Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis

Liver carcinogenesis is a complex and multi-factorial process, in which both environmental and genetic features interfere and contribute to malignant transformation. Patients with cirrhosis are particularly exposed and justify periodical screenings in order to detect the early development of hepatocellular carcinoma (HCC). The risk of HCC is, however, not identical from one patient to another. The identification of host factors that may also play an important role in HCC development may improve our understanding of the implications of the various biological pathways involved in liver carcinogenesis; such progress may as well help refine the selection of patients who could benefit from specific preventative measures or could be given adapted screening policies. Numerous candidate-gene studies have reported associations between single nucleotide polymorphisms (SNPs) and the presence of HCC. Some of these publications unfortunately suffer from major methodological drawbacks because of their case-control, retrospective and monocentric aspect. Prospective cohort studies conducted in large homogeneous populations and comprising a sufficient number of events during follow-up may overcome these pitfalls, but require a long time to be conducted and are still scarce. More recently, the first Genome Wide Association studies (GWAs) have enabled the identification of unsuspected loci that may be involved in various steps implicated in liver tumourigenesis. Taken together, these studies highlight variants that modulate oxidative stress, iron metabolism, inflammatory and immune responses, DNA repair mechanisms or systems involved in cell-cycle regulation as genetic traits susceptible to modify the natural history of cirrhotic patients and partly explain the observed differences in the risk of HCC occurrence. However, large genetic epidemiology studies in the field of cancer diseases have suggested the limited ability of polymorphic traits, alone, to refine individual prognosis. The integration of various panels of genes into clinical scores may in the near future define a "genomic risk prediction" specific to liver cancer developed in cirrhotic patients.     

Respiratory tract infections and subsequent risk of chronic lymphocytic leukemia

Recent evidence suggests that chronic lymphocytic leukemia (CLL) might occur following a response to an infectious agent. We conducted a population-based study including 4249 CLL patients diagnosed in Denmark from 1977 to 1997 and 15 690 frequency-matched controls to quantify risk of CLL following various airway infections. Through data linkage we gathered information on hospital inpatient/outpatient discharges that listed infections present at least 1 year prior to CLL. Using logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Personal history of pneumonia was associated with significantly increased CLL risk (OR = 1.4; 1.2-1.8); risk was restricted to 1 to 4.99 years prior to CLL diagnosis (OR = 1.6; 1.2-2.0). Individuals with 3 or more prior pneumonia events had a significant 2.5-fold (1.1-5.6) elevated CLL risk, and risk increased with the number of pneumonia episodes (P(trend) < .001). None of 9 other respiratory-tract infections was significantly associated with CLL risk. Pneumonia might be a potential CLL trigger or it could represent premalignant immune disruption preceding CLL.     

Familial chronic lymphocytic leukemia

Familial aggregation of chronic lymphocytic leukemia (CLL) has been observed more frequently than familial aggregation of any other type of oncohematologic disorder. The presence of cells with a CLL-like immunophenotype (CLL-like cells) was recently documented in 13.5% healthy first-degree relatives of CLL patients. We present a family with CLL in which 2 brothers, a sister and their mother were affected.     

Epigenetics and chronic lymphocytic leukemia

The DNA methylation level in patients with chronic lymphocytic leukemia is generally lower than healthy individuals. Although DNA methylation is globally decreased, regional hypermethylation of gene promoters leads to gene silencing. Many of these genes have tumor suppressor phenotypes. Unlike mutations or deletions, hypermethylation is potentially reversible after inhibition with DNA methylation modulators. Myelodysplastic syndrome has been a model disease in which treatment of patients results in demethylation of specific genes. The story in patients with chronic lymphocytic leukemia is slowly unraveling as epigenetic modifications likely also play an important role. Ongoing clinical trials correlating clinical response to gene expression after treatment with DNA methylation inhibitors will ultimately allow us to better risk stratify and predict the subgroup of patients who will benefit from treatment with this class of drugs.     

Genetic bottlenecks, perceived racism, and hypertension risk among African Americans and first-generation African immigrants

The complexity of factors influencing the development of hypertension (HTN) in African Americans has given rise to theories suggesting that genetic changes occurred due to selection pressures/genetic bottleneck effects (ie, constriction of existing genetic variability) over the course of the slave trade. Ninety-nine US-born and 86 African-born health professionals were compared in a cross-sectional survey examining genetic and psychosocial predictors of HTN. We examined the distributions of three genetic loci (G-protein, AGT-235, and ACE I/D) that have been associated with increased HTN risk. There were no significant differences between US-born African Americans and African-born immigrants in the studied genetic loci or biological variables (eg, plasma renin and angiotensin converting enzyme activity), except that the AGT-235 homozygous T genotype was somewhat more frequent among African-born participants than US-born African Americans. Only age, body mass index, and birthplace consistently demonstrated associations with HTN status. Thus, there was no evidence of a genetic bottleneck in the loci studied, ie, that US-born African Americans have different genotype distributions that increase their risk for HTN. In fact, some of the genotypic distributions evidenced lower frequencies of HTN-related alleles among US-born African Americans, providing evidence of European admixture. The consistent finding that birthplace (ie, US vs Africa) was associated with HTN, even though it was not always significant, suggests potential and unmeasured cultural, lifestyle, and environmental differences between African immigrants and US-born African Americans that are protective against HTN.     

Treatment of chronic lymphocytic leukemia

The therapeutic landscape of chronic lymphocytic leukemia (CLL) is changing rapidly. Advances in the understanding of the biology of the CLL cell and development of new and effective therapies for CLL are starting to shift the treatment paradigm from palliation towards therapy with curative intent. Traditional chemotherapy with alkylators and/or nucleoside analogs achieves complete remissions in up to 30% to 40% of patients. Combinations of monoclonal antibodies with chemotherapy agents (chemo-immunotherapy) have almost doubled clinical complete remissions to 60% to 70%. In addition, eradication of residual disease and achievement of molecular responses have now become possible. New therapeutic agents in development and modifications of stem cell transplant are being evaluated in clinical trials. It is hoped that the combined effort of molecular biology and new therapies will lead to risk-adapted strategies and cure for some patients with CLL.     

Staging of chronic lymphocytic leukemia

One-hundred and eighty-eight patients with chronic lymphocytic leukemia were analyzed for prognosis based on Rai's staging system. It was found that stages I and II were not homogeneous as to prognosis. Stage II patients presenting with isolated splenomegaly had a long survival and were pooled with stage 0 patients (low risk group, 30% of cases, relative death rate 0.24, median survival greater than 10 yr). Stages I and II patients with a lymphocyte count higher than 40 x 10(9)/liter had a short survival and were pooled with stages III and IV patients (high risk group, 39% of cases, relative death rate 1.91, median survival 3.3 yr). Stages I and II patients with a lymphocyte count lower than 40 x 10(9)/liter made up an intermediate or standard risk group (31% of cases, relative death rate 1.00, median survival 6.2 yr). This modified staging system applied successfully to both old and young patients (more and less than 60 yr old, respectively).     

Chemoimmunotherapy of chronic lymphocytic leukemia

The past two decades have seen a major paradigm shift in the therapy of chronic lymphocytic leukemia (CLL), with the treatment goal shifting from symptom palliation to the attainment of maximal disease control using the most effective frontline regimens available, thus prolonging survival and possibly leading to cure. The most potent therapeutic regimens developed to date include the chemoimmunotherapy combinations incorporating purine analogs and monoclonal antibodies. We review the evolution of modern chemoimmunotherapy for CLL, and discuss current research directions for further refining the potency of these regimens.     

Immunobiology of chronic lymphocytic leukemia

B-cell chronic lymphocytic leukemia increasingly is being recognized as a useful model disease with which to study more general processes involved in the evolution of neoplastic disease. The accessibility of the tumor cells and the capacity to confirm their clonal relatedness allow for evaluation of the processes associated with neoplastic transformation and/or disease progression. Recent studies have provided fascinating insight into the potential pathogenesis and pathophysiology of this disease. In addition, features of leukemia cells have been identified that can distinguish subsets of patients that have different tendencies for disease progression. Gene expression studies have identified a relatively small number of genes that are differentially expressed between these subsets, allowing for focused attention on proteins that might contribute to the noted differences in clinical behavior. Finally, recognition that chronic lymphocytic leukemia cells depend upon specific microenvironmental growth and survival factors identifies novel targets for disease intervention. This article focuses on the reports of the past year that have contributed to these areas of active research on chronic lymphocytic leukemia, the most common adult leukemia in Western societies.     

Biology of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clonal proliferation of mature-appearing, but maturationally immature B cells; T cells are rarely involved. Most data suggest that CLL cells are frozen at an early step in maturation; this can be overcome by several techniques such as in vitro incubation with tumor promotors. Although B-CLL involves B cells, and abnormal T cell function is common, its etiology is uncertain. Oncogene abnormalities and retroviral infection have been reported in rare cases of CLL; their role in more typical cases is unknown.     

Sleep-disordered breathing and hypertension among African Americans

This study investigated differences in sleep-disordered breathing (SDB) between hypertensives without a family history of hypertension and hypertensives with a family history. Furthermore, it examined whether these two groups differed in the severity of SDB. Patients were African Americans (n=162, mean age=51.19+/-13.77 years; mean body mass index (BMI)=37.85+/-9.51 kg/m2, male=57%), who were referred to the clinic because of a sleep complaint. Sleep was recorded in the laboratory using standard physiological parameters; all parameters were analysed by a trained scorer. Altogether, 91% of the patients received an SDB diagnosis. Of these patients, 25% were hypertensives without a family history, 20% were hypertensives with a family history, and 55% were normotensives. We found a significant difference between these patient groups regarding the severity of SDB (F14,158=1.823, P<0.05), but no significant group difference was observed in the rate of SDB. Increasing weight was accompanied by increasing severity of SDB. The finding that hypertensive patients with or without a positive family history showed worse oxygenation and respiratory characteristics than did normotensives is consistent with previous research. Of note, hypertensives reporting a family history were characterized by a greater number of oxygen desaturations and apnoea hypopnoea index than those typified only by a current diagnosis of hypertension. Hypertensives with a family history are likely to show a profile of greater blood pressure, higher BMI, and more severe SDB, which by all accounts are more common among African Americans.