Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP. A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed. Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients. Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations. DNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed. DNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10−4 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035). Our results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.

UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver. UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated. After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379–0.737, P = 1.7 × 10−4) and better overall survival (HR = 0.787, 95% CI 0.627–0.990, P = 0.040) as compared with homozygotes for both polymorphisms. Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

TEA domain family members (TEADs) play important roles in tumor progression. Till now, the genomic status of TEADs in patients with glioma has not been well investigated. To confirm whether the genomic status of TEADs could affect the prognosis of patients with glioma, the copy number variation (CNV), mutation and expression data of glioma cohorts in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas were comprehensively analyzed. Results showed that TEAD CNV frequency in lower grade gliomas (LGGs) was higher than in glioblastoma multiforme (GBM). Multivariate cox regression analysis showed that TEAD4 CNV increase was significantly associated with overall survival (OS) and disease-free survival (DFS) in LGGs (OS p = 0.022, HR = 1.444, 95% CI: 1.054–1.978; DFS p = 0.005, HR = 1.485, 95% CI: 1.124–1.962), while not in GBM. Patients with TEAD4 CNV increase showed higher expression level of TEAD4 gene. In LGG patients with IDH mutation, those with higher TEAD4 expression levels had shorter OS and DFS. Integrating TEAD4 CNV increase, IDH mutations, TP53 mutation, ATRX mutation and 1p19q co-deletion would separate patients with LGG into four groups with significant differences in prognosis. These study results suggested that TEAD4 variations were independent predictive biomarkers for the prognosis in patients with LGG with IDH mutation.

Aim: To confirm whether the expression level of Fn14 could affect progression or prognosis of glioma patients. Methods: Glioma cohorts in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas databases were comprehensively analyzed. Results: Low-grade patients had lower expression level of Fn14, while patients with higher expression of Fn14 tended to harbor shorter overall survival and disease-free survival. The expression level of Fn14 was downregulated by IDH1/IDH2 mutations while its gene body methylation was upregulated. After adjusting age, the expression level of Fn14 was still significantly associated with overall survival and disease-free survival in low-grade gliomas. In a cell line data analysis, Fn14 expression was positively correlated with temozolomide dosage. Conclusion: Fn14 was an independent predictive biomarker for the progression and prognosis in low-grade gliomas.

Tobacco smoking is associated with increased risks of nearly 20 types of cancer. Although the association between smoking and gliomas, the most prevalent type of adult brain tumor, is still unconclusive, here, we found that the frequency of NF1 mutations was significantly increased in the glioma patients with smoking history compared to non-smoking patients (24% vs. 10%, P = 0.021). NF1 acts as a tumor suppressor gene is highly mutated in gliomas. The TCGA data analysis indicated that glioma patients carrying NF1 somatic mutations have worse overall survival (median survival time: smoking 19.9 months vs. non-smoking 36.8 month; P = 0.0018). In addition, we revealed that the NF1 and IDH1 mutations were mutually exclusive suggesting NF1 mutation has independent molecular mechanism involved in glioma biology.