Background: The FAS and FASL system plays a key role in regulating apoptotic cell death and corruption of this signalling pathway has been shown to participate in immune escape and tumorigenesis. There is reduced expression of FAS but elevated expression of FASL in many types of human cancers including lung cancer. We recently reported an association between functional polymorphisms in FAS (21377GRA) and FASL (2844TRC) and risk of oesophageal cancer. Objective: To examine the contribution of these polymorphisms to risk of developing lung cancer. Methods: Genotypes of 1000 lung cancer patients and 1270 controls were analysed by PCR based restriction fragment length polymorphism. Associations with risk of lung cancer were estimated by logistic regression. Results: Compared with non-carriers, there was a 1.6 fold excess risk of developing lung cancer for carriers of the FAS 21377AA genotype (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.21 to 2.10; p = 0.001), and 1.8 fold excess risk (OR 1.79, 95% CI 1.26 to 2.52; p = 0.001) for carriers of FASL 2844CC. Gene-gene interaction of FAS and FASL polymorphisms increased risk of lung cancer in a multiplicative manner (OR for the carriers of both FAS 21377AA and FASL 2844CC genotypes 4.18, 95% CI 2.83 to 6.18). Gene-environment interaction of FAS or FASL polymorphism and smoking associated with increased risk of lung cancer was also found. Conclusion: These results are consistent with our initial findings in oesophageal cancer and further support the hypothesis that the FAS and FASL triggered apoptosis pathway plays an important role in human carcinogenesis.

Dysregulation of hepcidin, a key iron regulating hormone, is important in the pathogenesis of iron overload in patients with myelodysplatic syndrome (MDS). However, most studies of hepcidin levels are complicated by concomitant RBC transfusions. To evaluate the relationship between iron metabolism and erythropoiesis, we measured serum levels of hepcidin, growth-differentiation factor-15 (GDF15) and other markers of erythropoiesis in 107 subjects with MDS not receiving RBC transfusions. Patients with MDS had significantly higher levels of hepcidin than normals. However, their hepcidin–ferritin ratio was markedly decreased compared to normals (P < 0.001) and varied substantially between MDS subtypes (P = 0.011). GDF15 levels positively correlated with percent of bone marrow erythroblasts (P < 0.001), soluble transferrin receptor (sTfR) (P = 0.018), and also with transferrin saturation (ISAT) (P = 0.038). The hepcidin–ferritin ratio negatively correlated with serum erythropoietin (EPO) levels (P < 0.001), and also with GDF15 levels (P = 0.014). Colony forming cells (CFC) were evaluated in 70 subjects. Those with serum ferritin (SF) levels <500 ng/ml had significantly more BFU-E than subjects with SF≥ 500 ng/L (P = 0.007), but numbers of granulocyte/macrophage-colony-forming cells (CFU-GM) were similar (P = 0.190). Our data indicate serum hepcidin levels are inappropriately low in patients MDS not receiving RBC transfusions. GDF15 levels correlated with low hepcidin levels and may contribute to iron overload in this setting. Iron overload may in turn suppress erythropoiesis by imparing the proliferative capacity of the erythroid progenitor cells.

U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty-six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P = .001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT-positive cases, whereas TP53MT, SF3B1MT, and complex karyotypes were inversely associated with U2AF1MT. U2AF subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower-risk and higher-risk MDS. U2AF1 subjects had more frequently platelet levels of <50 × 10 /L (P = .043) and U2AF1 /U2AF1 subjects had more frequently hemoglobin concentrations at <80 g/L (P = .008) and more often overt fibrosis (P = .049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics.

Recently, the Revised International Prognostic Scoring System (IPSS-R) has been developed for assessing the prognosis of primary myelodysplastic syndromes (MDS) and has shown satisfactory outcomes for prognostic stratification. In this new system, cytogenetics remains the key stratification parameter and karyotypic abnormalities are classified into five prognostic subgroups with more uncommon cytogenetic subsets. Using this system, we analyzed the cytogenetic features of 532 adult Chinese patients with primary MDS and assessed the impacts of the IPSS-R cytogenetic categories on the prognosis of the disease without intensive treatment. Here, we show that the cytogenetic features of this cohort of Chinese patients are different from those of previously reported Western populations with MDS. In our Chinese patients, trisomy 8 was the most common anomaly, and the incidence rate of del(5q) was lower than that in the Western population. In the IPSS-R cytogenetic subgroups, the median survival was 59 months for the good risk, 36 months for the intermediate risk, 15 months for the poor risk and 10 months for the very poor risk subgroups (p < 0.001). In conclusion, the IPSS-R can effectively stratify the prognosis of MDS based on cytogenetics, but the prognostic significances of some karyotypes in the IPSS-R still need to be confirmed by larger multicenter cooperative studies.