Two Single Nucleotide Polymorphisms of the ETS2 Transcriptional Factor Gene Predispose Individuals to High-Risk Acute Myelogenous Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2729-2729
Author(s):  
Il-Kwon Lee ◽  
Jeong-Hwa Choi ◽  
Yeo-Kyeoung Kim ◽  
Hee Nam Kim ◽  
Kyeong-Soo Park ◽  
...  
Keyword(s):  
Transcription Factor ◽  
High Risk ◽  
Secondary Structure ◽  
Statistical Significance ◽  
Myelogenous Leukemia ◽  
International Hapmap Project ◽  
Nucleotide Polymorphisms ◽  
Factor Gene ◽  
Increased Risk ◽  
Polymorphic Variants

Abstract ETS2 (v-ets avian erythroblastosis virus E2 oncogene homolog 2) is a transcription factor located in the human chromosomal region 1q22.3 encoding a 56-kDa protein. In this study we carefully selected a set of haplotype-tagging SNPs (htSNP) and genotyped their frequencies in order to identify polymorphic variants that contributes to the inter-individual differences in susceptibility to disease phenotypes. Here we report polymorphisms of ETS2, a hematopoietic transcription factor gene is associated with increased risk to AML. Seven SNPs derived from genomic region of the ETS2 gene, rs1209953, rs3746882, rs2298560, rs457705, rs2070531, rs711 and rs5307 were genotyped to estimate allele frequency, haplotype block and linkage disequilibrium (LD) map. Among those rs711 and rs530 were shown to be associated with increased risk to AML with statistical significance. The odds ratio (OR) for rs711 and rs530 relative to wild type genotypes are 1.76 (95% C.I. 1.2–2.5, p=0.0019) and 1.67 (95% C.I. 1.3–2.2, p=0.0003) respectively. Cumulative frequencies of four common haplotypes are 72%, among which T-T-G-T-C-G-T was the most ancestral haplotype comprising 36% of total haplotypes. We also examined the possibility of haplotype association, but no association was found. When we compared LD map with LDs constructed from the International HapMap project, Korean LD map was similar to Japanese LD, but least similarity was shown with LDs from African(Yoruba in Ibadan, Nigeria). Since these two SNPs are located in the 3′ UTR region we simulated the change in secondary structure in silico of the 3′ UTR region with two variants sequence. Severe change in the secondary structure was observed in the rs530 containing domain suggesting this change might affects stability of mRNA. Real time Q-PCR and western blot revealed that expression of ETS2 decreased in a dosage-dependant manner, showing most abundant expression when homozygously T/T at rs530, least expression with the homozygous A/A and intermediate level of expression when the heterozygous genotype. Our results suggest that polymorphic variants in the 3′ UTR region predispose individual to high-risk AML by altering the secondary structure of mRNA.

Association of cis-Acting rs530 of the ETS2 Transcriptional Factor Gene with High-Risk Acute Myelogenous Leukemia (AML) and Allelic Expression Imbalance Assessment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2230-2230
Author(s):  
Il-Kwon Lee ◽  
Jeong-Hwa Choi ◽  
Hee Nam Kim ◽  
Yeo-Kyeoung Kim ◽  
Kyeong-Soo Park ◽  
...  
Keyword(s):  
High Risk ◽  
Secondary Structure ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Heterozygous Genotype ◽  
Factor Gene ◽  
Cis Acting ◽  
Increased Risk ◽  
Acute Myelogenous

Abstract We have previously implicated ETS2 in the etiopathogenesis of acute myeloid leukemia through case-control study by revealing that polymorphisms of ETS2, a hematopoietic transcription factor gene is associated with increased risk to acute myelogenous leukemia (AML). Two SNPs out of 7 genotyped sites, rs711 and rs530 were shown to be associated with increased risk to AML with the odds ratio (OR) of 1.76 (95% C.I. 1.2–2.5, p=0.0019) for rs711 and 1.67 (95% C.I. 1.3–2.2, p=0.0003) for rs530 relative to wild type genotypes respectively. Haplotype and linkage disequilibrium (LD) map was estimated, but haplotype association was not found with statistical significance. Korean LD structure was similar to Japanese LD, but least similarity was shown with LDs from African (Yoruba in Ibadan, Nigeria). Since these two SNPs are located in the 3′ UTR region we simulated the change in secondary structure in silico of the 3′ UTR region with two variants introduced in the sequence. Most dramatic change in the secondary structure was observed in the rs530 containing domain suggesting this variant of being cis-acting genetic variant. Real time Q-PCR and western blot analysis showed that expression of ETS2 decreased in individuals with heterozygous or mutant homozygous genotypes, showing most abundant expression with two wild type copies of rs530, less expression with the rare homozygous or heterozygous genotype. Sequencing cDNA of 55 heterozygous AML patients revealed mRNA expression imbalance in 13 cases (24%) effectively reverting heterozygous genotype to homozygous wild type mRNA species. The detection of a discrepancy between the mRNA alleles of rs530 clearly proves cis-acting effect of rs530. However there was not a case in 51 healthy control samples suggesting differing transcript levels derived from the two alleles of an autosomal gene is disease-specific phenomena. Taken together, our results suggest that two polymorphic variants in the 3′ UTR region predispose individual to high-risk AML by inducing change in mRNA expression as a cis-acting variant.

scholarly journals Potential Prognostic Impact of Dopamine Receptor D1 (rs4532) Polymorphism in Post-stroke Outcome in the Elderly

2021 ◽  
Vol 12 ◽  
Author(s):  
Hae-Yeon Park ◽  
Youngkook Kim ◽  
Hyun Mi Oh ◽  
Tae-Woo Kim ◽  
Geun-Young Park ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Statistical Significance ◽  
The Elderly ◽  
Minor Allele ◽  
Prognostic Impact ◽  
Nucleotide Polymorphisms ◽  
Unique Identifier ◽  
Clinical Trial Registration ◽  
Post Stroke ◽  
Increased Risk

Background: Single-nucleotide polymorphisms (SNPs) may affect post-stroke motor recovery, and some SNPs have been implicated in swallowing disturbances after stroke. Certain SNPs may also have altered influences according to different age.Objective: This post-hoc study investigated whether SNPs have different effects on dysphagia recovery between the elderly vs. young stroke patients.Methods: Analysis was conducted from a previous study including 218 stroke subjects with dysphagia. They were stratified into two groups, aged <65 and aged ≥65 years. The primary outcome was persistence of nil per mouth (NPM) at 3 months post-stroke onset. Association between outcome and nine different SNPs were investigated.Results: The elderly group (50%, n = 103) showed poorer swallowing outcomes than the young group. The minor allele of the dopamine receptor D1 (DRD1, rs4532) polymorphism showed potential association (p = 0.022) with an increased risk of NPM at 12 weeks post-stroke in the elderly, both in the additive (OR, 2.94; 95% CI, 1.17–7.37) and dominant models (OR, 2.93; 95% CI, 1.04–8.23) but did not reach statistical significance after Bonferonni correction. Logistic regression analysis showed that in those aged ≥65 years, models including the minor allele of rs4532 predicted the risk of the poor outcome with good accuracies even after adjustment of clinical factors, such as previous pneumonia episodes (AUROC, 0.86; 95% CI, 0.79–0.93) or the National Institutes of Health Stroke Scale (AUROC, 0.82; 95% CI, 0.67–0.92). In contrast, those aged <65 years seemed not to be affected by the presence of the rs4532 polymorphism, and models that included intubation history (AUROC, 0.81; 95% CI, 0.73–0.90) or previous pneumonia episodes (AUROC, 0.77; 95% CI, 0.68–0.87) showed modest levels of accuracies in predicting NPM at 12 weeks poststroke.Conclusions: Our study suggests a possible association between the rs4532 and post-stroke swallowing recovery, primarily in those aged ≥65 years. Certain SNPs may lead to less favorable outcomes in the elderly. The gene–age interaction should be considered in post-stroke swallowing recovery.Clinical Trial Registration:https://www.clinicaltrials.gov, Unique identifier [NCT03577444].

scholarly journals Bioinformatic Prediction of SNP Markers in WRKY Sequences of Palms

CORD ◽  
2011 ◽  
Vol 27 (2) ◽  
pp. 9 ◽  
Author(s):  
Arunachalam, V
Keyword(s):  
Transcription Factor ◽  
Disease Resistance ◽  
Wrky Transcription Factor ◽  
Snp Markers ◽  
Nucleotide Polymorphisms ◽  
Transcription Factor Gene ◽  
Wrky Transcription Factors ◽  
Nucleotide Level ◽  
Single Nucleotide ◽  
Factor Gene

WRKY transcription factors are unique to plants and performs many imperative functions mainly disease resistance. In the present study we have analyzed the WRKY transcription factor gene sequences to assess the variation at single nucleotide level. We have retrieved 525 sequences of WRKY genes of palms of 334 Kb size. The sequences were purified by employing EST trimmer and were clustered into 31 contigs using CAP3. Single nucleotide Polymorphisms (SNP) and insertion/deletions (indels) were detected in contigs using the AUTOSNP software. Alternatively candidate SNP containing contigs were aligned by Clustal X to locate the SNPs. Results from these two methods were compared and false SNPs were eliminated. Finally, about 568 SNPs were found including 250 transitions, 120 transversions and 198 indels. The SNPs were seen at a frequency of 2.84/100bp in the WRKY sequences of palms. Primers were designed flanking to SNP/ indel sites with potential as markers in palms. We could obtain two novel WRKY-SNP markers (WRKY 7 and WRKY 12) which are not reported before in palms.

Incidence of venous thromboembolic disease (VTE) in a cohort of patients with colorectal cancer (CRC) according to KRAS, NRAS and BRAF status.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15136-e15136
Author(s):  
Pilar Garcia-Alfonso ◽  
Laura Ortega Morán ◽  
Iria Gallego Gallego ◽  
Gonzalo García González ◽  
Gabriela Torres Pérez-Solero ◽  
...  
Keyword(s):  
High Risk ◽  
Predictive Model ◽  
Metastatic Disease ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Low Risk ◽  
Intermediate Risk ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Cancer Associated Thrombosis

e15136 Background: A recent study has suggested that KRAS mutation could increase the risk of VTE in patients with CRC. The role of others biomarkers, such as BRAF, in this setting is unknown. The aim of this study is to analyze the incidence of cancer-associated thrombosis in a cohort of patients with CRC based on KRAS, NRAS and BRAF status. Methods: We performed a retrospective review of patients with metastatic CRC and KRAS/NRAS/BRAF status known, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain) between January 2010 and January 2018. Results: 194 patients were identified and included in the analysis. The median age was 64 years (18-86). Most were metastatic at diagnosis (58.1%). Khorana’s predictive model: low-risk 67.7%, intermediate-risk 31.0%, high-risk 2.3%. The median follow-up was 35 months (2-240). 41 patients (21.1%) experienced VTE (11 pulmonary embolism, 15 lower extremity deep-vein thrombosis, 12 visceral vein thrombosis, 2 catheter-related thrombosis, 1 unknown). Most had metastatic disease at the moment of VTE (90.2%). 40% of the events occurred at the time of diagnosis or within the first 6 months. 65% were incidental events. Khorana’s predictive model in VTE patients: low-risk 63.4%, intermediate-risk 24.5%, high-risk 7.3%. According to biomarkers, the incidence was 19.1% (13/68) in KRAS/NRAS mutated patients, 28.6% (6/21) in BRAF mutated patients and 21% (22/105) in triple-wild-type patients. 6/38 patients (15.8%) developed recurrent thrombosis. In the univariate analysis, the presence of chronic kidney disease (p = 0.022), ECOG ≥ 2 (p = 0.038) and high-risk Khorana score (p = 0.011) were significantly associated with increased risk of VTE. Metastatic disease showed a trend towards the statistical significance (p = 0.053). In the multivariate model, including this variables, age, sex and biomarkers, only ECOG ≥ 2 remained independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). Conclusions: The biomarkers have not been associated with the risk of VTE. We have observed a high incidence of VTE in BRAF mutated patients that should be investigated in further studies.

Single Nucleotide Polymorphisms in CD40L Predict Endothelial Complications and Mortality After Allogeneic Stem-Cell Transplantation

2018 ◽  
Vol 36 (8) ◽  
pp. 789-800 ◽  
Author(s):  
Sivaramakrishna P. Rachakonda ◽  
Hao Dai ◽  
Olaf Penack ◽  
Olga Blau ◽  
Igor Wolfgang Blau ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Graft Versus Host ◽  
Increased Risk ◽  
Acute Graft

Purpose Endothelial vulnerability is a potential risk factor for complications after allogeneic stem-cell transplantation (alloSCT). The CD40/CD40 ligand (CD40L) axis contributes to inflammatory diseases and is upregulated in endothelial cells upon activation, suggesting a role in alloSCT biology. Here, we studied single nucleotide polymorphisms (SNPs) in the CD40L gene in recipients of alloSCT. Patients and Methods Three CD40L SNPs (rs3092920, rs3092952, rs3092936) were analyzed for association with transplant-associated thrombotic microangiopathy, overall nonrelapse mortality (NRM), and NRM after acute graft-versus-host disease in 294 recipients of alloSCT without statin-based endothelial prophylaxis (SEP). The significant genotype was then put into perspective with established thrombomodulin ( THBD) gene polymorphisms. Findings were validated in an independent cohort without SEP and in an additional 344 patients who received SEP. Results The rs3092936 CC/CT genotype was associated with an increased risk of transplant-associated thrombotic microangiopathy ( P = .001), overall NRM ( P = .03), and NRM after acute graft-versus-host disease ( P = .01). The rs3092936 CC/CT genotype was largely mutually exclusive of high-risk THBD SNPs. Both CD40L and THBD SNPs predicted adverse overall survival (OS) and overall NRM to a similar extent in training cohort (OS, P = .04; NRM, P < .001) and validation cohort (OS, P = .01; NRM, P = .001) without SEP. In contrast, SEP completely abolished the influence of the high-risk CD40L and THBD SNPs ( P = .40). Conclusion An increased risk of endothelial complications can be predicted before alloSCT by genetic markers in the recipient’s genome. The normalization of mortality risks in patients treated with SEP suggests a way of overcoming the negative effect of high-risk genotypes and warrants further clinical validation.

Use of optical biomarkers from nondysplastic metaplastic cells on the detection of high-grade dysplasia and adenocarcinoma from Barrett’s esophagus.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 14-14
Author(s):  
Randall Brand ◽  
Sumera Rizvi ◽  
Jon M. Davison ◽  
Rajan Bista ◽  
Kevin Staton ◽  
...  
Keyword(s):  
High Risk ◽  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Statistical Significance ◽  
Optical Path Length ◽  
High Grade Dysplasia ◽  
High Grade ◽  
Novel Approach ◽  
Increased Risk ◽  
Protocol Biopsies

14 Background: Patients with Barrett’s esophagus (BE), defined as presence of intestinal metaplasia (IM) in the esophagus, require surveillance due to an increased risk of developing esophageal adenocarcinoma (EAC). The biggest challenge in the current surveillance methodology (i.e., Seattle protocol) is random sampling with the inability to identify those patients with non-dysplastic BE on surveillance who have occult high grade dysplasia (HGD) or will eventually progress to HGD or EAC. We propose a novel approach based on the concept of field effect to detect HGD or EAC through the analysis of non-dysplastic IM, thus identifying a high risk BE population. Our group uses a unique microscope – spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to detect changes in nuclear structure as small as 0.9 nm, a scale 1000 times smaller than what conventional microscopy detects. We hypothesize that the SL-QPM-derived optical biomarkers of non-dysplastic IM would distinguish BE patients with EAC/HGD from those without neoplasia. Methods: We performed a retrospective study of 60 BE patients who underwent Seattle protocol biopsies: 33 BE patients with IM only and 27 BE patients with HGD or EAC (21 HGD, 6 EAC). H&E stained slides with non-dysplastic IM on review by an expert pathologist were used. The distance between the selected IM biopsy and HGD/EAC was 1 to 4 cm. Forty to 60 columnar cells from each case were analyzed. Results: We identified three optical biomarkers (nuclear optical path length, intra-nuclear uniformity, entropy) that can distinguish non-dysplastic BE from patients with HGD and EAC with statistical significance (P < 0.01). A prediction model combining all three optical biomarkers can distinguish BE patients with HGD/EAC from those with IM only at 89% sensitivity and 76% specificity (accuracy = 0.87). Conclusions: The accurate assessment of nanoscale optical biomarkers by SL-QPM is a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium from non-dysplastic IM. This approach could potentially simplify BE surveillance by identifying a subset of high-risk BE patients that warrant intensive surveillance.

scholarly journals From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

Breast Care ◽  
2021 ◽  
pp. 1-12
Author(s):  
Emma R. Woodward ◽  
Elke M. van Veen ◽  
D. Gareth Evans
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Reproductive Factors ◽  
Risk Scores ◽  
Clinical Indication ◽  
Nucleotide Polymorphisms ◽  
Moderate Risk ◽  
Risk Genes ◽  
Increased Risk ◽  
Gene Panels

<b><i>Background:</i></b> There has been huge progress over the last 30 years in identifying the familial component of breast cancer. <b><i>Summary:</i></b> Currently around 20% is explained by the high-risk genes <i>BRCA1</i> and <i>BRCA2</i>, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes <i>ATM</i> and<i> CHEK2</i>. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. <b><i>Key-Messages:</i></b> There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as <i>CDH1</i> and <i>TP53</i>, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.

scholarly journals Lenalidomide and Risk of Acute Myeloid Leukemia (AML) Transformation Among Myelodysplastic Syndrome (MDS) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1912-1912
Author(s):  
Dana E Rollison ◽  
Kenneth H. Shain ◽  
Ji-Hyun Lee ◽  
Shalaka S Hampras ◽  
William Fulp ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Lower Risk ◽  
Research Funding ◽  
Case Control ◽  
Myelogenous Leukemia ◽  
Cancer Center ◽  
Control Analysis ◽  
Increased Risk ◽  
Case Control Analysis

Abstract Introduction: Lenalidomide is currently approved by the FDA for treatment of transfusion-dependent, lower risk, deletion 5q (del(5q)) MDS patients. In practice, lenalidomide is often used for treatment of non-del(5q) anemic, lower risk MDS patients as endorsed by national guidelines. The risk of AML transformation among non-del(5q) MDS patients treated with lenalidomide has not been well studied, nor among del(5q) MDS patients outside the context of original clinical trials. We conducted a retrospective cohort study of 1,248 MDS patients treated with or without lenalidomide at the Moffitt Cancer Center (MCC) to investigate the association between lenalidomide and AML transformation. Methods: Patients treated for MDS at MCC in 2004-2012 were identified through MCC's data warehouse, including data from the Cancer Registry, electronic medical records and disease-specific databases. A total of 1,248 MDS patients, ages 18+ years, were identified, corresponding to International Classification of Diseases for Oncology Third Edition (ICD-O-3) codes 99801, 99803, 99833, 99843, 99853, 99863, 99873, 99891 and 99893. A total of 150 cases of AML transformation were verified by two hematologists confirming the MDS diagnosis and AML transformation. Incidence rates and 95% confidence intervals (CI) for AML transformation were estimated based on the Poisson distribution. Cox proportional hazards ratios (HR) and 95% CIs were calculated to estimate age-adjusted associations between lenalidomide treatment and AML transformation in the overall cohort, and stratified by lower (low and intermediate-1) risk versus higher (intermediate-2 and high) risk IPSS. To obtain additional details on lenalidomide treatment and potential confounders, medical chart abstraction was conducted for all AML cases and a sample of MDS patients from the baseline cohort who had not developed AML; these controls were matched to cases 1:1 on age at MDS diagnosis (<60 versus 60+ years), gender, follow-up time (+/- 6 months), date of diagnosis, (+/- 1 year), lower versus higher risk IPSS, and presence or absence of del (5q). Based on the abstracted data for the nested case-control sample, associations between lenalidomide and AML transformation were adjusted for cytogenetic risk, use of erythroid-stimulating agents (ESA), percent bone marrow myeloblasts, and MDS histology. Results: Overall, 1,248 MDS patients were followed for an average of 30 months, including patients treated with (n=210) or without (n=1,038) lenalidomide. AML transformation was observed among 16 patients treated with lenalidomide (2.4 per 100 person-years) and 134 patients treated without lenalidomide (5.5 per 100 person-years), corresponding to an age-adjusted HR of 0.44 (95% CI=0.26-0.74). Only two of the 150 MDS patients who transformed to AML had MDS del(5q). When stratified by IPSS, there was no increased risk of AML transformation associated with lenalidomide among patients with lower risk IPSS (HR=0.27, 95% CI=0.12-0.64) or patients with higher risk IPSS (HR=0.99, 95% CI=0.51-1.93). Based on the nested case-control analysis, 16.0% and 20.7% of MDS-AML cases and matched MDS controls who did not develop AML were treated with lenalidomide, respectively, corresponding to an adjusted odds ratio (OR) of 1.16 (95% CI=0.52-2.56). Although a significant interaction was noted between lenalidomide and IPSS in relation to AML in the cohort analysis (Figure 1), lenalidomide was not associated with AML transformation among lower risk (OR=0.44, 95% CI=0.10-1.94) or higher risk (OR=2.06, 95% CI=0.69-6.18) MDS patients after adjustment for prognostic factors in the case-control analysis. Conclusion: To our knowledge, this study represents the largest cohort investigated outside the context of clinical trials for the rate of AML transformation among MDS patients treated with lenalidomide and the first to specifically examine non-del(5q) patients. Lenalidomide treatment was not associated with an increased risk of AML transformation among this large cohort of MDS patients. Figure 1: Incidence of acute myelogenous leukemia (AML) among myelodysplastic syndrome (MDS) patients treated with or without lenalidomide (Lena) and stratified by lower risk IPSS (low risk or intermediate-1 [0,1]) versus higher risk IPSS (intermediate-2 or high risk [2,3]), Moffitt Cancer Center, 2004-2012 Figure 1:. Incidence of acute myelogenous leukemia (AML) among myelodysplastic syndrome (MDS) patients treated with or without lenalidomide (Lena) and stratified by lower risk IPSS (low risk or intermediate-1 [0,1]) versus higher risk IPSS (intermediate-2 or high risk [2,3]), Moffitt Cancer Center, 2004-2012 Disclosures Rollison: Celgene, Inc.: Research Funding. Off Label Use: Lenalidomide given as treatment for non-del(5q) MDS and/or multiple myeloma . Shain:L&M Healthcare/Onyx/Amgen: Research Funding, Speakers Bureau; Envision/Celgene: Research Funding, Speakers Bureau. Lee:Celgene, Inc.: Research Funding. Hampras:Celgene, Inc: Research Funding. Fulp:Celgene, Inc.: Research Funding. Fisher:Celgene, Inc: Research Funding. Al Ali:Celgene, Inc: Research Funding. Padron:Icyte: Speakers Bureau; Novartis: Speakers Bureau. Lancet:Celgene, Inc: Consultancy, Research Funding. Xu:Celgene, Inc.: Employment, stock options Other. Knight:Celgene, Inc: Employment, stock options Other. List:Celgene, Inc.: Consultancy. Dalton:Genentech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene, Inc.: Research Funding. Komrokji:Celgene: Consultancy, Research Funding.

Fludarabine, but Not Mitoxantrone, Increases the Risk of a Poor Stem Cell Harvest and Treatment-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia (tMDS/AML) after Autologous Stem Cell Transplantation (ASCT) in Patients with Follicular Lymphoma (FL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2192-2192
Author(s):  
Jason Waterman ◽  
Lisa Rybicki ◽  
Brian Bolwell ◽  
Ronald Sobecks ◽  
Brad Pohlman ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Stem Cell ◽  
Total Dose ◽  
Statistical Significance ◽  
Cleveland Clinic ◽  
Subsequent Development ◽  
Cox Proportional Hazards ◽  
Prior Exposure ◽  
Myelogenous Leukemia ◽  
Increased Risk

Abstract Both fludarabine (FLU) and mitoxantrone (MIT) are effective agents used to treat FL, but each are suspected as risk factors for poor stem cell harvesting (SCH) and the subsequent development of tMDS/AML in patients undergoing ASCT. We hypothesized that in FL patients treated with ASCT, the association of FLU and MIT with poor SCH and the development of tMDS/AML is either a function of dose, timing, or the concomitant use of these agents pre-transplant. Methods: A total of 171 evaluable patients with FL who received ASCT from 1991–2007 using a uniform preparative regimen of busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP) were identified from the Cleveland Clinic Transplant Center’s Unified Transplant Database (UTD). All patients had taken part in IRB approved clinical trials and gave permission for access to their medical records for the purposes of this research. Demographic, clinical, and outcomes data were extracted from the UTD, and a retrospective chart review was then performed on all patients looking at pre-ASCT chemotherapy regimens including exact dates and doses for FLU and MIT. Results: A total of 59 patients were treated with FLU or MIT (FLU alone = 31, MIT alone = 7, FLU + MIT = 21), and 112 patients treated with neither agent. Logistic regression analysis tested the association of FLU dose (total dose &gt; or ≤ 500mg) and timing (last dose of FLU ≤ or &gt; 3 months prior to ASCT) with the number of days of leukopheresis required to harvest an adequate number of CD34+ cells after mobilization; with and without adjustment for MIT dose (total dose &gt; or ≤ 50mg). A poor SCH was defined as one that required &gt; 5 days of leukopheresis. Patients treated with FLU at any dose &gt;3 months prior to ASCT, showed an increased risk of poor SCH, which was not significantly impacted when adjusted for MIT exposure (FLU ≤ 500mg, OR = 10.14, 95% confidence interval (CI) = 1.54–66.61, P = 0.016; FLU &gt;500mg, OR = 4.00, CI = 1.18–13.68, P = 0.027). The 6 patients receiving &gt;500mg of FLU ≤ 3 months prior to ASCT also showed a trend towards a poor SCH, but this association did not reach statistical significance (P=0.08). In order to quantify risk of a poor SCH, logistic regression models were used to calculate model-based probabilities. Adjusting for mitoxantrone dose, these probabilities ranged from 11–19% for patients with no prior FLU exposure, 13–24% for those receiving ≤ 500 mg FLU ≤ 3 months before ASCT, 32–49% for those receiving &gt;500 mg &gt;3 months before ASCT, 35–52% for those receiving &gt;500 mg ≤ 3 months before ASCT, and 55–71% for those receiving ≤ 500 mg &gt;3 months before ASCT. Six patients were identified with tMDS/AML. Cox proportional hazards analysis identified univariable prognostic factors for tMDS/AML, and the only factors to show statistically increased risk are: the number of prior chemotherapy regimens (HR = 1.70, 95% CI = 1.18–2.45, P = 0.004), prior exposure to any FLU (HR = 13.2, CI = 1.54–113, P = 0.019), prior exposure to &gt;500mg FLU (HR = 17.9, CI = 1.85–173, P = 0.013), timing of FLU with the last dose being &gt;3 months prior to ASCT (HR = 17.7, CI = 1.93–162, P = 0.011), and a poor SCH (HR = 18.1, CI = 2.10–156). Conclusions: FL patients who undergo ASCT with pre-transplant FLU exposure &gt;3 months prior to transplant have increased risk of poor SCH and development of tMDS/AML irrespective of FLU dose and MIT exposure. Patients who receive &gt;500mg of FLU ≤ 3 months prior to ASCT have an increased risk of tMDS/AML, and there is a trend towards an increase in the number of poor SCHs for these patients. However, those patients who receive ≤ 500mg of FLU ≤ 3 months prior to ASCT show no significant increase in poor SCH or tMDS/AML. For all patients, poor SCH predicted a higher risk of developing t-MDS/t-AML. Our data should inform treatment decisions in pts with FL who are potential candidates for ASCT.

Genetic variants associated with toxicity-related discontinuation of adjuvant aromatase inhibitor (AI) therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 525-525
Author(s):  
Norah Lynn Henry ◽  
Todd C. Skaar ◽  
Jessica Dantzer ◽  
Lang Li ◽  
Anne T Nguyen ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Genetic Variants ◽  
Germ Line ◽  
Statistical Significance ◽  
A Priori ◽  
Treatment Discontinuation ◽  
Estrogen Metabolism ◽  
Nucleotide Polymorphisms ◽  
Hormone Receptor Positive ◽  
Increased Risk

525 Background: Discontinuation of adjuvant AI therapy due to intolerable symptoms occurs in up to 30% of patients. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. Methods: We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane (exe) versus letrozole (let). Using multiple genetic models, we evaluated potential associations between 136 single nucleotide polymorphisms (SNP) in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling, and discontinuation of AI therapy because of toxicity. To account for multiple comparisons, statistical significance was defined as p<0.0003. Results: Of the 467 enrolled patients who had available germ line DNA, 152 (33%) discontinued AI therapy because of toxicity. After adjusting for multiple covariates, multivariable analyses revealed that two inherited genetic variants in ESR1, which encodes estrogen receptor (ER) alpha, and one in CYP19A1 were associated with increased risk of discontinuation of AI therapy because of toxicity (Table). A variant in NCOR1 (ER co-repressor) was associated with decreased risk of discontinuation of letrozole because of toxicity. Conclusions: Variants in genes involved in estrogen metabolism and signaling may be associated with toxicity of AI therapy. [Table: see text]

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