Two novel genetic variants in the STK38L and RAB27A genes are associated with glioma susceptibility

Glioma is the most common malignant primary brain tumors with poor prognosis. Genome wide association studies (GWAS) of glioma in populations with Western European ancestry were completed in the US and UK. However, our previous results strongly suggest the genetic heterogeneity could be important in glioma risk. To systematically investigate glioma risk–associated variants in Chinese population, we performed a multistage GWAS of glioma in the Han Chinese population, with a total of 3,097 glioma cases and 4,362 controls. In addition to confirming two associations reported in other ancestry groups, this study identified one new risk-associated locus for glioma on chromosome 12p11.23 (rs10842893, p_meta = 2.33x10-12, STK38L) as well as a promising association at 15q15-21.1 (rs4774756, p_meta = 6.12x10-8, RAB27A) in 3,097 glioma cases and 4,362 controls. Our findings demonstrate two novel association between the glioma risk region marked by variant rs10842893 and rs4774756) and glioma risk. These findings may advance the understanding of genetic susceptibility to glioma.     

Exome-Wide Association Study Identifies Low-Frequency Coding Variants in 2p23.2 and 7p11.2 Associated with Survival of Non–Small Cell Lung Cancer Patients

IntroductionA growing body of evidence has suggested that low-frequency or rare coding variants might have strong effects on the development and prognosis of cancer. Here, we aim to assess the role of low-frequency and rare coding variants in the survival of NSCLC in Chinese populations.MethodsWe performed an exome-wide scan of 247,870 variants in 1008 patients with NSCLC and replicated the promising variants by using imputed genotype data of The Cancer Genome Atlas (TCGA) with a Cox regression model. Gene-based and pathway-based analysis were also performed for nonsynonymous or splice site variants. Additionally, analysis of gene expression data in the TCGA was used to increase the reliability of candidate loci and genes.ResultsA low-frequency missense variant in chaperonin containing TCP1 subunit 6A gene (CCT6A) (rs33922584: adjusted hazard ratio [HR_adjusted] = 1.75, p = 6.06 × 10^-4) was significantly related to the survival of patients with NSCLC, which was further replicated by the TCGA samples (HR_adjusted = 4.19, p = 0.015). Interestingly, the G allele of rs33922584 was significantly associated with high expression of CCT6A (p = 0.019) that might induce the worse survival in the TCGA samples (HR_adjusted = 1.15, p = 0.047). Besides, rs117512489 in gene phospholipase B1 gene (PLB1) (HR = 2.02, p = 7.28 × 10^-4) was also associated with survival of the patients with NSCLC in our samples, but it was supported only by gene expression analysis in the TCGA (HR_adjusted = 1.15, p = 0.023). Gene-based and pathway-based analysis revealed a total of 32 genes, including CCT6A and 34 potential pathways might account for the survival of NSCLC, respectively.ConclusionThese results provided more evidence for the important role of low-frequency or rare variants in the survival of patients with NSCLC.     

Données actuelles sur la toxicité de l’oxygène

Oxygen, as a molecule, is inert towards living bodies despite its biradical structure, and enzymatic activities are necessary for its utilisation by aerobic organisms. In vivo, oxidative species can be produced from the superoxide anion, and generate cellular and tissular injury. Under 100 % FiO₂, death occurs within 100 hours. Cellular lesions start at the endothelial level and are followed by alveolar cell damage. Adaptive phenomena to hyperoxia exist, characterised by an increased activity of antioxidant enzymes. In patients with respiratory failure, high levels of FiO₂ are frequently used for prolonged periods without obvious visible toxicity. This paradoxical observation could be explained by the lack of partial pressure rise in the arterial blood, while the alveolar cells are more prone to resist hyperoxia. The underlying lung injury can also mask the toxic effects of oxygen. The use of high FiO₂ in the critically ill patient might therefore be limited in time.     

A polymorphism in miR‐1262 regulatory region confers the risk of lung cancer in Chinese population

It has been proposed that the majority of disease‐associated loci identified by genome‐wide association studies (GWAS) are enriched in non‐coding regions, such as the promoter, enhancer or non‐coding RNA genes. Thus, we performed a two‐stage case‐control study to systematically evaluate the association of genetic variants in miRNA regulatory regions (promoter and enhancer) with lung cancer risk in 7,763 subjects (discovery stage: 2,331 cases and 3,077 controls; validation stage: 1,065 cases and 1,290 controls). As a result, we identified that rs12740674 (C > T) in miR‐1262 enhancer was significantly associated with the increased risk of lung cancer (additive model in discovery stage: adjusted OR = 1.31, 95%CI = 1.13–1.53, p = 3.846 × 10^?4 in Nanjing GWAS; adjusted OR = 1.20, 95%CI = 1.00–1.44, p = 0.041 in Beijing GWAS; validation stage: adjusted OR = 1.20, 95%CI = 1.03–1.41, p = 0.024). In meta‐analysis, the p value for the association between rs12740674 and lung cancer risk reached 6.204 × 10^?6 (adjusted OR = 1.24, 95%CI = 1.13–1.36). Using 3DSNP database, The Cancer Genome Atlas (TCGA) data and functional assays, we observed that the risk T allele of rs12740674 reduced the expression level of miR‐1262 in lung tissue through chromosomal looping, and overexpression of miR‐1262 inhibited lung cancer cell proliferation probably through targeting the expression levels of ULK1 and RAB3D . Our findings confirmed the important role that genetic variants of noncoding sequence play in lung cancer susceptibility and indicated that rs12740674 in miR‐1262 may be biologically relevant to lung carcinogenesis.     

Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population

Genome‐wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. We evaluated the genetic variants at 9p21.3 reported in cancer genome‐wide association studies with a case–control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B, and CDKN2B‐AS1 in paired ESCC tumor and adjacent normal tissues. We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per‐allele odds ratio of 0.84 (95% confidence interval, 0.77–0.91; P = 2.95 × 10^?5). The rs7023329‐G allele was related to a high expression of MTAP (P = 0.020). The rs1679013‐C allele was independently associated with an increased risk of ESCC with a per‐allele odds ratio of 1.12 (95% confidence interval, 1.01–1.24; P = 0.039). We also found that the carriers of the risk allele rs1679013‐C had lower expression of CDKN2B than non‐carriers (P = 0.035). CDKN2B was also significantly downregulated in ESCC tumor tissues compared with adjacent normal tissues (P = 3.50×10^?5). Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility. This may further advance our understanding of the 9p21.3 locus in cancer development.     

Obesity and Cancer Treatment Outcomes: Interpreting the Complex Evidence

A wealth of epidemiological evidence, combined with plausible biological mechanisms, present a convincing argument for a causal relationship between excess adiposity, commonly approximated as body mass index (BMI, kg/m²), and incident cancer risk. Beyond this relationship, there are a number of challenges posed in the context of interpreting whether being overweight (BMI 25.0–29.9 kg/m²) or obese (BMI ≥ 30.0 kg/m²) adversely influences disease progression, cancer mortality and survival. Elevated BMI (≥ 25.0 kg/m²) may influence treatment selection of, for example, the approach to surgery; the choice of chemotherapy dosing; the inclusion of patients into randomised clinical trials. Furthermore, the technical challenges posed by an elevated BMI may adversely affect surgical outcomes, for example, morbidity (increasing the risk of surgical site infections), reduced lymph node harvest (and subsequent risk of under-staging and under-treatment) and increased risk of margin positivity. Suboptimal chemotherapy dosing, associated with capping chemotherapy in obese patients as an attempt to avoid excess toxicity, might be a driver of poor prognostic outcomes. By contrast, the efficacy of immune checkpoint inhibition may be enhanced in patients who are obese, although in turn, this observation might be due to reverse causality. So, a central research question is whether being overweight or obese adversely affects outcomes either directly through effects of cancer biology or whether adverse outcomes are mediated through indirect pathways. A further dimension to this complex relationship is the obesity paradox, a phenomenon where being overweight or obese is associated with improved survival where the reverse is expected. In this overview, we describe a framework for evaluating methodological problems such as selection bias, confounding and reverse causality, which may contribute to spurious interpretations. Future studies will need to focus on prospective studies with well-considered methodology in order to improve the interpretation of causality.     

MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer

Tumor Biology - Hypoxia-inducible factor 2α (HIF2α) plays critical roles in cancer progression. Although the mechanisms of HIF2α translation and degradation have been well studied,...