Augusto Villanueva - Academia.edu (original) (raw)
Papers by Augusto Villanueva
Gut
With increasing knowledge on molecular tumour information, precision oncology has revolutionised ... more With increasing knowledge on molecular tumour information, precision oncology has revolutionised the medical field over the past years. Liquid biopsy entails the analysis of circulating tumour components, such as circulating tumour DNA, tumour cells or tumour-derived extracellular vesicles, and has thus come as a handy tool for personalised medicine in many cancer entities. Clinical applications under investigation include early cancer detection, prediction of treatment response and molecular monitoring of the disease, for example, to comprehend resistance patterns and clonal tumour evolution. In fact, several tests for blood-based mutation profiling are already commercially available and have entered the clinical field.In the context of hepatocellular carcinoma, where access to tissue specimens remains mostly limited to patients with early stage tumours, liquid biopsy approaches might be particularly helpful. A variety of translational liquid biopsy studies have been carried out to...
ABSTRACTBackgroundHepatocellular carcinoma (HCC) is among the deadliest malignancies and surveill... more ABSTRACTBackgroundHepatocellular carcinoma (HCC) is among the deadliest malignancies and surveillance tools for early detection are suboptimal. Extracellular vesicles (EVs) have gained increasing scientific interest due to their involvement in tumor initiation and metastasis, however, most extracellular RNA (exRNA) biomarker studies are limited to annotated genomic regions.MethodsEVs were isolated with ultracentrifugation and nanoDLD and quality assessed by electron microscopy, immunoblotting, nanoparticle tracking, and deconvolution analysis. We performed genome-wide small exRNA sequencing, including unannotated transcripts. We identified small RNA clusters (smRCs) and delineated their key genomic features across biospecimens (blood, urine, tissue) and EV isolation techniques. A 3-smRC signature for early HCC detection was trained and validated in two independent cohorts.ResultsEV-derived smRCs were dominated by uncharacterized, unannotated small RNA and uniformly tiled across the ...
Hepatology
The clinical management of primary liver cancers such as hepatocellular carcinoma (HCC) and chola... more The clinical management of primary liver cancers such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) has significantly changed in the last 3 years. The introduction of systemic therapies, including immune‐based therapies and biomarker‐driven therapies, has significantly improved survival, particularly in patients at advanced stages of disease. Survival is still poor, and projections from the World Health Organization underscore the need to improve outcomes in these patients. Biomarkers have emerged as powerful tools for the diagnosis, prognosis, and prediction of treatment responses to improve patient stratification and maximize clinical benefits. Recent advances in understanding the molecular alterations of HCC have not yet translated into biomarkers. Some reasons for the lack of progress are the absence of druggable mutations in the majority of liver cancers and the significant heterogeneity of the disease. In contrast, several therapeutic targets have been identified in CCA, and biomarker‐driven therapies are currently under evaluation in phase 2/3 clinical trials. Here, we summarize the status on biomarker development for HCC and CCA.
Histopathology
Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other mal... more Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages, and paired primary–metastatic comparisons between samples from the same patient are difficult.
Gastroenterology, Sep 14, 2017
Agents that induce an immune response against tumors by altering T-cell regulation have increased... more Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors. We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumors samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune c...
Gastroenterology, Jan 30, 2016
Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore ... more Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocy...
Gastroenterologia Y Hepatologia, Dec 16, 2011
Recently, interest in hepatocellular carcinoma (HCC) has grown due to its high mortality and incr... more Recently, interest in hepatocellular carcinoma (HCC) has grown due to its high mortality and increased incidence. Unlike other malignancies, HCC mainly arises in the context of chronic liver injury, complicating its management and the prediction of prognosis. The Barcelona Clinic Liver Cancer (BCLC) staging classification currently offers an efficient decision-making guide in these patients. However, preoperative identification of patients with a higher risk of recurrence after resection and of those who could benefit from liver transplantation despite not meeting the Milan criteria would be useful. New high-throughput genomic technologies that can be applied to paraffin-embedded tissue have facilitated the identification of gene signatures and other biomarkers able to predict prognosis in HCC patients. None of these biomarkers, based on transcriptome, microRNAs or metilome, has been incorporated into clinical practice, although in future they may be able to complement the prognostic value of clinical and pathologic variables.
Induction of angiogenesis represents one of the major hallmarks of cancer. The growth of new vess... more Induction of angiogenesis represents one of the major hallmarks of cancer. The growth of new vessels is crucial to provide malignant cells with an adequate supply of oxygen and nutrients. It is generally accepted that vascular endothelial growth factor (VEGF) is a major driver of the angiogenic process in physiological and pathological processes in both embryo and adult. VEGF is often found overexpressed in tumors, as well as its receptors VEGFR1 and VEGFR2. Hence, several different strategies have been designed to target VEGF signal transduction. In the last decades, multiple inhibitors have been therapeutically validated in preclinical models and several clinical trials. Neutralizing monoclonal antibodies against VEGF and small molecule tyrosine kinase inhibitors targeting VEGFRs have been shown to block its angiogenic activity, resulting in tumor vascular regression, anti-tumor effects and improvements in patient survival. However, side effects and lack of efficacy in some instances challenge the potential clinical impact of these therapies. This review examines the role of VEGF signaling in cancer and outlines the current status of anti-angiogenic therapies against VEGF pathway.
Journal of Hepatology, 2013
The high failure rate of phase 3 trials in oncology is forcing the scientific community to rethin... more The high failure rate of phase 3 trials in oncology is forcing the scientific community to rethink drug development strategies and optimize trial design. The current paradigm of systemic therapies is progressively favoring molecular-based patient selection. In hepatocellular carcinoma, four out of the five phase 3 trials that tested molecular therapies in the last 5 years have been negative. None of them included enriched populations using predicted biomarkers of response. Hence, there is an increasing need to provide new targets and refine selection criteria in HCC clinical trials using molecular readouts of tumor biology.
Journal of Hepatology, 2008
Background: Recurrent Hepatitis C (HCV) after liver transplantation (LT) can lead to graft cirrho... more Background: Recurrent Hepatitis C (HCV) after liver transplantation (LT) can lead to graft cirrhosis in up to 30% of patients within 5 years. However, the natural history of HCV graft cirrhosis is not well defined. Aim: To define the natural history of recurrent HCV cirrhosis after LT in a US population. Methods: All adult patients undergoing LT for HCV were prospectively monitored with protocol liver biopsies at month 4 and yearly post-LT. Cirrhosis was defined as fibrosis score 5 or 6 (modified Ishak scale). Antiviral therapy for HCV was initiated when fibrosis score was >2. Demographic, clinical and histologic data were collected. Kaplan-Meier curves were calculated to estimate probability of decompensation and patient survival. Cox regression analysis was used to determine risk factors of decompensation and survival. Results: Of the 1,085 adult LT performed at our institution from 1991 to 2007, 505 patients were performed for HCV cirrhosis. 69 (14%) patients had biopsy proven cirrhosis by median time of 36-months, and 53 (77%) of them were clinically compensated at diagnosis. 26 (49%) had at least one episode of decompensation. The median time to the first decompensation event was 15 months. The cumulative probability of clinical decompensation was 22% at 1 year and 54% at 3 years after cirrhosis developed. A MELD score of 17 was predictive of decompensation (RR 8.7, 95% CI 1.7−44.4). A sustained virologic response to interferon treatment reduced the risk of decompensation (RR 0.1, 95% CI 0.02−0.7). Cumulative survival at 1 and 5 years was 92% and 78% in compensated patients, which was significantly better than the 1 and 5 year survival of 64% and 17% found in decompensated patients (p = 0.001). Poor survival was predicted by MELD score 17, (RR = 15.3; 95% CI 2.0-114), HCC (RR = 7.8; 95% CI 1.7−35), and progression to cirrhosis in <2 years (RR = 3.9; 95% CI 1.1−13.7). Conclusions: We report the largest natural history series of recurrent HCV cirrhosis in the U.S. The rate of decompensation is four times faster than a non-transplant population, but slower than previous reports. Successful antiviral therapy may protect against decompensation; however, once decompensation occurs, survival is negatively effected.
Journal of Hepatology, 2006
Journal of Clinical Investigation, 2009
Nature Communications
Clonal evolution of a tumor ecosystem depends on different selection pressures that are principal... more Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how...
Nature Communications
Clonal evolution of a tumor ecosystem depends on different selection pressures that are principal... more Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how...
Gastroenterology, Jan 19, 2015
Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortalit... more Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years there has been a clear delineation of the landscape of genetic alterations in HCC including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in pre-neoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25-30% of HCC patients, that in addition to low frequency mutated genes (e.g., AXIN1, ARID2, ARI...
Gastroenterology
In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or abla... more In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona-Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues. We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287) and adjacent nontumor, cirrhotic tissue (n = 226). We evaluated gene expression signatures with reported prognostic ability generated from tumor or cirrhotic tissue in 18 and 4 reports, respectively. In 15 additional patients, we profiled samples from the center and periphery of the tumor, to determine stability of signatu...
Best practice & research. Clinical gastroenterology
Inherited liver disorders that cause chronic inflammation, fibrosis, and cirrhosis can lead to th... more Inherited liver disorders that cause chronic inflammation, fibrosis, and cirrhosis can lead to the development of liver cancer. Because of the rarity and diversity of some of these syndromes, the relative risk of developing HCC in these patients and the age at which tumours typically arise cannot be accurately estimated. Among patients with hereditary hemachromatosis (HH), the annual incidence of HCC is 4% once cirrhosis has been established. Fibrosis and portal hypertension associated with HH can be partially reversed with therapeutic phlebotomy, but it is unclear whether this treatment alters the incidence of HCC in these patients. Importantly, it seems likely that coincidence of these genetic disorders with known HCC risk factors such as alcoholism and viral hepatitis would amplify their oncogenic potential. For this reason, patients with known genetic disorders of the liver should be repeatedly counselled to avoid environmental and toxic injury to the liver. Treatment of HCC in ...
Nature Reviews Clinical Oncology, 2015
Gut, Jan 4, 2015
We used an informatics approach to identify and validate genes whose expression is unique to hepa... more We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells and assessed the prognostic capability of their expression in cirrhosis. We defined a hepatic stellate cell gene signature by comparing stellate, immune and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables, using overall survival as the primary clinical outcome. This signature was derived in a retrospective-prospective cohort of hepatitis C-related early-stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC) (n=82, prognostic index validation set). We then examined the association between hepatic stellate cell signature expression and decompensation, HCC incidence and progression of Child-Pugh class as additional outcomes in the prognostic index derivation...
Nature genetics, Jan 30, 2015
Genomic analyses promise to improve tumor characterization to optimize personalized treatment for... more Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-speci...
Gut
With increasing knowledge on molecular tumour information, precision oncology has revolutionised ... more With increasing knowledge on molecular tumour information, precision oncology has revolutionised the medical field over the past years. Liquid biopsy entails the analysis of circulating tumour components, such as circulating tumour DNA, tumour cells or tumour-derived extracellular vesicles, and has thus come as a handy tool for personalised medicine in many cancer entities. Clinical applications under investigation include early cancer detection, prediction of treatment response and molecular monitoring of the disease, for example, to comprehend resistance patterns and clonal tumour evolution. In fact, several tests for blood-based mutation profiling are already commercially available and have entered the clinical field.In the context of hepatocellular carcinoma, where access to tissue specimens remains mostly limited to patients with early stage tumours, liquid biopsy approaches might be particularly helpful. A variety of translational liquid biopsy studies have been carried out to...
ABSTRACTBackgroundHepatocellular carcinoma (HCC) is among the deadliest malignancies and surveill... more ABSTRACTBackgroundHepatocellular carcinoma (HCC) is among the deadliest malignancies and surveillance tools for early detection are suboptimal. Extracellular vesicles (EVs) have gained increasing scientific interest due to their involvement in tumor initiation and metastasis, however, most extracellular RNA (exRNA) biomarker studies are limited to annotated genomic regions.MethodsEVs were isolated with ultracentrifugation and nanoDLD and quality assessed by electron microscopy, immunoblotting, nanoparticle tracking, and deconvolution analysis. We performed genome-wide small exRNA sequencing, including unannotated transcripts. We identified small RNA clusters (smRCs) and delineated their key genomic features across biospecimens (blood, urine, tissue) and EV isolation techniques. A 3-smRC signature for early HCC detection was trained and validated in two independent cohorts.ResultsEV-derived smRCs were dominated by uncharacterized, unannotated small RNA and uniformly tiled across the ...
Hepatology
The clinical management of primary liver cancers such as hepatocellular carcinoma (HCC) and chola... more The clinical management of primary liver cancers such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) has significantly changed in the last 3 years. The introduction of systemic therapies, including immune‐based therapies and biomarker‐driven therapies, has significantly improved survival, particularly in patients at advanced stages of disease. Survival is still poor, and projections from the World Health Organization underscore the need to improve outcomes in these patients. Biomarkers have emerged as powerful tools for the diagnosis, prognosis, and prediction of treatment responses to improve patient stratification and maximize clinical benefits. Recent advances in understanding the molecular alterations of HCC have not yet translated into biomarkers. Some reasons for the lack of progress are the absence of druggable mutations in the majority of liver cancers and the significant heterogeneity of the disease. In contrast, several therapeutic targets have been identified in CCA, and biomarker‐driven therapies are currently under evaluation in phase 2/3 clinical trials. Here, we summarize the status on biomarker development for HCC and CCA.
Histopathology
Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other mal... more Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages, and paired primary–metastatic comparisons between samples from the same patient are difficult.
Gastroenterology, Sep 14, 2017
Agents that induce an immune response against tumors by altering T-cell regulation have increased... more Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors. We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumors samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune c...
Gastroenterology, Jan 30, 2016
Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore ... more Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocy...
Gastroenterologia Y Hepatologia, Dec 16, 2011
Recently, interest in hepatocellular carcinoma (HCC) has grown due to its high mortality and incr... more Recently, interest in hepatocellular carcinoma (HCC) has grown due to its high mortality and increased incidence. Unlike other malignancies, HCC mainly arises in the context of chronic liver injury, complicating its management and the prediction of prognosis. The Barcelona Clinic Liver Cancer (BCLC) staging classification currently offers an efficient decision-making guide in these patients. However, preoperative identification of patients with a higher risk of recurrence after resection and of those who could benefit from liver transplantation despite not meeting the Milan criteria would be useful. New high-throughput genomic technologies that can be applied to paraffin-embedded tissue have facilitated the identification of gene signatures and other biomarkers able to predict prognosis in HCC patients. None of these biomarkers, based on transcriptome, microRNAs or metilome, has been incorporated into clinical practice, although in future they may be able to complement the prognostic value of clinical and pathologic variables.
Induction of angiogenesis represents one of the major hallmarks of cancer. The growth of new vess... more Induction of angiogenesis represents one of the major hallmarks of cancer. The growth of new vessels is crucial to provide malignant cells with an adequate supply of oxygen and nutrients. It is generally accepted that vascular endothelial growth factor (VEGF) is a major driver of the angiogenic process in physiological and pathological processes in both embryo and adult. VEGF is often found overexpressed in tumors, as well as its receptors VEGFR1 and VEGFR2. Hence, several different strategies have been designed to target VEGF signal transduction. In the last decades, multiple inhibitors have been therapeutically validated in preclinical models and several clinical trials. Neutralizing monoclonal antibodies against VEGF and small molecule tyrosine kinase inhibitors targeting VEGFRs have been shown to block its angiogenic activity, resulting in tumor vascular regression, anti-tumor effects and improvements in patient survival. However, side effects and lack of efficacy in some instances challenge the potential clinical impact of these therapies. This review examines the role of VEGF signaling in cancer and outlines the current status of anti-angiogenic therapies against VEGF pathway.
Journal of Hepatology, 2013
The high failure rate of phase 3 trials in oncology is forcing the scientific community to rethin... more The high failure rate of phase 3 trials in oncology is forcing the scientific community to rethink drug development strategies and optimize trial design. The current paradigm of systemic therapies is progressively favoring molecular-based patient selection. In hepatocellular carcinoma, four out of the five phase 3 trials that tested molecular therapies in the last 5 years have been negative. None of them included enriched populations using predicted biomarkers of response. Hence, there is an increasing need to provide new targets and refine selection criteria in HCC clinical trials using molecular readouts of tumor biology.
Journal of Hepatology, 2008
Background: Recurrent Hepatitis C (HCV) after liver transplantation (LT) can lead to graft cirrho... more Background: Recurrent Hepatitis C (HCV) after liver transplantation (LT) can lead to graft cirrhosis in up to 30% of patients within 5 years. However, the natural history of HCV graft cirrhosis is not well defined. Aim: To define the natural history of recurrent HCV cirrhosis after LT in a US population. Methods: All adult patients undergoing LT for HCV were prospectively monitored with protocol liver biopsies at month 4 and yearly post-LT. Cirrhosis was defined as fibrosis score 5 or 6 (modified Ishak scale). Antiviral therapy for HCV was initiated when fibrosis score was >2. Demographic, clinical and histologic data were collected. Kaplan-Meier curves were calculated to estimate probability of decompensation and patient survival. Cox regression analysis was used to determine risk factors of decompensation and survival. Results: Of the 1,085 adult LT performed at our institution from 1991 to 2007, 505 patients were performed for HCV cirrhosis. 69 (14%) patients had biopsy proven cirrhosis by median time of 36-months, and 53 (77%) of them were clinically compensated at diagnosis. 26 (49%) had at least one episode of decompensation. The median time to the first decompensation event was 15 months. The cumulative probability of clinical decompensation was 22% at 1 year and 54% at 3 years after cirrhosis developed. A MELD score of 17 was predictive of decompensation (RR 8.7, 95% CI 1.7−44.4). A sustained virologic response to interferon treatment reduced the risk of decompensation (RR 0.1, 95% CI 0.02−0.7). Cumulative survival at 1 and 5 years was 92% and 78% in compensated patients, which was significantly better than the 1 and 5 year survival of 64% and 17% found in decompensated patients (p = 0.001). Poor survival was predicted by MELD score 17, (RR = 15.3; 95% CI 2.0-114), HCC (RR = 7.8; 95% CI 1.7−35), and progression to cirrhosis in <2 years (RR = 3.9; 95% CI 1.1−13.7). Conclusions: We report the largest natural history series of recurrent HCV cirrhosis in the U.S. The rate of decompensation is four times faster than a non-transplant population, but slower than previous reports. Successful antiviral therapy may protect against decompensation; however, once decompensation occurs, survival is negatively effected.
Journal of Hepatology, 2006
Journal of Clinical Investigation, 2009
Nature Communications
Clonal evolution of a tumor ecosystem depends on different selection pressures that are principal... more Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how...
Nature Communications
Clonal evolution of a tumor ecosystem depends on different selection pressures that are principal... more Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how...
Gastroenterology, Jan 19, 2015
Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortalit... more Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years there has been a clear delineation of the landscape of genetic alterations in HCC including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in pre-neoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25-30% of HCC patients, that in addition to low frequency mutated genes (e.g., AXIN1, ARID2, ARI...
Gastroenterology
In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or abla... more In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona-Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues. We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287) and adjacent nontumor, cirrhotic tissue (n = 226). We evaluated gene expression signatures with reported prognostic ability generated from tumor or cirrhotic tissue in 18 and 4 reports, respectively. In 15 additional patients, we profiled samples from the center and periphery of the tumor, to determine stability of signatu...
Best practice & research. Clinical gastroenterology
Inherited liver disorders that cause chronic inflammation, fibrosis, and cirrhosis can lead to th... more Inherited liver disorders that cause chronic inflammation, fibrosis, and cirrhosis can lead to the development of liver cancer. Because of the rarity and diversity of some of these syndromes, the relative risk of developing HCC in these patients and the age at which tumours typically arise cannot be accurately estimated. Among patients with hereditary hemachromatosis (HH), the annual incidence of HCC is 4% once cirrhosis has been established. Fibrosis and portal hypertension associated with HH can be partially reversed with therapeutic phlebotomy, but it is unclear whether this treatment alters the incidence of HCC in these patients. Importantly, it seems likely that coincidence of these genetic disorders with known HCC risk factors such as alcoholism and viral hepatitis would amplify their oncogenic potential. For this reason, patients with known genetic disorders of the liver should be repeatedly counselled to avoid environmental and toxic injury to the liver. Treatment of HCC in ...
Nature Reviews Clinical Oncology, 2015
Gut, Jan 4, 2015
We used an informatics approach to identify and validate genes whose expression is unique to hepa... more We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells and assessed the prognostic capability of their expression in cirrhosis. We defined a hepatic stellate cell gene signature by comparing stellate, immune and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables, using overall survival as the primary clinical outcome. This signature was derived in a retrospective-prospective cohort of hepatitis C-related early-stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC) (n=82, prognostic index validation set). We then examined the association between hepatic stellate cell signature expression and decompensation, HCC incidence and progression of Child-Pugh class as additional outcomes in the prognostic index derivation...
Nature genetics, Jan 30, 2015
Genomic analyses promise to improve tumor characterization to optimize personalized treatment for... more Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-speci...