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274


Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis

Richardson, Timothy E; Snuderl, Matija; Serrano, Jonathan; Karajannis, Matthias A; Heguy, Adriana; Oliver, Dwight; Raisanen, Jack M; Maher, Elizabeth A; Pan, Edward; Barnett, Samuel; Cai, Chunyu; Habib, Amyn A; Bachoo, Robert M; Hatanpaa, Kimmo J
According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.
PMID: 28421459
ISSN: 1573-7373
CID: 2532622

Loss of Plakophilin-2 expression causes alternative splicing misregulation. A new component in the molecular substrate of arrhythmogenic right ventricular cardiomyopathy (ARVC) [Meeting Abstract]

Montnach, J; Van, Opbergen C; Xianming, L; Zhang, M; Dolgalev, I; Heguy, A; Van, Veen T; Delmar, M; Cerrone, M
Background and Rationale: Mutations in Plakophilin-2 (PKP2) are the most common cause of ARVC, an inherited disease characterized by fibro- or fibrofatty infiltration of RV predominance, ventricular arrhythmias and sudden death in the young. The relation between PKP2 expression and the heart transcriptome in vivo, is unknown. Furthermore, while splicing misregulation has been associated with other inherited diseases, PKP2-dependent exon usage differences remain unexplored. We generated a murine line of cardiac-restricted, tamoxifen activated PKP2 deficiency ("PKP2-cKO") and defined PKP2- dependent exon usage in adult non-failing hearts. Methods and Results: The first disease manifestation was an increase in RV area, detected by echocardiography 14 days after tamoxifen injection (14 days post-injection or "dpi"), followed by marked RV dilation and reparative fibrosis (21 dpi), then bi-ventricular dilated cardiomyopathy (28 dpi), heart failure and death (30-50 dpi). To capture the earliest molecular events, hearts 14 dpi were used for RNAseq and exon usage. Comparing RV vs LV revealed minor changes in transcript abundance, but significant differences in alternative splicing (AS) program. We found ~75% of differentially spliced exons flanked by sequences that bind RBFox2, an RNA-binding protein that acts as central AS regulator of the adult heart, and that is necessary to maintain cardiac structure. Western blot analysis at 14 dpi and thereafter showed reduced abundance of RBFox2. RNAseq at 21 dpi showed that in addition to RBFox2, transcripts were reduced for RBFox1, MBNL1, MBNL2 and RBM20 (also molecules that control the AS program). Exon usage analysis at 21 dpi identified massive AS misregulation, similar to that of a failing heart, even though ejection fraction at this stage was ~50%. Misregulated genes included several involved in electrical rhythm and intracellular calcium homeostasis. Conclusion: We generated a model of PKP2-dependent ARVC. Our studies point to a previously unrecognized association between a desmosomal molecule, a splicing regulator, and the control of electrical and mechanical function. AS misregulation may be a substrate for sudden unexpected arrhythmic death in the young
EMBASE:617041340
ISSN: 1556-3871
CID: 2620942

Synthesis, debugging, and effects of synthetic chromosome consolidation: synVI and beyond

Mitchell, Leslie A; Wang, Ann; Stracquadanio, Giovanni; Kuang, Zheng; Wang, Xuya; Yang, Kun; Richardson, Sarah; Martin, J Andrew; Zhao, Yu; Walker, Roy; Luo, Yisha; Dai, Hongjiu; Dong, Kang; Tang, Zuojian; Yang, Yanling; Cai, Yizhi; Heguy, Adriana; Ueberheide, Beatrix; Fenyo, David; Dai, Junbiao; Bader, Joel S; Boeke, Jef D
We describe design, rapid assembly, and characterization of synthetic yeast Sc2.0 chromosome VI (synVI). A mitochondrial defect in the synVI strain mapped to synonymous coding changes within PRE4 (YFR050C), encoding an essential proteasome subunit; Sc2.0 coding changes reduced Pre4 protein accumulation by half. Completing Sc2.0 specifies consolidation of 16 synthetic chromosomes into a single strain. We investigated phenotypic, transcriptional, and proteomewide consequences of Sc2.0 chromosome consolidation in poly-synthetic strains. Another "bug" was discovered through proteomic analysis, associated with alteration of the HIS2 transcription start due to transfer RNA deletion and loxPsym site insertion. Despite extensive genetic alterations across 6% of the genome, no major global changes were detected in the poly-synthetic strain "omics" analyses. This work sets the stage for completion of a designer, synthetic eukaryotic genome.
PMID: 28280154
ISSN: 1095-9203
CID: 2476892

Lung Cancer And Lung Microbiome [Meeting Abstract]

Tsay, JJ; Clemente, J; Lhakhang, T; Li, Y; Yie, T-A; Wu, BG; Kapoor, B; Wang, J; Sterman, DH; Heguy, A; Rom, WN; Blaser, M; Segal, LN
ISI:000400372500002
ISSN: 1535-4970
CID: 2591562

Apolipoprotein L1 risk variants associate with prevalent atherosclerotic disease in African American systemic lupus erythematosus patients

Blazer, Ashira; Wang, Binhuan; Simpson, Danny; Kirchhoff, Tomas; Heffron, Sean; Clancy, Robert M; Heguy, Adriana; Ray, Karina; Snuderl, Matija; Buyon, Jill P
OBJECTIVE: Atherosclerosis is exaggerated in African American (AA) systemic lupus erythematosus (SLE) patients, with doubled cardiovascular disease (CVD) risk compared to White patients. The extent to which common Apolipoprotein L1 (APOL1) risk alleles (RA) contribute to this trend is unknown. This retrospective cohort study assessed prevalent atherosclerotic disease across APOL1 genotypes in AA SLE patients. METHODS: One hundred thirteen AA SLE subjects were APOL1-genotyped and stratified as having: zero risk alleles, one risk allele, or two risk alleles. Chart review assessed CVD manifestations including abdominal aortic aneurysm, angina, carotid artery disease, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke, and vascular calcifications. Associations between the genotypes and a composite endpoint defined as one or more CVD manifestations were calculated using logistic regression. Symptomatic atherosclerotic disease, excluding incidental vascular calcifications, was also assessed. RESULTS: The 0-risk-allele, 1-risk-allele and 2-risk-allele groups, respectively, comprised 34%, 53%, and 13% of the cohort. Respectively, 13.2%, 41.7%, and 60.0% of the 0-risk allele, 1-risk-allele, and 2-risk-allele groups met the composite endpoint of atherosclerotic CVD (p = 0.001). Adjusting for risk factors-including smoking, ESRD, BMI >25 and hypertension-we observed an association between carrying one or more RA and atherosclerotic CVD (OR = 7.1; p = 0.002). For symptomatic disease, the OR was 3.5 (p = 0.02). In a time-to-event analysis, the proportion of subjects free from the composite primary endpoint, symptomatic atherosclerotic CVD, was higher in the 0-risk-allele group compared to the 1-risk-allele and 2-risk-allele groups (chi2 = 6.5; p = 0.04). CONCLUSIONS: Taken together, the APOL1 RAs associate with prevalent atherosclerotic CVD in this cohort of AA SLE patients, perhaps reflecting a potentiating effect of SLE on APOL1-related cardiovascular phenotypes.
PMCID:5574561
PMID: 28850570
ISSN: 1932-6203
CID: 2679052

Identification of differentially expressed genes associated with clinical response after treatment of breast cancer skin metastases with imiquimod. [Meeting Abstract]

Rozenblit, Mariya; Heguy, Adriana; Chiriboga, Luis; Loomis, Cynthia; Darvishian, Farbod; Egeblad, Mikala; Shao, Yongzhao; Adams, Sylvia
ISI:000411895702111
ISSN: 0732-183x
CID: 5525542

CHARACTERIZING AND THERAPEUTICALLY TARGETING G-QUADRUPLEX DNA IN ATRX-MUTANT GLIOMA [Meeting Abstract]

Wang, Yuxiang; Danussi, Carla; Lansdorp, Peter; Heguy, Adriana; Huse, Jason
ISI:000398604102073
ISSN: 1523-5866
CID: 2545102

ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMAS: A CLINICOPATHOLOGIC AND MOLECULAR PROFILE [Meeting Abstract]

Segal, Devorah; Thomas, Cheddhi; Bowman, Christopher; Kannan, Kasthuri; Wang, Shiyang; Heguy, Adriana; Liechty, Benjamin; Jones, David TW; Hovestadt, Volker; Pfister, Stefan M; Karajannis, Matthias; Snuderl, Matija
ISI:000398604103008
ISSN: 1523-5866
CID: 2545142

ASTROCYTOMA MUTATIONS IDH1, p53 AND ATRX COOPERATE TO BLOCK DIFFERENTIATION OF NEURAL STEM CELLS VIA Sox2 [Meeting Abstract]

Modrek, Aram; Golub, Danielle; Khan, Themasap; Zhang, Guoan; Kader, Michael; Bowman, Christopher; Prado, Jod; Bayin, NSumru; Frenster, Joshua; Lhakhang, Tenzin; Heguy, Adriana; Dankert, John; Tsirigos, Aristotelis; Snuderl, Matija; Neubert, Thomas; Placantonakis, Dimitris
ISI:000398604104095
ISSN: 1523-5866
CID: 2545182

GPR133 PROMOTES HYPOXIA-DRIVEN TUMOR PROGRESSION IN GLIOBLASTOMA [Meeting Abstract]

Frenster, Joshua; Bayin, NSumru; Kane, Josh Robert; Rubenstein, Jordan; Modrek, Aram; Baitamal, Rabaa; Dolgalev, Igor; Rudzenski, Katie; Snuderl, Matija; Golfinos, John; Doyle, Werner; Pacione, Donato; Chi, Andrew; Heguy, Adriana; Shohdy, Nadim; MacNeil, Douglas; Huang, Xinyan; Parker, Erik; Zagzag, David; Placantonakis, Dimitris
ISI:000398604104099
ISSN: 1523-5866
CID: 2545192