The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related ...pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.
The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C ...virus, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have been approved recently for treatment of HCC, and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer.
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has ...a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development.
Liver transplantation outcomes have significantly improved over the past few decades owing largely to the introduction of effective immunosuppression medications. Further comprehension of the unique ...immune microenvironment of the liver has led to the development of newer molecular targeted therapeutics. Understanding the mechanism of action and adverse effect profiles of these medications is crucial for appropriate management of posttransplant patients. In this review, the author describes the immunologic response elicited by liver transplantation, chronicles the various immunosuppressant drug classes, discusses the evidence behind their use, and evaluates the management of special subpopulations of posttransplantation patients.
Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related mortality worldwide. Early detection of HCC enables patients to avail curative therapies that can improve patient survival. Current ...international guidelines advocate for the enrollment of patients at high risk for HCC, like those with cirrhosis, in surveillance programs that perform ultrasound every 6 months. In recent years, many studies have further characterized the utility of established screening strategies and have introduced new promising tools for HCC surveillance. In this review, we provide an overview of the most promising new imaging modalities and biomarkers for the detection of HCC. We discuss the role of imaging tools like ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) in the early detection of HCC, and describe recent innovations which can potentially enhance their applicability, including contrast enhanced ultrasound, low‐dose CT scans, and abbreviated MRI. Next, we outline the data supporting the use of three circulating biomarkers (i.e., alpha‐fetoprotein AFP, AFP lens culinaris agglutinin‐reactive fraction, and des‐gamma‐carboxy prothrombin) in HCC surveillance, and expand on multiple emerging liquid biopsy biomarkers, including methylated cell‐free DNA (cfDNA), cfDNA mutations, extracellular vesicles, and circulating tumor cells. These promising new imaging modalities and biomarkers have the potential to improve early detection, and thus improve survival, in patients with HCC.
HCC is a challenging disease to detect in the early stages due to poor adherence to screening guidelines, and more importantly, a paucity of highly sensitive and specific screening tools. Recent advances in ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) techniques have improved upon the sensitivity and specificity for detection, but they are in large part hindered by cost, safety and availability. The future of HCC surveillance likely lies in circulating liquid biopsy biomarkers which have the potential to be cost‐effectively and non‐invasively implemented in populations worldwide.
The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) ...cell numbers in SRα-tTA/Tet-O-MYC
mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYC
T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.
Tumor heterogeneity, a key hallmark of hepatocellular carcinomas (HCCs), poses a significant challenge to developing effective therapies or predicting clinical outcomes in HCC. Recent advances in ...next-generation sequencing-based multi-omic and single cell analysis technologies have enabled us to develop high-resolution atlases of tumors and pull back the curtain on tumor heterogeneity. By combining multiregion targeting sampling strategies with deep sequencing of the genome, transcriptome, epigenome, and proteome, several studies have revealed novel mechanistic insights into tumor initiation and progression in HCC. Advances in multiparametric immune cell profiling have facilitated a deeper dive into the biological complexity of HCC, which is crucial in this era of immunotherapy. Moreover, studies using liquid biopsy have demonstrated their potential to circumvent the need for tissue sampling to investigate heterogeneity. In this review, we discuss how multi-omic and single-cell sequencing technologies have advanced our understanding of tumor heterogeneity in HCC.
Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients.
In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit ICU admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death.
Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years IQR 47–66, 102 68% men, 49 32% women) and 627 patients who had not undergone liver transplantation (median age 73 years 44–84, 329 52% men, 298 48% women). The groups did not differ with regard to the proportion of patients hospitalised (124 82% patients in the liver transplant cohort vs 474 76% in the comparison cohort, p=0·106), or who required intensive care (47 31% vs 185 30%, p=0·837). However, ICU admission (43 28% vs 52 8%, p<0·0001) and invasive ventilation (30 20% vs 32 5%, p<0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% 95% CI −7·7 to 10·4). Multivariable logistic regression analysis showed that age (odds ratio 1·06 95% CI 1·01 to 1·11 per 1 year increase), serum creatinine concentration (1·57 1·05 to 2·36 per 1 mg/dL increase), and non-liver cancer (18·30 1·96 to 170·75) were associated with death among liver transplant recipients.
Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic.
European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.
PDF
