Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk

Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes - in subjects carrying simultaneously deviations from the common genotype in more than one gene - were over-represented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations of CYP1A1, GSTM1 and GSTT1 alleles in the development of lung cancer in heavy smokers

The Von Hippel-Lindau (VHL) tumor-suppressor gene is not mutated in sporadic human colon adenocarcinomas

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome, where the affected kindreds manifest multiple tumors, mainly of the central nervous system, renal and pancreatic tissue (Maher and Kaelin, 1997). The gene responsible for the disorder is a tumor-suppressor gene (Latif et al., 1993). Numerous germline mutations of VHL gene have been identified among families with various patterns of disease phenotypes (Zbar et al., 1996). Mutations of VHL, as well as allelic loss at the gene locus 3p25-26, have been repeatedly described in series from sporadic cases of the tumor types involved in VHL disease (Bailly et al., 1995; Lee et al., 1998). Frequent detection of somatic mutations of the gene in renal clear cell carcinoma (Gnarra et al., 1994; Foster et al., 1994; Shuin et al., 1994) and central nervous system hemangioblastomas (Kanno et al., 1994) provides evidence that these events are critical to the pathogenesis of such tumor types. This was further enhanced by the recent association of carcinogen exposure with specific VHL mutations in renal cell carcinoma (Brauch et al., 1999)

Beta-2 glycoprotein1: function in health and disease

Beta-2 glycoprotein I (β2GPI) is the principal target of autoantibodies in the antiphospholipid syndrome (APS). It is abundant in human plasma and shares high homology between different mammalian species. Although the exact physiological function of β2GPI has not been fully elucidated, several interactions have been described with other proteins and with negatively charged surfaces, such as anionic phospholipids, dextran and heparin. β2GPI is involved in the coagulation pathway, exerting both procoagulant and anticoagulant activities. Plasma from β2GPI-deficient mice exhibits impaired thrombin generation in vitro. Recently, it has been demonstrated that β2GPI binds factor (F) XI in vitro at concentrations lower than those of the protein in human plasma, and this binding inhibits FXI activation to FXIa by thrombin and FXIIa. Proteolytic cleavage of the fifth domain of β2GPI abolishes its inhibition of FXI activation and results in reduced ability of the cleaved β2GPI to bind phospholipids. It retains its ability to bind FXI. In vivo activation of FXI by thrombin is thought to be an important mechanism by which coagulation is accelerated via components of the contact activation pathway. Thus β2GPI may attenuate the contact activation pathway by inhibiting activation of FXI by thrombin. Moreover, because β2GPI is the dominant autoantigen in patients with APS, dysregulation of this pathway by autoantibodies may be an important mechanism for thrombosis in patients with APS

Beta-2 glycoprotein I and its role in antiphospholipid syndrome: lessons from knockout mice

The antiphospholipid syndrome is characterized by the presence in serum of autoantibodies against h2GPI. Although the role of h2GPI in the pathogenesis of antiphospholipid antibody syndrome (APS) is well recognized, its exact physiological functions still remain undisclosed. Several interactions of h2GPI with components of the coagulation cascade have been proposed, resulting in both procoagulant and anticoagulant effects. Additionally, h2GPI has been implicated in the mechanism of recurrent fetal loss entailed in APS. Recently, using a homologous recombination approach, reproduction of mice homozygous for deletion of the b2GPI gene has been feasible. h2GPI knockout mice offer a valuable tool for revealing the physiological role of the protein. These mice show decreased in vitro ability for thrombin generation. Furthermore, although mice lacking h2GPI are fertile, the success of early pregnancy is moderately compromised and functional h2GPI is believed necessary for optimal implantation and placental morphogenesis

Allelic loss in breast cancer

Breast cancer is the most prevalent cancer type in women and allelic loss constitutes one of the commonest genetic alterations in mammary neoplasias. Frequent detection of Loss of Heterozygosity indicates genes with putative tumour suppressor activity in breast carcinomas. Imbalance between two alleles might also be related with increased expression of an oncogene within a locus. Loci exhibiting frequent allelic loss in breast cancer have been detected, spread throughout the genome, and may contain genes with potential significance in breast carcinogenesis. Loss of Heterozygosity patterns in breast cancer give evidence for multiple clonality of the disease, and that accumulation of such lesions is probably implicated in disease development. Studies on deletions of known breast cancer genes suggest interactions with other common genetic events during disease initiation and progression. Allelic loss has been repeatedly associated with adverse characteristics and poor outcome in breast neoplasms. Detection of allelic loss in the serum of breast cancer patients and in premalignant breast lesions could herald the potential for diagnosis of the disease at an early, and thus curable, stage

Differential expression and mutation of the ras family genes in human breast cancer

The expression of ras mRNA levels in 27 human sporadic breast cancer specimens was examined, and compared to the corresponding adjacent normal tissue using the RT-PCR technique. Eighteen out of the 27 specimens (67%) exhibited two- to four-fold increased expression of ras mRNA levels, compared to corresponding normal tissue. The rates of augmented mRNA expression were similar among the three ras genes. A statistically significant correlation of overexpression of ras genes in specimens classified as Stage I disease was observed, compared to tumors in a more advanced stage (II or III). The incidence of codon 12 point mutations of the K-ras gene in fresh tissue samples was also assessed in 61 human sporadic breast cancer cases. Point mutations were detected in four (6.5%) out of the 61 cases examined; no correlation was found with any clinicopathological parameter. This is the first report to our knowledge of the differential expression of the ras family genes in breast carcinoma. Our findings indicate that the aberrant expression of ras genes may be an initial event in breast cancer oncogenesis and that K-ras point mutations are rarely involved in the development of mammary neoplasias

Lymphoma presenting as chronic aortic dissection in Marfan syndrome

Dear Editor, An 18-year-old man with Marfan syndrome (MFS) fainted after experiencing retrosternal pain and was brought to the emergency department. Conscious upon admission, he reported that he had been experiencing this pain intermittently (but not so intensely) for approximately 2 months while feeling debilitated. MFS had been diagnosed during infancy due to skeletal abnormalities, subluxation of the lenses and positive family history

Serial serum procalcitonin changes in the prognosis of acute stroke

Inflammatory response is a principal early component in the pathophysiology of stroke [1]. Serum procalcitonin (PCT)-a marker of septicemia and infection severity [2]-has also been proposed as an indicator of systemic inflammatory response in noninfectious situations [3,4]. As no data exist thus far on PCT in stroke, this study aimed to evaluate serum PCT changes in the acute stroke setting, and to correlate them with clinical and laboratory parameters and patient\u27s outcome

The burden of the rheumatic diseases in the general adult population of Greece: the ESORDIG study

OBJECTIVE: To estimate the burden of rheumatic diseases in terms of disability and health-care utilization in the Greek general adult population. METHODS: The study was conducted on the total adult population of seven communities (8547 subjects), as well as on 2100 out of 5686 randomly selected subjects in an additional two communities. Rheumatologists visited the participants at their homes to assess the prevalence of six morbidity indicators concerning disability and health-care utilization associated with rheumatic diseases or other major disease groups. RESULTS: The participation rate in the study was 82.1%. The prevalence of chronic health problems, long-term disability, short-term disability, physician office visits and prescription or non-prescription drug use due to rheumatic diseases in the total target adult population was 14.3, 4.3, 2.9, 2.8, 7.2 and 2.0%, respectively. Compared with all other major disease groups, rheumatic diseases were the most common cause of chronic health problems (38.7%), long-term disability (47.2%), short-term disability (26.2%) and physician office visits (20.5%), while they ranked second for the use of prescription (24.0%) or non-prescription drugs (17.7%). Rheumatic diseases were the main cause of morbidity in five out of six indicators in subjects aged \u3c or =65 yr. Logistic regression analysis revealed an association of female gender, age \u3e or =45 yr and obesity with almost all morbidity indicators related to rheumatic diseases. CONCLUSION: These findings suggest that rheumatic diseases constitute a major public health problem and should be considered in planning undergraduate and postgraduate medical education, research and health-care services