Home About us Contact
|
Home About us Contact | ||
|
|
||
Discovery Set (discovery + set)
Selected AbstractsMolecular profiling of platinum resistant ovarian cancer,INTERNATIONAL JOURNAL OF CANCER, Issue 8 2006Jozien Helleman Abstract The aim of this study is to discover a gene set that can predict resistance to platinum-based chemotherapy in ovarian cancer. The study was performed on 96 primary ovarian adenocarcinoma specimens from 2 hospitals all treated with platinum-based chemotherapy. In our search for genes, 24 specimens of the discovery set (5 nonresponders and 19 responders) were profiled in duplicate with 18K cDNA microarrays. Confirmation was done using quantitative RT-PCR on 72 independent specimens (9 nonresponders and 63 responders). Sixty-nine genes were differentially expressed between the nonresponders (n = 5) and the responders (n = 19) in the discovery phase. An algorithm was constructed to identify predictive genes in this discovery set. This resulted in 9 genes (FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE, PCNA), which were confirmed with qRT-PCR. This gene set predicted platinum resistance in an independent validation set of 72 tumours with a sensitivity of 89% (95% CI: 0.68,1.09) and a specificity of 59% (95% CI: 0.47,0.71)(OR = 0.09, p = 0.026). Multivariable analysis including patient and tumour characteristics demonstrated that this set of 9 genes is independent for the prediction of resistance (p < 0.01). The findings of this study are the discovery of a gene signature that classifies the tumours, according to their response, and a 9-gene set that determines resistance in an independent validation set that outperforms patient and tumour characteristics. A larger independent multicentre study should further confirm whether this 9-gene set can identify the patients who will not respond to platinum-based chemotherapy and could benefit from other therapies. © 2005 Wiley-Liss, Inc. [source] Association of a KCNA5 gene polymorphism with systemic sclerosis,associated pulmonary arterial hypertension in the European Caucasian populationARTHRITIS & RHEUMATISM, Issue 10 2010J. Wipff Objective Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor , receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. Methods Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. Results The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48,0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13,0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21,0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. Conclusion Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc. [source] Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritisARTHRITIS & RHEUMATISM, Issue 8 2010Ana M. Valdes Objective Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor , signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA),like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large-joint OA in humans. Methods Ten tag single-nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA. Results A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta-analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12,1.34), P < 7.5 × 10,6. For hip OA, the OR was 1.22 (95% CI 1.09,1.36), P < 4.0 × 10,4. No evidence for heterogeneity was found (I2 = 0%). Conclusion Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA. [source] STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosisARTHRITIS & RHEUMATISM, Issue 8 2009P. Dieudé Objective Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5. Methods Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects. Results STAT4 rs7574865 was shown to be associated with SSc (P = 0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11,1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiplicatively increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86,3.99) for combinations of genotypes with ,3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P = 2.2 × 10,4, OR 1.97, 95% CI 1.28,3.04). Conclusion Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis. [source] Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: A new perspective for pulmonary fibrosisARTHRITIS & RHEUMATISM, Issue 1 2009P. Dieudé Objective There is now growing evidence that connective tissue diseases, including systemic sclerosis (SSc), share a common genetic background. Microarray studies support a pivotal role of type I interferon (IFN) in the pathophysiology of connective tissue diseases. Interferon regulatory factors coordinate the expression of type I IFNs, and the IRF5 gene has been identified as a susceptibility gene of systemic lupus and Sjögren's syndrome. The aim of this study was to determine whether the IRF5 rs2004640 single-nucleotide polymorphism is associated with SSc. Methods The IRF5 rs2004640 (GT) functional polymorphism was genotyped in 1,641 subjects of French European Caucasian origin: a discovery set comprising 427 patients with SSc and 380 control subjects and a replication set comprising 454 patients with SSc and 380 control subjects. Results In both the discovery set and the replication set, the TT genotype was significantly more common in patients with SSc than in control subjects, with an odds ratio (OR) for the combined populations of 1.58 (95% confidence interval [95% CI] 1.18,2.11 [P for trend 0.002]). Analyses of the whole SSc population showed a significant association between homozygosity for the T allele and the presence of antinuclear antibodies (corrected P [Pcorr] = 0.04, OR 1.59, 95% CI 1.16,2.17) and fibrosing alveolitis (Pcorr = 0.001, OR 2.07, 95% CI 1.38,3.11). In a multivariate analysis model including the diffuse cutaneous subtype of SSc and positivity for anti,topoisomerase I antibodies, the IRF5 rs2004640 TT genotype remained associated with fibrosing alveolitis (P = 0.029, OR 1.92, 95% CI 1.07,3.44). Conclusion The IRF5 rs2004640 GT substitution is associated with susceptibility to SSc. These data provide new insight into the pathogenesis of SSc, including clues to the mechanisms leading to fibrosing alveolitis. [source] | ||||||||||