole blood ALB mRNA genotypes were compared with the DNA genotypes in the recipients and donors. Our data revealed that ALB mRNA in plasma was liver-derived, while tissue compartments other than the liver also contributed to the ALB mRNA detected in whole blood. We then used a reverse transcription quantitative real-time PCR assay to show that the plasma ALB mRNA concentrations were elevated in patients with hepatocellular carcinoma, cirrhosis or chronic hepatitis B than healthy controls. Only 21.5% of patients with liver pathologies had elevated alanine transaminase (ALT) when 73.8% of them had elevated plasma ALB mRNA concentrations. Only 49% of the hepatocellular carcinoma patients had elevated serum alphafetoprotein, while 91.4% had elevated plasma ALB mRNA concentrations. Liver-derived plasma mRNA may become a new class of biomarkers for the sensitive detection of liver diseases. Acknowledgement: Supported by the Hong Kong Research Grants Council Earmarked Research Grant (CUHK463207). LIVER TRANSPLANTATION IN AUSTRALIA AND NEW ZEALAND Simone Strasser AW Morrow Gastroenterology and Liver Centre and Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, NSW, Australia Liver transplantation (LTx) was established in Australia and New Zealand in 1985. To December 2010, 3781 LTx were performed in 3510 patients (2871 adults; 639 children). Chronic viral hepatitis, often with hepatocellular carcinoma, is the most common indication, accounting for over 40% of adult transplants. Biliary atresia is the most common indication in children. One year post-LTx survival is >90% and 5 year survival is >80%. The greatest limitation to delivery of LTx is donor availability. Expanded criteria donors are increasingly used, including older donors, donors with hepatitis C virus (HCV)/hepatitis B virus (HBV), split livers, deceased after cardiac death (DCD) donors and live donors. Organ allocation to recipients aims to ensure equity and utility. Model for end-stage liver disease (MELD)-based allocation is utilised. Waiting list mortality is 10–15%. Standard immunosuppressive protocols are based on calcineurin inhibitors (tacrolimus or CSA) corticosteroids azathioprine/ mycophenolate mofetil. Graft loss from rejection is uncommon. Prophylaxis protocols for HBV, cytomegalovirus (CMV) and Pneumocystis carinii pneumonia fungal infections are standardised. HCV recurrence accounts for high rates of graft failure. Histological recurrence occurs in 80%; 30% are cirrhotic by 5 years. Factors associated with severe HCV recurrence include older donors, intense immunosuppression, high HCV viral load and CMV. Currently, post LTx antiviral treatment is poorly tolerated and often ineffective, however new agents offer great promise. Hepatocellular carcinoma, primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic steatohepatitis may recur postLTx. Recurrent disease, infection, malignancy and cardiovascular disease remain the major causes of patient death post-LTx.
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CANCER ASSESSMENT BY PLASMA NUCLEIC ACID ANALYSIS Rossa W. K. Chiu Li Ka Shing Institute of Health Sciences and Department of Chemical Pathology, The Chinese University of Hong Kong Tumour-derived nucleic acid molecules have been found in the plasma of cancer patients. Our group and others showed that the detection and quantification of circulating tumour-derived nucleic acid molecules offered value for the detection, prognostication and monitoring of cancers. A number of classes of circulating nucleic acid species have been found to be released by tumour tissues and include DNA molecules showing tumourspecific mutations or translocations, RNA transcripts, DNA methylation signatures and viral-associated sequences. A number of analytical approaches have been developed to achieve sensitive and specific detection of such tumour-specific nucleic acid markers in plasma. Strategies included the real-time polymerase chain reaction quantification of Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma, methylation-sensitive restriction enzyme based detection of hypermethylated Ras association domain family 1 A (RASSF1A) sequences in plasma of hepatocellular carcinoma patients, and digital polymerase chain reaction detection of epidermal growth factor receptor (EGFR) mutations in plasma of lung cancer patients. Acknowledgement: Supported by the Research Grants Council of the Hong Kong Special Administrative Region, China [T12-404/ 11]. NEW CONSENSUS GUIDELINES FOR THE DIAGNOSIS OF GESTATIONAL DIABETES Alison Nankervis Royal Melbourne and Royal Women’s Hospitals, Melbourne, Vic, Australia Australian guidelines for the diagnosis of gestational diabetes (GDM) were formulated in 1991, based largely on expert opinion. Review of these guidelines was precipitated by the publication of the Hyperglycaemia and Pregnancy Outcome Study (HAPO) and subsequent recommendations published by the International Diabetes in Pregnancy Study Groups (IADPSG). HAPO was a prospective, blinded study of 23 316 women and reported a strong correlation between glycaemia at 24–28 weeks gestation and adverse maternal and neonatal outcomes. IADPSG consensus was that cut-points for oral glucose tolerance test (OGTT) plasma glucose levels with an odds ratio of 1.75 for adverse outcomes should be designated the diagnostic levels for GDM. The new recommended diagnostic criteria for GDM are fasting venous plasma glucose (VPG) of 5.1 mmol/L; or 1-hour VPG 10.1 mmol/L; or 2-hour VPG 8.5 mmol/L, based on an OGTT routinely performed at 24–28 weeks gestation. Glucose challenge tests are no longer part of the diagnostic algorithm. It is anticipated that adoption of these criteria will increase the prevalence of GDM to 12–13%, with significant implications for workload management. Recommendations for early screening for DM in pregnancy are being considered. The consensus view is that there should be universal screening at the first pregnancy visit with method and interpretation of testing not yet defined.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
We hypothesised that liver-derived mRNA, such as albumin (ALB) mRNA, would be released into human plasma as a result of liver cell death. We genotyped the ALB mRNA molecules in plasma and whole blood of liver or bone marrow transplantation recipients by RNA-single nucleotide polymorphism analysis. The plasma and whole blood ALB mRNA genotypes were compared with the DNA genotypes in the recipients and donors. Our data revealed that ALB mRNA in plasma was liver-derived, while tissue compartments other than the liver also contributed to the ALB mRNA detected in whole blood. We then used a reverse transcription quantitative real-time PCR assay to show that the plasma ALB mRNA concentrations were elevated in patients with hepatocellular carcinoma, cirrhosis or chronic hepatitis B than healthy controls. Only 21.5% of patients with liver pathologies had elevated alanine transaminase (ALT) when 73.8% of them had elevated plasma ALB mRNA concentrations. Only 49% of the hepatocellular carcinoma patients had elevated serum alphafetoprotein, while 91.4% had elevated plasma ALB mRNA concentrations. Liver-derived plasma mRNA may become a new class of biomarkers for the sensitive detection of liver diseases. Acknowledgement: Supported by the Hong Kong Research Grants Council Earmarked Research Grant (CUHK463207). LIVER TRANSPLANTATION IN AUSTRALIA AND NEW ZEALAND Simone Strasser AW Morrow Gastroenterology and Liver Centre and Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, NSW, Australia Liver transplantation (LTx) was established in Australia and New Zealand in 1985. To December 2010, 3781 LTx were performed in 3510 patients (2871 adults; 639 children). Chronic viral hepatitis, often with hepatocellular carcinoma, is the most common indication, accounting for over 40% of adult transplants. Biliary atresia is the most common indication in children. One year post-LTx survival is >90% and 5 year survival is >80%. The greatest limitation to delivery of LTx is donor availability. Expanded criteria donors are increasingly used, including older donors, donors with hepatitis C virus (HCV)/hepatitis B virus (HBV), split livers, deceased after cardiac death (DCD) donors and live donors. Organ allocation to recipients aims to ensure equity and utility. Model for end-stage liver disease (MELD)-based allocation is utilised. Waiting list mortality is 10–15%. Standard immunosuppressive protocols are based on calcineurin inhibitors (tacrolimus or CSA) corticosteroids azathioprine/ mycophenolate mofetil. Graft loss from rejection is uncommon. Prophylaxis protocols for HBV, cytomegalovirus (CMV) and Pneumocystis carinii pneumonia fungal infections are standardised. HCV recurrence accounts for high rates of graft failure. Histological recurrence occurs in 80%; 30% are cirrhotic by 5 years. Factors associated with severe HCV recurrence include older donors, intense immunosuppression, high HCV viral load and CMV. Currently, post LTx antiviral treatment is poorly tolerated and often ineffective, however new agents offer great promise. Hepatocellular carcinoma, primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic steatohepatitis may recur postLTx. Recurrent disease, infection, malignancy and cardiovascular disease remain the major causes of patient death post-LTx.
S19
CANCER ASSESSMENT BY PLASMA NUCLEIC ACID ANALYSIS Rossa W. K. Chiu Li Ka Shing Institute of Health Sciences and Department of Chemical Pathology, The Chinese University of Hong Kong Tumour-derived nucleic acid molecules have been found in the plasma of cancer patients. Our group and others showed that the detection and quantification of circulating tumour-derived nucleic acid molecules offered value for the detection, prognostication and monitoring of cancers. A number of classes of circulating nucleic acid species have been found to be released by tumour tissues and include DNA molecules showing tumourspecific mutations or translocations, RNA transcripts, DNA methylation signatures and viral-associated sequences. A number of analytical approaches have been developed to achieve sensitive and specific detection of such tumour-specific nucleic acid markers in plasma. Strategies included the real-time polymerase chain reaction quantification of Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma, methylation-sensitive restriction enzyme based detection of hypermethylated Ras association domain family 1 A (RASSF1A) sequences in plasma of hepatocellular carcinoma patients, and digital polymerase chain reaction detection of epidermal growth factor receptor (EGFR) mutations in plasma of lung cancer patients. Acknowledgement: Supported by the Research Grants Council of the Hong Kong Special Administrative Region, China [T12-404/ 11]. NEW CONSENSUS GUIDELINES FOR THE DIAGNOSIS OF GESTATIONAL DIABETES Alison Nankervis Royal Melbourne and Royal Women’s Hospitals, Melbourne, Vic, Australia Australian guidelines for the diagnosis of gestational diabetes (GDM) were formulated in 1991, based largely on expert opinion. Review of these guidelines was precipitated by the publication of the Hyperglycaemia and Pregnancy Outcome Study (HAPO) and subsequent recommendations published by the International Diabetes in Pregnancy Study Groups (IADPSG). HAPO was a prospective, blinded study of 23 316 women and reported a strong correlation between glycaemia at 24–28 weeks gestation and adverse maternal and neonatal outcomes. IADPSG consensus was that cut-points for oral glucose tolerance test (OGTT) plasma glucose levels with an odds ratio of 1.75 for adverse outcomes should be designated the diagnostic levels for GDM. The new recommended diagnostic criteria for GDM are fasting venous plasma glucose (VPG) of 5.1 mmol/L; or 1-hour VPG 10.1 mmol/L; or 2-hour VPG 8.5 mmol/L, based on an OGTT routinely performed at 24–28 weeks gestation. Glucose challenge tests are no longer part of the diagnostic algorithm. It is anticipated that adoption of these criteria will increase the prevalence of GDM to 12–13%, with significant implications for workload management. Recommendations for early screening for DM in pregnancy are being considered. The consensus view is that there should be universal screening at the first pregnancy visit with method and interpretation of testing not yet defined.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.