Muscle RAS oncogene homolog (MRAS) recurrent mutation in Borrmann type IV gastric cancer

Abstract

The prognosis of patients with Borrmann type IV gastric cancer (Type IV) is extremely poor. Thus, there is an urgent need to elucidate the molecular mechanisms underlying the oncogenesis of Type IV and to identify new therapeutic targets. Although previous studies using whole-exome and whole-genome sequencing have elucidated genomic alterations in gastric cancer, none has focused on comprehensive genetic analysis of Type IV. To discover cancer-relevant genes in Type IV, we performed whole-exome sequencing and genome-wide copy number analysis on 13 patients with Type IV. Exome sequencing identified 178 somatic mutations in protein-coding sequences or at splice sites. Among the mutations, we found a mutation in muscle RAS oncogene homolog (MRAS), which is predicted to cause molecular dysfunction. MRAS belongs to the Ras subgroup of small G proteins, which includes the prototypic RAS oncogenes. We analyzed an additional 46 Type IV samples to investigate the frequency of MRAS mutation. There were eight nonsynonymous mutations (mutation frequency, 17%), showing that MRAS is recurrently mutated in Type IV. Copy number analysis identified six focal amplifications and one homozygous deletion, including insulin-like growth factor 1 receptor (IGF1R) amplification. The samples with IGF1R amplification had remarkably higher IGF1R mRNA and protein expression levels compared with the other samples. This is the first report of MRAS recurrent mutation in human tumor samples. Our results suggest that MRAS mutation and IGF1R amplification could drive tumorigenesis of Type IV and could be new therapeutic targets.

This is the first report of the genomic profile of Borrmann type IV gastric cancer. We found that muscle RAS oncogene homolog (MRAS) is recurrently mutated in Borrmann type IV gastric cancer. We also detected IGF1R gene amplification and that it was correlated with high levels of mRNA and protein expression.

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GPX3 methylation in bone marrow predicts adverse prognosis and leukemia transformation in myelodysplastic syndrome

Abstract

Epigenetic inactivation of GPX3 has been identified in various cancers including leukemia. Moreover, aberrant DNA methylation was also found as a dominant mechanism of disease progression in myelodysplastic syndrome (MDS). This study intended to explore GPX3 promoter methylation and its clinical relevance in 110 patients with MDS. GPX3 methylation was examined by real-time quantitative methylation-specific PCR (RQ-MSP) and bisulfite sequencing PCR (BSP). GPX3 methylation was identified in 15% (17/110) MDS patients, and significantly higher than controls, and lower than acute myeloid leukemia (AML) patients (P = 0.024 and 0.041). GPX3 methylated patients had older age and higher frequency of DNMT3A mutation (P = 0.015 and 0.066). Cases with GPX3 methylation showed significantly shorter overall survival (OS) time than those with GPX3 unmethylation analyzed with Kaplan–Meier analysis (P = 0.012). Moreover, Cox regression analysis revealed that GPX3 methylation might act as an independent prognostic indicator in MDS (HR = 1.847, P = 0.072). GPX3 methylation density was significantly increased during the progression from MDS to secondary acute myeloid leukemia (sAML) in three follow-up paired patients. Our study concludes that GPX3 methylation in bone marrow is associated with adverse prognosis and leukemia transformation in MDS.

GPX3 methylation was identified in 15% myelodysplastic syndrome (MDS) patients, and was associated with adverse prognosis. GPX3 methylation density was significantly increased during the progression from MDS to sAML in follow-up patients.

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DLL4 overexpression increases gastric cancer stem/progenitor cell self-renewal ability and correlates with poor clinical outcome via Notch-1 signaling pathway activation

Abstract

Gastric cancer is one of the most common malignant diseases, and poses a serious threat to the quality of human life. Gastric cancer stem/progenitor cells (GCSPCs) have critical effects on tumor formation, affecting specific features of self-renewal and differentiation and playing a critical role in metastasis. The Notch-1 pathway is crucially important to GCSPCs and is regulated by DLL4. In this study, DLL4 and Nestin levels were measured in 383 gastric cancer tissue samples by immunohistochemistry, and the clinico-pathological features of patients assessed. After DLL4 silencing in selected gastric cancer cell lines, the expression of GCSPC markers and colony formation ability were analyzed and the self-renewal and differentiation capacities of the cells were evaluated. The relationship between DLL4 levels and Notch-1 signaling pathway effector amounts was assessed via Western blotting and immunofluorescence. Finally, the tumor formation ability of the gastric cancer cells was evaluated with different levels of DLL4 and multiple cell densities in vivo. Our results indicate that DLL4 expression is associated with TNM stage and cancer metastasis, with high amounts of DLL4 leading to poor outcome. DLL4 silencing inhibited the self-renewal ability of GCSPCs and increased their multidifferentiation capacity, resulting in reduced GCSPC ratios. DLL4 knockdown also blocked the Notch-1 pathway, weakening invasion ability and resistance to 5-FU chemotherapy. In vivo, DLL4 silencing inhibited the tumor formation ability of GCSPCs. In conclusion, DLL4 affects GCSPC stemness, altering their pathological behavior. DLL4 silencing inhibits GCSPC metastatic potential both in vitro and in vivo by impeding Notch-1 signaling pathway activation, indicating that DLL4 may be a new potential therapeutic target.

DLL4 expression is associated with TNM stage and cancer metastasis, with high amounts of DLL4 leading to poor outcome. DLL4 silencing inhibited the self-renewal ability of GCSPCs and increased their multidifferentiation capacity, resulting in reduced GCSPC ratios. DLL4 knockdown also blocked the Notch-1 pathway, weakening invasion ability, and resistance to 5-FU chemotherapy.

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Marijuana use and inpatient outcomes among hospitalized patients: analysis of the nationwide inpatient sample database

Abstract

The purpose of this paper is to examine the relationship between marijuana use and health outcomes among hospitalized patients, including those hospitalized with a diagnosis of cancer. A total of 387,608 current marijuana users were identified based on ICD-9 codes for marijuana use among hospitalized patients in the Nationwide Inpatient Sample database between 2007 and 2011. Logistic regression analysis was performed to determine the association between marijuana use and heart failure, cardiac disease, stroke, and in-hospital mortality. All models were adjusted for age, gender, race, residential income, insurance, residential region, pain, and number of comorbidities. Among hospitalized patients, marijuana use was associated with a 60% increased odds of stroke (OR: 1.60, 95% CI: 1.44–1.77) compared with non-users, but significantly reduced odds of heart failure (OR: 0.78, 95% CI: 0.75–0.82), cardiac disease (OR: 0.86, 95% CI: 0.82–0.91), or in-hospital mortality (OR: 0.41, 95% CI: 0.38–0.44). Among cancer patients, odds of in-hospital mortality was significantly reduced among marijuana users compared with non-users (OR: 0.44, 95% CI: 0.35–0.55). Hospitalized marijuana users were more likely to experience a stroke compared with non-users, but less likely to experience in-hospital mortality. Prospective studies will be needed to better characterize the health effects of marijuana use, especially among older, sicker, and/or hospitalized patients. In the meantime, conversations regarding marijuana use/misuse may be warranted in the clinical setting in order for patients and healthcare providers to adequately weigh the anticipated benefits of marijuana use with potentially significant health risks.

In view of the rapidly increased use of marijuana in the general population. There is significant interest in examining the health effects of marijuana use among adults in general, but more importantly among those with health conditions or chronic diseases. In this study we examined the relationships between marijuana use and health outcomes among hospitalized patients, including hospitalized patients with and without a diagnosis of cancer.

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Does radiotherapy still have a role in unresected biliary tract cancer?

Abstract

The benefits of radiotherapy for inoperable biliary tract cancer remain unclear due to the lack of randomized data. We evaluated the impact of radiotherapy on survival in elderly patients using the SEER-Medicare database. Patients in the SEER-Medicare database with inoperable biliary tract tumors diagnosed between 1998 and 2011 were included. We used multivariate logistic regression to evaluate factors associated with treatment selection, and multivariate Cox regression and propensity score matching to evaluate treatment selection in relation to subsequent survival. Of the 2343 patients included, 451 (19%) received radiotherapy within 4 months of diagnosis. The use of radiotherapy declined over time, and was influenced by receipt of chemotherapy and patient age, race, marital status, poverty status, and tumor stage and type. Median survival was 9.3 (95% CI 8.7–9.7) months among patients who did not receive radiation and 10.0 (95% CI 9.1–11.3) months among those who received radiation, conditional on having survived 4 months. In patients who received chemotherapy (n = 1053), receipt of radiation was associated with improved survival, with an adjusted hazard ratio of 0.82 (95% 0.70–0.97, P = 0.02). In patients who did not receive chemotherapy (n = 1290), receipt of radiation was not associated with improved survival, with an adjusted hazard ratio of 1.09 (95% 0.91–1.30, P = 0.34). Propensity-scored matched analyses showed similar results. Despite the survival benefit associated with the addition of radiotherapy to chemotherapy, the use of radiation for unresectable biliary tract cancers has declined over time.

The benefits of radiotherapy for elderly patients with inoperable biliary tract cancer remain unclear due to the lack of randomized data given the rarity of this cancer. Using the SEER-Medicare database, we found that the use of radiotherapy has declined over time, and is influenced by tumor, patient, and socioeconomic factors, and that any survival benefit with radiotherapy is confined to those patients who received concurrent chemotherapy.

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Quantitative T1-mapping detects cloudy-enhancing tumor compartments predicting outcome of patients with glioblastoma

Abstract

Contrast enhancement of glioblastomas (GBM) is caused by the decrease in relaxation time, T1. Here, we demonstrate that the quantitative measurement of T1 (qT1) discovers a subtle enhancement in GBM patients that is invisible in standard MRI. We assessed the volume change of this "cloudy" enhancement during radio-chemotherapy and its impact on patients' progression-free survival (PFS). We enrolled 18 GBM patients in this observational, prospective cohort study and measured 3T-MRI pre- and post contrast agent with standard T1-weighted (T1w) and with sequences to quantify T1 before radiation, and at 6-week intervals during radio-chemotherapy. We measured contrast enhancement by subtracting pre from post contrast contrast images, yielding relative signal increase ∆T1w and relative T1 shortening ∆qT1. On ∆qT1, we identified a solid and a cloudy-enhancing compartment and evaluated the impact of their therapy-related volume change upon PFS. In ∆qT1 maps cloudy-enhancing compartments were found in all but two patients at baseline and in all patients during therapy. The qT1 decrease in the cloudy-enhancing compartment post contrast was 21.64% versus 1.96% in the contralateral control tissue (P < 0.001). It was located at the margin of solid enhancement which was also seen on T1w. In contrast, the cloudy-enhancing compartment was visually undetectable on ∆T1w. A volume decrease of more than 21.4% of the cloudy-enhancing compartment at first follow-up predicted longer PFS (P = 0.038). Cloudy-enhancing compartment outside the solid contrast-enhancing area of GBM is a new observation which is only visually detectable with qT1-mapping and may represent tumor infiltration. Its early volume decrease predicts a longer PFS in GBM patients during standard radio-chemotherapy.

Quantitative T1 subtraction maps uncover a cloudy-enhancing compartment that is not detected in conventional MRI and has prognostic value for patients with glioblastoma.

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Muscle RAS oncogene homolog (MRAS) recurrent mutation in Borrmann type IV gastric cancer

Abstract

The prognosis of patients with Borrmann type IV gastric cancer (Type IV) is extremely poor. Thus, there is an urgent need to elucidate the molecular mechanisms underlying the oncogenesis of Type IV and to identify new therapeutic targets. Although previous studies using whole-exome and whole-genome sequencing have elucidated genomic alterations in gastric cancer, none has focused on comprehensive genetic analysis of Type IV. To discover cancer-relevant genes in Type IV, we performed whole-exome sequencing and genome-wide copy number analysis on 13 patients with Type IV. Exome sequencing identified 178 somatic mutations in protein-coding sequences or at splice sites. Among the mutations, we found a mutation in muscle RAS oncogene homolog (MRAS), which is predicted to cause molecular dysfunction. MRAS belongs to the Ras subgroup of small G proteins, which includes the prototypic RAS oncogenes. We analyzed an additional 46 Type IV samples to investigate the frequency of MRAS mutation. There were eight nonsynonymous mutations (mutation frequency, 17%), showing that MRAS is recurrently mutated in Type IV. Copy number analysis identified six focal amplifications and one homozygous deletion, including insulin-like growth factor 1 receptor (IGF1R) amplification. The samples with IGF1R amplification had remarkably higher IGF1R mRNA and protein expression levels compared with the other samples. This is the first report of MRAS recurrent mutation in human tumor samples. Our results suggest that MRAS mutation and IGF1R amplification could drive tumorigenesis of Type IV and could be new therapeutic targets.

This is the first report of the genomic profile of Borrmann type IV gastric cancer. We found that muscle RAS oncogene homolog (MRAS) is recurrently mutated in Borrmann type IV gastric cancer. We also detected IGF1R gene amplification and that it was correlated with high levels of mRNA and protein expression.

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