Integrated Multi-omic Analysis of Esthesioneuroblastomas Identifies Two Subgroups Linked to Cell Ontogeny.

Esthesioneuroblastoma (ENB) is a rare cancer of the olfactory mucosa, with no established molecular stratification to date. We report similarities of ENB with tumors arising in the neural crest and perform integrative analysis of these tumors. We propose a molecular-based subtype classification of ENB as basal or neural, both of which have distinct pathological, transcriptomic, proteomic, and immune features. Among the basal subtype, we uncovered an IDH2 R172 mutant-enriched subgroup (∼35%) harboring a CpG island methylator phenotype reminiscent of IDH2 mutant gliomas. Compared with the basal ENB methylome, the neural ENB methylome shows genome-wide reprogramming with loss of DNA methylation at the enhancers of axonal guidance genes. Our study reveals insights into the molecular pathogenesis of ENB and provides classification information of potential therapeutic relevance.

Expression of long non-coding RNA MFI2-AS1 is a strong predictor of recurrence in sporadic localized clear-cell renal cell carcinoma.

Prediction of recurrence is a challenge for the development of adjuvant treatments in clear-cell renal cell carcinoma (ccRCC). In these tumors, expression of long non-coding RNAs (lncRNAs) are deregulated and closely associated with prognosis. Thus, we aimed to predict ccRCC recurrence risk using lncRNA expression. We identified prognostic lncRNAs in a training set of 351 localized ccRCCs from The Cancer Genome Atlas and validated lncRNA-based recurrence classification in an independent cohort of 167 localized ccRCCs. We identified lncRNA MFI2-AS1 as best candidate in the training set. In the validation cohort, MFI2-AS1 expression was independently associated with shorter disease-free survival (Hazard Ratio (HR) for relapse 3.5, p = 0.0001). Combined with Leibovich classification, MFI2-AS1 status improved prediction of recurrence (C-index 0.70) compared to MFI2-AS1 alone (0.67) and Leibovich classification alone (0.66). In patients with aggressive tumors (Leibovich ≥5), MFI2-AS1 expression was associated with dramatically increased risk of relapse (HR 12.16, p < 0.0001) compared to patients with undetectable MFI2-AS1 who had favorable outcomes. Compared to normal samples, MFI2-AS1 was upregulated in tumor tissue, and higher expression was associated with metastatic dissemination. Overall, MFI2-AS1 status improves patient stratification in localized ccRCC, which supports further integration of lncRNAs in molecular cancer classifications.

NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas.

Extensive dysregulation of chromatin-modifying genes in clear cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the cross-talk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear cell CpG island methylator phenotype (C-CIMP) subgroup associated with promoter methylation of VEGF genes (FLT4, FLT1, and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the histone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets. NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of NSD1 displayed a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome. Thus, we concluded that epigenetic silencing of genes involved in angiogenesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss of function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC. Cancer Res; 77(18); 4835-45. ©2017 AACR.

Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis.

CONTEXT: Despite dual antiplatelet therapy, stent thrombosis remains a devastating and unpredictable complication of percutaneous coronary intervention (PCI). OBJECTIVE: To perform a sequential analysis of clinical and genetic factors associated with definite early stent thrombosis. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted in 10 centers in France between January 2007 and May 2010 among 123 patients undergoing PCI who had definite early stent thrombosis and DNA samples available, matched on age and sex with 246 stent thrombosis-free controls. MAIN OUTCOME MEASURE: Accuracy of early stent thrombosis prediction by 23 genetic variants. RESULTS: Among the 23 genetic variants investigated in 15 different genes, the significant determinants of early stent thrombosis were CYP2C19 metabolic status (adjusted odds ratio [OR], 1.99; 95% CI, 1.47-2.69), ABCB1 3435 TT genotype (adjusted OR, 2.16; 95% CI, 1.21-3.88), and ITGB3 PLA2 carriage (adjusted OR, 0.52; 95% CI, 0.28-0.95). Nongenetic independent correlates were acuteness of PCI (adjusted OR, 3.05; 95% CI, 1.54-6.07), complex lesions (American College of Cardiology/American Heart Association type C) (adjusted OR, 2.33; 95% CI, 1.40-3.89), left ventricular function less than 40% (adjusted OR, 2.25; 95% CI, 1.09-4.70), diabetes mellitus (adjusted OR, 1.82; 95% CI, 1.02-3.24), use of proton pump inhibitors (adjusted OR, 2.19; 95% CI, 1.29-3.75), and higher clopidogrel loading doses (adjusted OR, 0.73; 95% CI, 0.57-0.93). The discriminative accuracy of the clinical-only model was similar to that of a genetic-only model (area under the curve, 0.73 [95% CI, 0.67-0.78] vs 0.68 [95% CI, 0.62-0.74], respectively; P = .34). A combined clinical and genetic model led to a statistically significant increase in the discriminatory power of the model compared with the clinical-only model (area under the curve, 0.78 [95% CI, 0.73-0.83] vs 0.73 [95% CI, 0.67-0.78]; P = .004). CONCLUSIONS: This case-control study identified 3 genes (CYP2C19, ABCB1, and ITGB3) and 2 clopidogrel-related factors (loading dose and proton pump inhibitors) that were independently associated with early stent thrombosis. Future studies are needed to validate the prognostic accuracy of these risk factors in prospective cohorts.

CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients.

BACKGROUND: Reduced concentrations of clopidogrel active metabolite have been associated with diminished platelet inhibition and higher rates of adverse cardiovascular events. Paraoxonase-1 (PON1) has recently been proposed as a key enzyme for clopidogrel metabolic activation. We tested the effects of PON1 polymorphisms on clopidogrel pharmacokinetics and pharmacodynamics and the occurrence of cardiovascular outcomes in young post-myocardial infarction (MI) patients treated with clopidogrel. METHODS AND RESULTS: We genotyped PON1 (Q192R and L55M) and CYP2C19 variants in 106 patients enrolled in the PK/PD CLOVIS-2 trial. Patients were randomly exposed to a 300-mg or 900-mg clopidogrel loading dose in a crossover study design. Clopidogrel active metabolite isomer H4 (clopi-H4) and platelet function testing were measured serially after loading dose. There was no significant association between PON1 Q192R or L55M and clopi-H4 formation or antiplatelet response to clopidogrel after either loading dose. Using multivariable linear regression analyses, the CYP2C19*2 allele was the only predictor of clopi-H4 generation and platelet response irrespective of the platelet function assay. CYP2C19 loss-of-function but not PON1 variants were significantly associated with increased risk of major cardiovascular events (death, MI, and urgent coronary revascularization) occurring during long-term clopidogrel exposure in 371 young post-MI patients (age <45 years) enrolled in the AFIJI cohort (CYP2C19 loss-of-function allele carrier versus noncarrier: hazard ratio, 2.26; 95% confidence interval, 1.15-4.41, P=0.02; PON1 QQ192 versus QR/RR192: hazard ratio, 1.03; 95% confidence interval, 0.50-2.11, P=0.93; PON1 LL55 versus LM/MM55: hazard ratio, 1.52; 95% confidence interval, 0.75-3.08, P=0.24). CONCLUSIONS: Our study does not confirm that PON1 Q192R or L55M can influence clopidogrel pharmacokinetics or pharmacodynamics in post-MI patients.