Citations

AbstractBackgroundAlthough the prognosis of core‐binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.MethodsEleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).ResultsComplete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease‐free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper‐ or hypodiploidy were included in a scoring system (named I‐CBFit). DFS rate at 2 years was 76% for patients with a low‐risk I‐CBFit score compared with 36% for those with a high‐risk I‐CBFit score (P < 0.0001). Low‐ vs high‐risk OS at 2 years was 89% vs 51% (P < 0.0001).ConclusionsI‐CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low‐risk I‐CBFit score).

Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P &lt; 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P &lt; 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Background Prognosis based on body fat percentage ( BF %) in patients with coronary artery disease has not been extensively studied. We tested the hypothesis that patients with coronary artery disease and increased BF % have a higher risk for major adverse cardiovascular events ( MACEs ) and that fat‐free mass is associated with better prognosis. Methods and Results We included 717 patients referred to cardiac rehabilitation after coronary artery disease events or procedures who underwent air displacement plethysmography to assess BF %; 75% were men, with a mean age 61.4±11.4 years and a mean body mass index of 30±5.4 kg/m 2 . Follow‐up was performed using a record linkage system. Patients were classified in sex‐specific quartiles of BF % and fat‐free mass index. The composite outcome of MACEs included acute coronary syndromes, coronary revascularization, stroke, or death from any cause. After a median follow‐up of 3.9 years, 201 patients had a MACE . After adjusting for covariates, body mass index was not associated with MACEs ( P =0.12). However, the risk of MACEs for those in the highest BF % quartile was nearly double when compared with those in the lowest quartile (hazard ratio, 1.89; 95% confidence interval, 1.30–2.77; P =0.0008). In contrast, fat‐free mass was inversely associated with MACEs . The risk of MACEs for those in the fourth fat‐free mass quartile was lower (adjusted hazard ratio, 0.53; 95% confidence interval, 0.35–0.82; P =0.004), when compared with those in the first quartile. Conclusions In patients with coronary artery disease, there is no obesity paradox when measuring BF % instead of body mass index. BF % is associated with a higher risk of MACEs , whereas fat‐free mass is associated with a lower risk of MACEs . Body mass index was not associated with MACEs .

Significance We describe the interaction between an intrinsically disordered protein (IDP), NUPR1, and the well-folded C-terminal region of RING1B protein of the Polycomb complex, involving residues Ala33 and Thr68 of the IDP. These observations are significant because they raise the possibility that NUPR1 aids the function of the members of the Polycomb complex, playing an active role in carcinogenesis.