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1.
Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study.
Schlenk, RF, Paschka, P, Krzykalla, J, Weber, D, Kapp-Schwoerer, S, Gaidzik, VI, Leis, C, Fiedler, W, Kindler, T, Schroeder, T, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;(6):623-632
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Abstract
PURPOSE High CD33 expression in acute myeloid leukemia (AML) with mutated NPM1 provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in NPM1-mutated AML. PATIENTS AND METHODS Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all-trans-retinoic acid with or without GO. The early (P = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment. RESULTS Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; P = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm (P = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm (P = .005), with no difference in the cumulative incidence of death (P = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and FLT3 internal tandem duplication-negative patients with respect to EFS and CIR. CONCLUSION The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.
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Epigenome-wide association of myocardial infarction with DNA methylation sites at loci related to cardiovascular disease.
Nakatochi, M, Ichihara, S, Yamamoto, K, Naruse, K, Yokota, S, Asano, H, Matsubara, T, Yokota, M
Clinical epigenetics. 2017;:54
Abstract
BACKGROUND Development of cardiovascular disease (CVD), including coronary artery disease, arrhythmia, and ischemic stroke, depends on environmental and genetic factors. To investigate the epigenetic basis of myocardial infarction (MI), we performed an epigenome-wide association study for this condition in elderly Japanese subjects. A total of 192 case subjects with MI and 192 control subjects were recruited from hospital attendees and the general population, respectively. Genome-wide DNA methylation (DNAm) profiles for DNA isolated from whole blood were obtained by analysis with an Infinium HumanMethylation450 BeadChip. The relation of DNAm sites found to be significantly associated with MI to nearby single nucleotide polymorphisms (SNPs) previously shown to be associated with CVD was assessed in the control group. FINDINGS Three DNAm sites (cg06642177, cg07786668, cg17218495) showed genome-wide significant associations with MI (p = 4.33 × 10-8, 3.96 × 10-10, and 3.77 × 10-8, respectively). Two of these sites (cg07786668, cg17218495) still showed such associations after adjustment for classical risk factors of MI (p = 1.04 × 10-7 and 6.60 × 10-8, respectively). The DNAm sites cg07786668 and cg17218495 are located in ZFHX3 (zinc finger homeobox 3) and SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4) genes, respectively. SNPs in ZFHX3 or SMARCA4 that were previously found to be associated with CVD were not significantly associated with these DNAm sites in our control subjects. CONCLUSIONS We identified two DNAm sites-cg07786668 in ZFHX3 and cg17218495 in SMARCA4- that are independently and significantly associated with MI. Our results suggest that the development of MI might be influenced by changes in DNAm at these sites via a pathway that differs from that affected by CVD-associated SNPs in these genes. The Kita-Nagoya Genomic Epidemiology (KING) study, which was the source of control samples in the present study, was registered in ClinicalTrials.gov (NCT00262691) on 6 December 2005.
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HIF1A (rs11549465) and AKNA (rs10817595) Gene Polymorphisms Are Associated with Primary Sjögren's Syndrome.
Hernández-Molina, G, Rodríguez-Pérez, JM, Fernández-Torres, J, Lima, G, Pérez-Hernández, N, López-Reyes, A, Martínez-Nava, GA
BioMed research international. 2017;:5845849
Abstract
Objective. To evaluate the allele and genotype frequencies of polymorphic sites of HIF1A and ANKA genes in primary Sjögren's syndrome (pSS). Methods. We included 110 patients with pSS and 141 ethnically matched healthy controls. Three HIF1A gene polymorphisms (Pro582Ser, Ala588Thr, and C191T) and two AKNA gene polymorphisms (-1372C>A and Pro624Leu) were genotyped using TaqMan probes in a Real-Time PCR instrument. Associations between pSS and genotypes, alleles, and inheritance models of the SNPs of interest were evaluated by logistic regression adjusted by age and gender. Results. The C/T genotype and the T allele of the HIF1A Pro582Ser polymorphism protected against pSS (OR = 0.22; 95% CI = 0.09-0.52; P < 0.01; OR = 0.26; 95% CI = 0.12-0.58; P < 0.01, resp.), whereas under a recessive model adjusted by age and gender, the AKNA -1372C>A polymorphism A/A genotype was associated with an increased risk of pSS (OR = 2.60; 95% CI = 1.11-6.12; P = 0.03). Conclusions. We identified HIF1A Pro582Ser T allele and C/T genotype as well as AKNA -1372C>A polymorphism A/A genotype as genetic factors associated with pSS. Further studies in other populations are needed to validate our findings and research is warranted in order to shed some light on their functional implications across biological pathways in this disease.
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Co-Expression of TWIST1 and ZEB2 in Oral Squamous Cell Carcinoma Is Associated with Poor Survival.
Kong, YH, Syed Zanaruddin, SN, Lau, SH, Ramanathan, A, Kallarakkal, TG, Vincent-Chong, VK, Wan Mustafa, WM, Abraham, MT, Abdul Rahman, ZA, Zain, RB, et al
PloS one. 2015;(7):e0134045
Abstract
Oral squamous cell carcinoma (OSCC) is an aggressive disease accounting for more than 260,000 cancer cases diagnosed and 128,000 deaths worldwide. A large majority of cancer deaths result from cancers that have metastasized beyond the primary tumor. The relationship between genetic changes and clinical outcome can reflect the biological events that promote cancer's aggressive behavior, and these can serve as molecular markers for improved patient management and survival. To this end, epithelial-mesenchymal transition (EMT) is a major process that promotes tumor invasion and metastasis, making EMT-related proteins attractive diagnostic biomarkers and therapeutic targets. In this study, we used immunohistochemistry to study the expression of a panel of transcription factors (TWIST1, SNAI1/2, ZEB1 and ZEB2) and other genes intimately related to EMT (CDH1 and LAMC2) at the invasive tumor front of OSCC tissues. The association between the expression of these proteins and clinico-pathological parameters were examined with Pearson Chi-square and correlation with survival was analyzed using Kaplan Meier analysis. Our results demonstrate that there was a significant differential expression of CDH1, LAMC2, SNAI1/2 and TWIST1 between OSCC and normal oral mucosa (NOM). Specifically, CDH1 loss was significantly associated with Broder's grading, while diffused LAMC2 was similarly associated with non-cohesive pattern of invasion. Notably, co-expression of TWIST1 and ZEB2 in OSCC was significantly associated with poorer overall survival, particularly in patients without detectable lymph node metastasis. This study demonstrates that EMT-related proteins are differentially expressed in OSCC and that the co-expression of TWIST1 and ZEB2 could be of clinical value in identifying patients with poor survival for appropriate patient management.
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Ancestry and other genetic associations with plasma PCSK9 response to simvastatin.
Theusch, E, Medina, MW, Rotter, JI, Krauss, RM
Pharmacogenetics and genomics. 2014;(10):492-500
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Abstract
OBJECTIVE Statins stimulate transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of the low-density lipoprotein receptor, thus blunting the cholesterol-lowering effects of statin treatment. Although there is interindividual variation in PCSK9 statin response, little is known about ancestral and other genetic factors that could contribute to this variation. METHODS We measured plasma PCSK9 levels before and after 6 weeks of treatment with 40 mg/day simvastatin in 901 participants of the Cholesterol and Pharmacogenetics clinical trial and tested phenotypic and genetic factors for correlation with PCSK9 statin response. RESULTS Statin-induced changes in plasma low-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B were all significantly correlated with statin-induced changes in PCSK9. A detailed examination of the associations of genetic ancestry with PCSK9 statin response revealed that Ashkenazi Jews had smaller statin-induced increases in PCSK9 levels than other self-reported Caucasians (P=0.016). Using genomewide association analysis, we found that the 'G' minor allele of rs13064411 in the WD repeat domain 52 (WDR52) gene was significantly associated with greater statin-induced increases in plasma PCSK9 in Caucasians (P=8.2 × 10(-8)) in the Cholesterol and Pharmacogenetics trial. CONCLUSION Overall, these results suggest that genetic ancestry and the rs13064411 genotype contribute to interindividual variation in PCSK9 statin response in Caucasians.
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The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals.
Abulí, A, Bujanda, L, Muñoz, J, Buch, S, Schafmayer, C, Valeria Maiorana, M, Veneroni, S, van Wezel, T, Liu, T, Westers, H, et al
PloS one. 2014;(4):e95022
Abstract
Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance", being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.
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Identification and validation of the methylated TWIST1 and NID2 genes through real-time methylation-specific polymerase chain reaction assays for the noninvasive detection of primary bladder cancer in urine samples.
Renard, I, Joniau, S, van Cleynenbreugel, B, Collette, C, Naômé, C, Vlassenbroeck, I, Nicolas, H, de Leval, J, Straub, J, Van Criekinge, W, et al
European urology. 2010;(1):96-104
Abstract
BACKGROUND Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers. OBJECTIVE To determine whether a panel of methylated genes would have the potential to identify primary bladder cancer (BCa) in voided urine samples. DESIGN, SETTING, AND PARTICIPANTS A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls. MEASUREMENTS A urine sample was classified as valid when > or = 10 copies of the gene encoding ß-actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared. RESULTS AND LIMITATIONS MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively. CONCLUSIONS Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (> or = 90%) sensitive and specific, noninvasive approach for detecting primary BCa. TRIAL REGISTRATION BlCa-001 study - EudraCt 2006-003303-40.
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Molecular scanning analysis of hepatocyte nuclear factor 1alpha (TCF1) gene in typical familial type 2 diabetes in African Americans.
Elbein, SC, Teng, K, Eddings, K, Hargrove, D, Scroggin, E
Metabolism: clinical and experimental. 2000;(2):280-4
Abstract
Type 2 diabetes mellitus (T2DM) is strongly inherited, but the major genes for this disease have been elusive. In contrast, early-onset, autosomal-dominant diabetes results from at least 5 loci, of which hepatocyte nuclear factor 1a (HNF1alpha or TCF1) is the most common cause. Mutations in HNF1alpha also cause later-onset diabetes in some Caucasian populations, but the role of these mutations has not been tested in African American populations. We used a variety of screening methods, including both single-strand conformation polymorphism (SSCP) analysis and dideoxy fingerprint analysis, to search for mutations in 51 African American subjects with onset of diabetes before age 50 years. Potential mutations were confirmed by direct sequencing. We identified 21 different variants, of which 11 were unique to African Americans. Four mutations either altered the amino acid sequence (Gly52Ala and Gly574Ser) or were close to a splice site (intron 1 and intron 10). A 5-nucleotide insertion in intron 1 was present in both diabetic members of a small family, but Gly52Ala, Gly574Ser, and the intron 10 mutation did not segregate with diabetes. Gly574Ser was present in 2 large families and 5% of controls, all of which appeared to share the same common HNF1alpha haplotype. Surprisingly, radioactive SSCP analysis under 2 room-temperature conditions performed as well as methods using fluorescent labeling that were expected to be more sensitive. We conclude that in African American individuals under age 50, variation in the HNF1a gene is common but unlikely to be a significant cause of T2DM.