Gene-expression signature-based disease classification and clinical outcome prediction has not been widely introduced in clinical medicine as initially expected, mainly due to the lack of extensive ...validation needed for its clinical deployment. Obstacles include variable measurement in microarray assay, inconsistent assay platform, analytical requirement for comparable pair of training and test datasets, etc. Furthermore, as medical device helping clinical decision making, the prediction needs to be made for each single patient with a measure of its reliability. To address these issues, there is a need for flexible prediction method less sensitive to difference in experimental and analytical conditions, applicable to each single patient, and providing measure of prediction confidence. The nearest template prediction (NTP) method provides a convenient way to make class prediction with assessment of prediction confidence computed in each single patient's gene-expression data using only a list of signature genes and a test dataset. We demonstrate that the method can be flexibly applied to cross-platform, cross-species, and multiclass predictions without any optimization of analysis parameters.
Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour ...resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, a “one-size-fits-all” approach to HCC screening for early tumour detection, as recommended by clinical practice guidelines, is utilised in less than 20% of the target population, and the performance of screening modalities, including ultrasound and alpha-fetoprotein, is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations, such as those with chronic hepatitis C after viral cure, or those with non-cirrhotic, non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve the sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailoured HCC screening of individual patients, maximising cost-effectiveness and optimising allocation of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalised chemoprevention, targeting high-risk patients for precision HCC prevention and substantially improving the dismal prognosis of HCC.
Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a ...RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs.
Objective
To assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC).
...Methods
This retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months.
Results
Qualitative (
r
= − 0.41–0.40,
p
< 0.042) and quantitative (
r
= − 0.52–0.45,
p
< 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (
r
= 0.41–0.47,
p
< 0.029) as well as PD1 and CTLA4 at mRNA expression level (
r
= − 0.48–0.47,
p
< 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76–0.80,
p
< 0.043), while immunoprofiling and genomic features did not (
p
= 0.098–0929).
Conclusions
MRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation.
Key Points
• MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma.
• Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.
Hepatitis C virus infection is a major cause of hepatocellular carcinoma worldwide. Interferon has been the major antiviral treatment, yielding viral clearance in approximately half of patients. New ...direct-acting antivirals substantially improved the cure rate to above 90%. However, access to therapies remains limited due to the high costs and under-diagnosis of infection in specific subpopulations, e.g., baby boomers, inmates, and injection drug users, and therefore, hepatocellular carcinoma incidence is predicted to increase in the next decades even in high-resource countries. Moreover, cancer risk persists even after 10 years of viral cure, and thus a clinical strategy for its monitoring is urgently needed. Several risk-predictive host factors, e.g., advanced liver fibrosis, older age, accompanying metabolic diseases such as diabetes, persisting hepatic inflammation, and elevated alpha-fetoprotein, as well as viral factors, e.g., core protein variants and genotype 3, have been reported. Indeed, a molecular signature in the liver has been associated with cancer risk even after viral cure. Direct-acting antivirals may affect cancer development and recurrence, which needs to be determined in further investigation.
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The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development.
A stable isogenic cross ...between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains.
Following initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4–8weeks), steatohepatitis (16–24weeks), progressive fibrosis (16weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD.
We here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH.
We have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH.
Background & Aims Epigenetic silencing of tumor suppressor genes contributes to the pathogenesis of hepatocellular carcinoma (HCC). To identify clinically relevant tumor suppressor genes silenced by ...DNA methylation in HCC, we integrated DNA methylation data from human primary HCC samples with data on up-regulation of gene expression after epigenetic unmasking. Methods We performed genome-wide methylation analysis of 71 human HCC samples using the Illumina HumanBeadchip27K array; data were combined with those from microarray analysis of gene re-expression in 4 liver cancer cell lines after their exposure to reagents that reverse DNA methylation (epigenetic unmasking). Results Based on DNA methylation in primary HCC and gene re-expression in cell lines after epigenetic unmasking, we identified 13 candidate tumor suppressor genes. Subsequent validation led us to focus on functionally characterizing 2 candidates, sphingomyelin phosphodiesterase 3 ( SMPD3 ) and neurofilament, heavy polypeptide ( NEFH ), which we found to behave as tumor suppressor genes in HCC. Overexpression of SMPD3 and NEFH by stable transfection of inducible constructs into an HCC cell line reduced cell proliferation by 50% and 20%, respectively (SMPD3, P = .003 and NEFH, P = .003). Conversely, knocking down expression of these genes with small hairpin RNA promoted cell invasion and migration in vitro (SMPD3, P = .0001 and NEFH, P = .022), and increased their ability to form tumors after subcutaneous injection or orthotopic transplantation into mice, confirming their role as tumor suppressor genes in HCC. Low levels of SMPD3 were associated with early recurrence of HCC after curative surgery in an independent patient cohort ( P = .001; hazard ratio = 3.22; 95% confidence interval: 1.6−6.5 in multivariate analysis). Conclusions Integrative genomic analysis identified SMPD3 and NEFH as tumor suppressor genes in HCC. We provide evidence that SMPD3 is a potent tumor suppressor gene that could affect tumor aggressiveness; a reduced level of SMPD3 is an independent prognostic factor for early recurrence of HCC.
ObjectiveColorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role ...of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure.DesignUtilising 1443 colorectal cancers in two US nationwide prospective cohort studies, the frequencies of molecular features (CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation and BRAF, KRAS and PIK3CA mutations) were examined along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon and caecum). The linearity and non-linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis.ResultsThe frequencies of CIMP-high, MSI-high and BRAF mutations gradually increased from the rectum (<2.3%) to ascending colon (36–40%), followed by falls in the caecum (12–22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence of non-linearity (p>0.09). Caecal cancers exhibited the highest frequency of KRAS mutations (52% vs 27–35% in other sites; p<0.0001).ConclusionsThe frequencies of CIMP-high, MSI-high and BRAF mutations in cancer increased gradually along colorectum subsites from the rectum to ascending colon. These novel data challenge the common conception of discrete molecular features of proximal versus distal colorectal cancers, and have a substantial impact on clinical, translational and epidemiology research, which has typically been performed with the dichotomous classification of proximal versus distal tumours.
Summary Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in ...the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.
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