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Kim, Jung Oh, Han Sung Park, Eun Ju Ko, Jung Hoon Sung, Jinkwon Kim, Seung Hun Oh, Ok Joon Kim, and Nam Keun Kim. "The 3′-UTR Polymorphisms in the Thymidylate Synthase (TS) Gene Associated with the Risk of Ischemic Stroke and Silent Brain Infarction." Journal of Personalized Medicine 11, no. 3 (March 12, 2021): 200. http://dx.doi.org/10.3390/jpm11030200.
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Thymidylate synthase (TS) is a key gene involved in the repair of DNA damage and DNA synthesis that plays an important role in vascular development and recovery. In particular, TS gene polymorphisms play a major role in the progression of vascular disease and cancer metastasis. Therefore, the aim of this study was to investigate the association of three TS polymorphisms (1100T>C [rs699517], 1170A>G [rs2790], and 1494ins/del [rs151264360]) with ischemic stroke and silent brain infarction (SBI) in Koreans. A total of 1299 participants (507 stroke patients, 383 SBI patients, and 409 controls) were enrolled in the study. Genotyping of the three TS polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. To examine the association between TS gene polymorphisms and the diseases, we performed statistical analyses, including multivariable logistic regression and Fisher’s exact tests. We found that TS 1100T>C and 1170A>G genotypes were strongly associated with ischemic stroke and SBI susceptibility. More specifically, the TS 1100T>C polymorphism was associated with the likelihood of ischemic stroke (TT vs. CC: AOR = 2.151, 95% CI = 1.275–3.628, P = 0.004) and SBI (TT vs. TC+CC: AOR = 1.443, 95 % CI = 1.009–2.063, P = 0.045). In contrast, the TS 1170A > G polymorphism exhibited lower correlation with the risk of stroke (AA vs. GG: AOR = 0.284, 95% CI = 0.151–0.537, P < 0.0001) and SBI (AA vs. GG: AOR = 0.070, 95% CI = 0.016–0.298, P = 0.0002). Furthermore, we confirmed that the TS 1100T>C polymorphism was synergistic with low folic acid levels (AOR = 6.749, P < 0.0001). Altogether, these results suggest that TS 1100T>C and 1170A > G polymorphisms are associated with the risk of ischemic stroke and SBI, and our study provides the first evidence that 3′-UTR variants in TS are potential biomarkers in ischemic stroke and SBI.
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Villafranca, Elena, Yury Okruzhnov, Miguel A. Dominguez, Jesús García-Foncillas, Ignacio Azinovic, Enrique Martínez, Jose J. Illarramendi, et al. "Polymorphisms of the Repeated Sequences in the Enhancer Region of the Thymidylate Synthase Gene Promoter May Predict Downstaging After Preoperative Chemoradiation in Rectal Cancer." Journal of Clinical Oncology 19, no. 6 (March 15, 2001): 1779–86. http://dx.doi.org/10.1200/jco.2001.19.6.1779.
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PURPOSE: Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)–based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival. PATIENTS AND METHODS: Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU–based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival. RESULTS: Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P = .036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P = .17). CONCLUSION: This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU–based chemoradiation.
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Ugrasena, I. Dewa Gede, Harianto Notopuro, Subijanto Marto Sudarmo, Ketut Sudiana, Djajadiman Gatot, and Ponpon Idjradinata. "MTHFR C677T and TS 5’-UTR 3R/3R Gene Polymorphism in Methotrexate-Resistant Childhood Acute Lymphoblastic Leukemia." Indonesian Biomedical Journal 12, no. 2 (June 29, 2020): 177–82. http://dx.doi.org/10.18585/inabj.v12i2.1109.
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BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy in Indonesia and often treated by methotrexate (MTX). Though it can be cured in 30-60% of patients, MTX resistance remains the major cause of treatment failure in childhood ALL. Previous sudies showed that its anti-leukemic property was moderated by MTX ability to inhibitmethylene tetra hydrofolate reductase (MTHFR) and thymidylate synthase (TS) in folate metabolism. This study investigates the correlation between MTHFR and TS polymorphism and MTX resistance in ALL children.METHODS: A total of 155 subjects obtained from all subjects prior to chemotherapy. DNA from blood samples were extracted and underwent polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) to evaluate MTHFR C677T and TS 5’-UTR 3R/3R polymorphism.RESULTS: There was significant correlation between MTHFR C677T and TS 5’-UTR 3R/3R gene polymorphism with MTX resistance. Subjectswith MTHFR C677T and TS 5’-UTR 3R/3R gene polymorphism were 4 times (p=0.007) and 6.4 times (p=0.001) more likely to be MTX resistant than those without gene polymorphisms, respectively.CONCLUSION: MTHFR C677T andTS 5’-UTR 3R/3R represent dominant gene polymorphism related to MTX resistance in childhood ALL.KEYWORDS: gene polymorphism, folate metabolism, acute lymphoblastic leukemia
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Chen, Jin-Yin, He-Jian Chen, and Pei-Feng Chen. "Association of expression and genotypes of thymidylate synthase in non-small cell lung cancer patients with different clinicopathological characteristics." Pteridines 32, no. 1 (January 1, 2021): 39–47. http://dx.doi.org/10.1515/pteridines-2020-0013.
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Abstract Objective To explore the expression and genotypes of thymidylate synthase (TS) in patients of non-small cell lung cancer (NSCLC) with different clinicopathological characteristics. Methods The expression profiles of TS were examined by immunohistochemical staining and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) in 160 patients with NSCLC. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect TS-5′UTR tandem repeats, G/C nucleotide polymorphisms, and 3′UTR 6 bp deletion/insertion polymorphisms. The relationships between clinicopathological characteristics and TS expression or genotypes were investigated through χ 2 test. Kaplan–Meier survival analysis was used to analyze the association between TS expression and overall survival (OS) and disease-free survival (DFS) of NSCLC patients. Results The expression levels of TS protein and TS gene in NSCLC tissues were significantly higher than that in paracancerous tissues (P < 0.05). Furthermore, high expression of TS protein and 5′UTR polymorphism of TS gene showed significant correlation with differentiation, TNM stage, and lymph node metastases. The frequency of −6 bp/−6 bp genotypes in patients with NSCLC was 43.13% (69/160), which was higher than others. In addition, the rate of TS protein overexpression in NSCLC patients with 3R/3R was 79.79%, which was higher than others. Interestingly, high expression of TS protein predicted shorter DFS and OS and lower 3-year DFS rate and 3-year OS rate. Conclusions The expression levels of TS in NSCLC were significantly increased and may help to predict the prognosis of NSCLC, and high expression of TS protein and 5′UTR polymorphism of TS gene were significantly related to differentiation, TNM stage, and lymph node metastases.
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Fariña-Sarasqueta, A., M. J. E. M. Gosens, E. Moerland, I. van Lijnschoten, V. E. P. P. Lemmens, G. D. Slooter, H. J. T. Rutten, and A. J. C. van den Brule. "TS Gene Polymorphisms Are Not Good Markers of Response to 5-FU Therapy in Stage III Colon Cancer Patients." Analytical Cellular Pathology 33, no. 1 (2010): 1–11. http://dx.doi.org/10.1155/2010/731873.
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Aim: Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy.Patients and Methods: 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5′-untranslated region of the TS gene were genotyped.Results: There was a positive association between tumor T stage and the VNTR genotypes (p=0.05). In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes.Conclusion: We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.
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Knop, Stefan, Juergen Loeffler, Michael Steffens, Markus Guenther, Agnieszka Korfel, Michael Weller, Holger Hebart, Hermann Einsele, and Ulrich Herrlinger. "Polymorphisms in Genes of Folate Metabolism and Response to High-Dose Methotrexate in Patients with Primary Central Nervous System Lymphoma." Blood 106, no. 11 (November 16, 2005): 4439. http://dx.doi.org/10.1182/blood.v106.11.4439.4439.
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Abstract The antifolate methotrexate (MTX) was shown to be the single most-effective agent in first-line treatment of patients with primary central nervous system lymphoma (PCNSL) when given intravenously in high doses. MTX inhibits 5,10-methylentetrahydrofolate reductase (MTHFR) as well as thymidylate synthase (TS) in target cells what eventually results in decreased DNA synthesis. Intracellular uptake of both folate and MTX is mediated by the reduced folate carrier (RFC). Genetic polymorphisms for all three proteins were described: a C to T base transition at nucleotide 667 (C677T) and an A to C transition at 1298 (A1298C) of MTHFR; a 28-base pair (bp) tandemly repeated sequence polymorphic in the numbers of the repeat (2R/2R; 3R/3R; and 2R/3R) in the 5′-UTR of TS; a 6bp insertion-(+6bp)/deletion(−6bp)-polymorphism in the 3′-UTR of TS; and a polymorphism at nucleotide 80 (G80A) of RFC. We hypothesized that these polymorphisms may be directly linked to response, survival and toxicity in patients with PCNSL who are treated with single high-dose MTX. We prospectively collected blood from 152 subjects who were enrolled into a German multicenter PCNSL trial. They were scheduled to receive HD-MTX 4 g/m2 every 2 weeks. Genomic DNA was extracted from mononuclear cells using QIAGEN DNA Blood Mini Kit®. Genotyping of the two MTHFR (C677T; A1298C) and the RFC (G80A) single nucleotide polymorphisms (SNPs) was performed by melting point analysis with Master Hybridization Probes® using the Light Cycler® technology. Genotyping of the TS 28bp tandem/triplet repeats in the 5′-UTR was performed by conventional PCR followed by high resolution agarose gel electrophoresis. The TS +6bp/−6bp polymorphism in the 3′-UTR was analyzed with PCR, followed by restriction enzyme digest with draI and agarose gel electrophoresis. The fragment sizes were 70 bp and 88 bp for the 6 bp insertion allele and 152 bp for the 6 bp deletion allele. Allele frequencies for heterozygosity and for homozygous mutations of the two MTHFR and the RFC SNPs as well as of the two TS polymorphisms were as expected for a Caucasian population. For the currently 120 evaluable patients logistic regression analysis, Armitage Trend test and Kaplan-Meier survival curves were performed to analyze the role of the polymorphisms as potential predictors for MTX response. Up to now, we only found a trend for an association between response to treatment and survival for the 2 MTHFR mutations. We will analyze haematological and non-haematological toxicities which will be presented at the meeting with updated results for survival and response in the patients who will have completed treatment until then.
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Ugrasena, IDG, Sutaryo Sutaryo, Edy Supriadi, Laura Vroling, Jacqueline Cloos, Jan Hendrik Hooijberg, and AJP Veerman. "High frequency of the 3R/3R polymorphism in the thymidylate synthase enhancer region in Indonesian childhood acute lymphoblastic leukemia." Paediatrica Indonesiana 46, no. 3 (October 18, 2016): 103. http://dx.doi.org/10.14238/pi46.3.2006.103-12.
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Background Deoxyuridylate monophosphate (dTMP) is neces-sary for DNA synthesis and thymidylate synthase (TS) is an im-portant target of cancer chemotherapy. Ethnic variations of thepolymorphic tandem repeat sequence in the enhancer region ofthe TS promoter has previously been described to influence theoutcome of acute lymphoblastic leukemia (ALL). A triple repeat isassociated with a higher TS gene expression than a double re-peat, resulting in poorer outcome of ALL patients treated with anti-folate methotrexate (MTX).Objective In this study, we determined the incidences of TS andmethylenetetrahydrofolate reductase (MTHFR) polymorphism andethnic variations between Indonesian and Caucasian ALL cellsamples obtained at diagnosis. Furthermore, we determined theinvolvement of TS polymorphisms in MTX sensitivity using athymidilate synthase inhibition assay (TSIA).Methods ALL cell samples were obtained at diagnosis from 101Indonesian and 157 Caucasian children treated with MTX prospec-tively. Genotyping for TS and MTHFR was analyzed by Genescanand Lightcycler. TS polymorphism was determined by PCR assayand MTHFR polymorphism and was analyzed by melting curveanalyses on lightcycler.Results Homozygous TS triple repeats were more than twice ascommon in Indonesian samples (76.3%) than in Caucasian samples(33.1%). Heterozygotes of the MTHFR mutations were seen in 15%of the screened Indonesian samples.Conclusion There are significant ethnic variations in TS generegulatory elements of leukemic cells. A difference was found be-tween the MTX sensitivity and a double or triple repeat in the Cau-casian ALL group. The samples with a triple repeat show a shift intheir distribution towards hypersensitivity to MTX. Further investi-gation on Indonesian samples may give insight in the role of poly-morphisms in MTX sensitivity
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Ichikawa, W., T. Takahashi, and Y. Sasaki. "Pharmacogenetic profiling and clinical outcome of patients (pts) with advanced gastric cancer (AGC) treated with S-1 monotherapy." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4600. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4600.
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4600 Background: Intra-tumor gene expressions of thymidylate synthase (TS) and orotate phosphoribosyltranseferase (OPRT) have been indicated to be positive predictive markers for the clinical outcome of pts treated by S-1 monotherapy for AGC (Int J Cancer 119:1245,2006). The aim of this study is to investigate whether polymorphisms with putative influence on S-1 activity are associated with clinical outcomes of pts with AGC. Patients and Methods: The study population consisted of consecutive 55 pts with AGC from 01/1999 to 03/2002 in our institute. All patients homogenously received the S-1 monotherapy (80mg/sqm/day, 4 wks with 2-wks drug holiday) as a first line treatment. The overall response rate was 40% and the median overall survival (OS) was 8.0 months (range, 2.1 to 23.0 months). Genomic DNA obtained before starting chemotherapy was used for genotyping 8 polymorphisms in 5 genes (DPD, TS, OPRT, MTHFR, CYP2A6). Results: No alleles of DPYD*2 were found in this Japanese cohort. There were no association among the clinical outcome, such as tumor response and OS, and genotypes including tandem repeat (VNTR) in TS 5’UTR, G/C polymorphism with in the 3R VNTR, OPRT G638C, MTHFR C677T, CYP2A6*4, and CYP2A6*9. Even if TS 5’UTR and G/C polymorphism were combined, TS 5’UTR 3G genotype (2R/3G, 3C/3G, 3G/3G) was not associated with the clinical outcome. Only 6-bp insertion/deletion (ins/del) in the TS 3’UTR was closely related to both tumor response and OS. The response rates were 23% and 55% in pts with del/del genotype and pts with ins/ins or ins/del, respectively, with a statistical significance (P=0.015). The median OS was 9.5 months in pts with the ins allele versus 6.2 months in pts with del homozygote (P=0.0345). Conclusion: This exploratory study shows that polymorphism in TS 3’UTR may influence clinical outcomes of AGC pts treated by S-1. No significant financial relationships to disclose.
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Aguiar, Samuel, Eloisa Olivieri, Dirce Maria Carraro, Celso Lopes Mello, Marcelo Fanelli, and Ademar Lopes. "Association of the polymorphisms of the tandem repeat sequence in the thymidylate synthase gene with tumor stage in colon cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e14688-e14688. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e14688.
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e14688 Background: Thymidylate synthase (TS) plays an important role in colorectal carcinogenesis and response to 5FU-based chemotherapy. TS expression can be modified due to polymorphisms in the 5'-untranslated region (5’-UTR) of the gene. The aim of this study is to investigate the association between TS polymorphisms with clinicopathological characteristics of colon carcinomas. Methods: we retrospectively studied 89 individuals with high risk stage II (obstruction, T4 stage, presence of lymphovascular invasion or preoperative CEA > 5.0) and stage III patients submitted to curative intent surgery. DNA was extracted from paraffin embedded tumor tissues and sequenced. The polymorphism studied was the variation of the number of the repeated 28-bp sequences (3 or 2 repeats) of the TS gene 5’-UTR. Results: The frequency of the polymorphisms was: 2R2R in 26 cases (29.2%), 2R3R in 36 cases (40.4%), and 3R3R in 27 cases (30.3%). We did not find associations between the frequencies of these polymorphisms and age, gender, presence of lymphovascular invasion, or level of preoperative CEA. We find a significantly higher proportion of T4 tumors between the 3R3R genotype compared with the 2R2R and 2R3R genotypes (OR=2.69; 95% CI: 1.05 – 6.94; p=0.04). By the other hand, a significantly lower proportion of positive lymph nodes were found among patients with tumors presenting the 3R3R genotype, by comparing with the 2R2R and 2R3R subgroup (OR: 0.28; 95%CI: 0.10 – 0.72; p=0.01). Five-year disease free survival and overall survival were, respectively, 81% and 85% among patients with tumors presenting the 3R3R genotype, and 62% and 67% among patients with tumors presenting 2R2R or 2R3R genotypes. These differences were not statistically significant. Conclusions: in this sample, the TS polymorphic tumor genotype 3R3R was associated with lower risk of lymph node metastases in colon carcinomas.
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Mulder, K. E., C. A. Butts, A. Scarfe, H. Au, S. Koski, A. Fields, J. Hanson, M. Kuzma, K. Graham, and M. B. Sawyer. "A prospective pharmacogenetic study of thymidylate synthase (TS) polymorphisms in high risk stage II or stage III colon cancer patients treated with 5-fluorouracil (5-FU) and leucovorin (LV)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13018. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13018.
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13018 Background: Retrospective studies suggest TS polymorphisms predict toxicity from TS inhibitors as well as therapeutic response. The TS promoter has a variable number of tandem repeats (VNTR) polymorphism containing putative E-box binding sites that bind upstream stimulatory factor (USF) -1 and -2. One E-box binding site exists in TSER*2 and 2 binding sites exist in TSER*3. A single nucleotide polymorphism (SNP) at position 12 (G→C) in TSER*3’s 2nd repeat abolishes binding of USF-1/2. Combined effects of VNTR and SNP means individuals may have 2, 3 or 4 enhancer regions. We hypothesized that decreased enhancer numbers predicts for patients at risk for grade ≥3 mucositis, diarrhea, neutropenia, and overall toxicity and performed a prospective pharmacogenetic study of TS polymorphisms in adjuvant colon cancer patients treated with 5-FU/LV. Methods: High risk Stage II or Stage III colon cancer patients treated with 5FU/LV (425 mg/m2/ 20 mg/m2) daily for 5 days every 4 weeks had blood drawn for genotyping prior to starting therapy. Patients were assessed for toxicity using NCI CTC 2.0 in cycle 1. Three year disease-free survival will also be assessed. Results: 103 patients were enrolled and genotyped with 95 evaluable for toxicity. Patient characteristics: median age 61yrs (36–79): M 52%/F 48%; Stage III 77%, Stage II 23%. Frequency of genotypes containing 2 enhancers (TSER*2/ TSER*2, TSER*2 / TSER*3C, TSER*3C/ TSER*3C), 3 enhancers (TSER*2/ TSER*3G, TSER*3C/ TSER*3G) and 4 enhancers (TSER*3G/ TSER*3G) was 0.64, 0.31, and 0.05 respectively. No significant difference was seen in overall toxicity, mucositis, diarrhea and neutropenia based on TS polymorphism genotypes. Frequency of recurrence in 2 enhancer patients was 13% versus 26% in 3/4 enhancer patients but this did not reach statistical significance (p = 0.16). Conclusions: This prospective study does not confirm previously published retrospective studies suggesting that TS VNTR and SNP predict toxicity from TS inhibitors in patients treated with 5-fluorouracil for colon cancer. There is a trend for prediction of recurrence which requires further follow-up. No significant financial relationships to disclose.
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Jeon, Young-Joo, Sung-Hwan Cho, Eo-Jin Kim, Chang-Soo Ryu, Han-Sung Park, Jong-Woo Kim, Jeong-Yong Lee, Hui-Jeong An, and Nam-Keun Kim. "3′-UTR Polymorphisms in Thymidylate Synthase with Colorectal Cancer Prevalence and Prognosis." Journal of Personalized Medicine 11, no. 6 (June 9, 2021): 537. http://dx.doi.org/10.3390/jpm11060537.
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Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related mortality in Western countries. Polymorphisms in one-carbon metabolism and angiogenesis-related genes have been shown to play important roles in tumor development, progression, and metastasis for many cancers, including CRC. Moreover, recent studies have reported that polymorphisms in specific microRNA (miRNA)-binding regions, which are located in the 3′-untranslated region (UTR) of miRNA-regulated genes, are present in a variety of cancers. Here, we investigated the association between two thymidylate synthase (TYMS or TS) 3′-UTR polymorphisms, 1100T>C [rs699517] and 1170A>G [rs2790], and CRC susceptibility and progression in Korean patients. A total of 450 CRC patients and 400 healthy controls were enrolled in this study, and genotyping at the TS locus was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) or TaqMan allelic discrimination assays. We found that TS 1170A>G genotypes, as well as the TS 1100T-1170G and 1100C-1170A haplotypes, are strongly associated with CRC. The TS 1100TC+CC type was associated with a poor survival (OS and RFS) rate. In addition, levels of the TS 1100C and TS 1170G allele were found to be significantly increased in CRC tissue. Our study provides the first evidence for 3′-UTR variants in TS genes as potential biomarkers of CRC prognosis and prevention.
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Takeda, R., T. Kamano, K. Sakamoto, M. Sugano, S. Hosoda, T. Watanabe, T. Maeda, and Y. Kojima. "Methylenetetrahydrofolate Reductase C677T is Not Associated with Expression of Pyrimidine Metabolic Enzyme Genes in Colorectal Cancer." Journal of International Medical Research 34, no. 3 (May 2006): 307–15. http://dx.doi.org/10.1177/147323000603400311.
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Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the chemosensitivity of colorectal cancers to fluorouracil (5-FU) by increasing intracellular 5, 10-methylenetetrahydrofolate. The effect of this polymorphism on the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP) in colorectal cancer was investigated. The MTHFR C677T polymorphism was analysed and TS, DPD, OPRT and TP mRNA expression was measured in tumour and adjacent normal mucosal tissue. In all patients, the genotypes of the tumour and normal tissues were identical. No differences were found in the expression of TS, DPD or TP mRNA by genotype in either tumour or normal tissue. Although the OPRT mRNA level in tumour tissue was not associated with the genotype, normal mucosa with the TT genotype showed a significantly higher OPRT mRNA level than mucosa with other genotypes. The MTHFR C667T polymorphism is not associated with intratumoural expression of TS, DPD, OPRT or TP.
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Etienne, Marie-Christine, Maurice Chazal, Pierre Laurent-Puig, Nicolas Magné, Christophe Rosty, Jean-Louis Formento, Mireille Francoual, et al. "Prognostic Value of Tumoral Thymidylate Synthase and p53 in Metastatic Colorectal Cancer Patients Receiving Fluorouracil-Based Chemotherapy: Phenotypic and Genotypic Analyses." Journal of Clinical Oncology 20, no. 12 (June 15, 2002): 2832–43. http://dx.doi.org/10.1200/jco.2002.09.091.
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PURPOSE: The aim of this multicenter prospective study was to evaluate the role of intratumoral parameters related to fluorouracil (FU) sensitivity in 103 metastatic colorectal cancer patients receiving FU–folinic acid. PATIENTS AND METHODS: Liver metastatic biopsy specimens were obtained for all patients and primary tumor biopsy specimens for 54 patients. Thymidylate synthase (TS), folylpolyglutamate synthetase, and dihydropyrimidine dehydrogenase were measured by radioenzymatic assays; TS promoter polymorphism (2R/2R v 2R/3R v 3R/3R) was determined by polymerase chain reaction; and p53 protein and mutations were analyzed by immunoluminometric assay and denaturing gradient gel electrophoresis, respectively. RESULTS: p53 mutations were observed in 56.7% of metastases. TS activity was significantly higher in 2R/3R tumors as compared with 2R/2R or 3R/3R. TS activity in metastasis was the only parameter linked to clinical responsiveness (responders exhibited the lower TS, P = .047). Univariate Cox analyses demonstrated that TS activity in primary tumor (the greater the TS, the poorer the survival; P = .040), TS promoter polymorphism in primary tumor (risk of death of 2R/3R v 2R/2R, 2.68; P = .035), and p53 stop mutation in metastasis (risk of death of stop mutations v wild type, 3.14; P = .018) were the only significant biologic predictors of specific survival. Stepwise analysis did not discriminate between TS activity and TS polymorphism. CONCLUSION: Present results confirm the value of tumoral TS activity for predicting FU responsiveness, point out the importance of detailed p53 mutation analysis for predicting survival, and suggest that TS genotype in primary tumor carries a prognostic value similar to that of TS activity.
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Goekkurt, Eray, Salah-Eddin Al-Batran, Jörg T. Hartmann, Ulrike Mogck, Gunter Schuch, Michael Kramer, Elke Jaeger, Carsten Bokemeyer, Gerhard Ehninger, and Jan Stoehlmacher. "Pharmacogenetic Analyses of a Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma With Fluorouracil and Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie." Journal of Clinical Oncology 27, no. 17 (June 10, 2009): 2863–73. http://dx.doi.org/10.1200/jco.2008.19.1718.
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PurposeTo evaluate the association of germ-line polymorphisms of genes that may impact treatment outcome of platinum and fluorouracil combination chemotherapy in advanced gastric cancer (AGC).Patients and MethodsBlood samples of 156 patients enrolled onto a phase III study comparing fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin were collected. Polymorphisms within genes of TS, MTHFR, MTR, OPRT, XPD, ERCC1, XRCC1, XPA, GSTP1, GSTT1, and GSTM1 were genotyped using polymerase chain reaction–based techniques.ResultsMedian overall survival (OS) was 11.8 months (95% CI, 9.75 to 13.79 months) and median progression-free survival (PFS) was 5.8 months (95% CI, 4.99 to 6.61 months). The TS-3R/+6 haplotype (P = .004), the GSTT1 deletion polymorphism (P = .015), and genotypes of OPRT-Gly213Ala (P = .003) and XRCC1-Arg399Gln (P = .023) could be identified as independent predictors of OS. For PFS analyses, the TS-3R/+6 haplotye (P = .003) and MTR-A2756G (P = .01) were identified as independent positive predictors. The association between the GSTT1 deletion polymorphism and PFS showed only borderline significance (P = .053). Treatment related hematotoxicity in terms of grade 3/4 leukopenia was lowest among TS-3R/+6 haplotype carriers (P = .037). Grade 3/4 neutropenia was directly associated with the MTR-2756G/G genotype (P = .011), GSTP1-105Ile/Ile genotype (P = .02), and with the ERCC1-118T/8092C-haplotype (P = .042). In addition, significant associations between GSTP1-105Ile/Ile genotype and neurotoxicity and between the XPD-Asn312/751Gln haplotype and nephrotoxicity could be identified (P = .028 and P = .005, respectively).ConclusionThese findings underline the hypothesis that germ-line polymorphisms may play an important role in individualizing chemotherapy in AGC and deserve further prospective evaluation in AGC patients.
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Jankovic, Radmila, Milena Cavic, Ana Krivokuca, Ksenija Jakovljevic, Emina Malisic, Jelena Spasic, Davorin Radosavljevic, and Sinisa Radulovic. "Gene polymorphisms of folate metabolizing enzymes and susceptibility to lung adenocarcinoma in Serbia." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e12020-e12020. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e12020.
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e12020 Background: Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are important enzymes of the folate metabolism and are suggested as new prognostic factors for lung cancer. Cytosine to thymine transition at nucleotide 677 (C677T) leads to reduced MTHFR activity. The TS promoter has a tandem repeat polymorphism (2R, 3R) and a guanine to cytosine transition in the 3R allele related to TS protein expression. The aim of this study was to analyze the association of MTHFR and TS polymorphisms with lung adenocarcinoma in Serbia. Methods: A case-control study including 55 late-stage lung adenocarcinoma patients and 53 healthy subjects was performed. Restriction fragment length polymorphism analysis was used for MTHFR and TS genotyping. Depending on the presence of high (3RG) or low (2R, 3RC) expression alleles, TS functional groups were subclassified into HH (3RG/3RG), HL (2R/3RG, 3RG/3RC) and LL (2R/2R, 2R/3RC, 3RC/3RC) groups. Descriptive analyses included genotype and allelic frequencies; the odds ratio (OR) and 95 % confidence interval (CI) were calculated as an estimate of relative risk. Significance was considered for p < 0.05. Results: The distribution of the MTHFR variants in patients vs. controls was 61.8 % vs. 24.5 % for CC, 32.7 % vs. 62.3 % for CT and 5.5 % vs. 13.2 % for TT. A significant difference in CC vs. TT+CT MTHFR genotype distribution was observed between patients and controls (χ2 = 13.79; OR = 4.98; 95 % CI, 2.14 – 11.61). There was no significant association between the TS polymorphisms and the risk of lung adenocarcinoma occurrence, but in the CT+TT MTHFR subgroup, a nonsignificant difference in LL vs. HL+HH TS genotype distribution was observed between patients and controls (χ2 = 0.04; OR = 1.07; 95% CI, 0.31 – 3.67). Conclusions: A significant corelation between the CC MTHFR genotype and lung adenocarcinoma occurence in Serbia was found. Also, there was no significant correlation with lung adenocarcinoma occurence in the CT+TT MTHFR subgroup for carriers of the LL TS genotype. As this study was performed on a relatively small sample size further large case-control studies including analysis of gene-gene interactions with genes coding for other folate metabolism enzymes is needed.
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Romkes, M., T. M. Feinstein, S. Zhong, S. Buch, M. K. Gibson, K. Skovira, and A. Argiris. "TS and MTHFR gene polymorphisms in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head or neck (SCCHN) treated with pemetrexed (P) and bevacizumab (B)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e17011-e17011. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e17011.
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e17011 Background: P inhibits multiple enzymes in folate metabolism. We examined polymorphisms in thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) in patients with SCCHN treated in a phase II clinical trial with P and B (ASCO 2008; A6069). Methods: All pts were treated with P 500 mg/m2 and B 15 mg/kg, given IV every 21 days until progression. Primary endpoint was time to progression (TTP). DNA was isolated from whole blood samples using commercially available kits. Polymorphisms examined were MTHFR (C677T, A1298C and G1793A) and TS (TS2R3R, TSG2RG and TSmut6). The MTHFR SNPs were detected using TaqMan based SNP genotyping kits from Applied Biosystems, run on the ABI Prism 7700 Sequence Detection systems v 1.7 (Foster City, CA). The TS promoter repeat and promoter SNP polymorphisms and the 3’ untranslated region 6 bp deletion polymorphism were determined using published methods to detect PCR product size and RFLP-PCR assays respectively. Results: 22 pts were genotyped from 34 enrolled. There was no significant difference in characteristics between pts with and without genotype data. For the MTHFR polymorphism C677T, there was a trend towards decreased disease control rate (DCR) (CR/PR/SD) (p = 0.058, Jonckheere-Terpstra trend test) and worse TTP (p = 0.04) transitioning from variant CC to CT to TT; comparing TT genotype versus CT and CC combined, pts with TT had inferior DCR (p = 0.03) and TTP (p = 0.0003); homozygotes with TT had a median TTP of 2.6 months (mo) 95% CI (1.4, NA) versus 5.6 mo (4.2, 11.4) for pts with CT or CC variants. For the MTHFR A1298C SNP, there was no significant difference in DCR between variants, median TTP for homozygotes pts with AA was 4.1 mo (2.6, NA) vs. 6.7 mo (5.1, NA) in pts with AC or CC variants (p = 0.084); median overall survival for AA was 10.2 mo (7.6, NA) and for AC or CC 17.6 mo (17, NA) (p = 0.045). The MTHFR G1793A and TS polymorphisms did not impact DCR, TTP or overall survival. There was no association between any polymorphism and the incidence of grade >2 toxicities. Conclusions: Polymorphisms in MTHFR are potentially associated with antitumor efficacy of P-based therapy in recurrent or metastatic SCCHN. These results warrant validation in larger studies with P in SCCHN. No significant financial relationships to disclose.
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Ioannou, Charalampia, Georgia Ragia, Ioanna Balgkouranidou, Nikolaos Xenidis, Kyriakos Amarantidis, Triantafyllia Koukaki, Eirini Biziota, Stylianos Kakolyris, and Vangelis G. Manolopoulos. "Gender-dependent association of TYMS-TSER polymorphism with 5-fluorouracil or capecitabine-based chemotherapy toxicity." Pharmacogenomics 22, no. 11 (July 2021): 669–80. http://dx.doi.org/10.2217/pgs-2021-0031.
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Aim: TYMS gene encodes for TS enzyme involved in 5-fluorouracil (5-FU) and capecitabine (CAP) metabolism. This study assessed the association of TYMS-TSER and 3RG>C polymorphisms with 5-FU/CAP adverse event (AE) incidence. Materials & methods: TYMS-TSER and 3RG>C polymorphisms were analyzed by use of PCR/PCR-RFLP in 313 5-FU/CAP-treated cancer patients. Results: Female TYMS-TSER 2R carriers were at increased risk for 5-FU/CAP AEs (odds ratio: 2.195; p = 0.032). 2R/2R genotype was the only factor that increased risk for delayed drug administration or therapy discontinuation (odds ratio: 5.049; p = 0.016). No other associations were found. Conclusion: TYMS-TSER 3R/2R polymorphism was associated with incidence of AEs in female cancer patients. This gender-driven association potentially implicates the ER that, in female patients, potentially regulates TS expression.
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Kuramochi, H., K. Tanaka, B. J. Lehman, C. M. Dunst, D. S. Oh, S. R. Demeester, J. A. Hagen, K. D. Danenberg, T. R. Demeester, and P. V. Danenberg. "Thymidylate synthase polymorphisms and its mRNA expression levels as independent chemo-predictive markers in esophageal adenocarcinoma patients receiving 5-fluorouracil chemotherapy." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4063. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4063.
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4063 Background: Thymidylate synthase (TS) has either a two or three 28bp tandemly repeated sequence in the 5’ untranslated (UTR) region. The triple repeat allele (3R) is classified into 2 subgroups (3RG, 3RC) according to a G/C polymorphism in the 3R sequences. Another polymorphism is a 6bp deletion in the 3’-UTR region. The genotype with either 3RG allele or 6bp insertion allele has been reported to be associated with high TS expression and chemoresistance to 5-FU. Methods: 83 patients with esophageal adenocarcinoma were assessed. Thirty-four had received 5-FU containing chemotherapy (16 adjuvant therapy, 12 upon recurrence, 3 both adjuvant and recurrence, 3 neoadjuvant) and 49 were treated with surgery alone. Surgically resected tumor tissues were analyzed for TS genotype and TS mRNA expression using a quantitative real-time RT-PCR method after microdissection. Results: No survival difference was seen between the patients with 3RG allele (3RG group) and non-3RG group among surgery-alone patients. However, among patients with a history of 5-FU-based chemotherapy, the non-3RG group showed significantly better overall survival compared to the 3RG group (p = 0.02). Moreover, whereas chemotherapy produced a significant increase in survival for the non-3RG group patients, those in the 3RG group obtained no survival benefit from chemotherapy. Patients with low TS mRNA levels had significantly better survival than the patients with high TS mRNA levels (p = 0.03) among chemotherapy-treated patients, despite the fact that there was no difference of median TS mRNA levels between 3RG and non-3RG group. Those who had both the non-3RG genotype and low TS mRNA levels obtained a significantly better survival benefit from chemotherapy than others (p = 0.02). The 3’-UTR polymorphism did not appeared to be associated with overall survival. Conclusions: The status of the TS 5’-UTR polymorphism and TS mRNA expression are independent predictive markers for survival benefit from 5-FU-based therapy in patients with esophageal adenocarcinoma. [Table: see text]
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Reia, Thaís Amanda, Roberta Fernanda da Silva, André Mourão Jacomini, Ana Maria Guilmo Moreno, Letícia Perticarra Ferezin, Sherliane Carla Pereira, Riccardo Lacchini, Thiago José Dionísio, Carlos Ferreira Santos, and Anderson Saranz Zago. "Acute Exercise, Plasma Nitric Oxide, and Blood Pressure in Older Adults With Different Levels of Training Status: The Influence of Polymorphisms of Endothelial Nitric Oxide Synthase." Journal of Physical Activity and Health 18, no. 5 (May 1, 2021): 516–23. http://dx.doi.org/10.1123/jpah.2020-0442.
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Background: This study aimed to analyze the acute effect of physical exercise on nitric oxide concentration and blood pressure (BP) in older adults with different levels of training status (TS) and verified the influence of endothelial nitric oxide synthase polymorphisms on these variables. Methods: A total of 145 older adults were divided into good TS (G1) and weak TS (G2). Participants were subjected to a 40-minute treadmill walk (40%–60% of maximum oxygen consumption) with BP measurements and blood collections for plasma nitrite and oxidative stress biomarkers at pretest and posttest moments. Data were analyzed by 2-way repeated-measures with Sidak post hoc test (P < .05) and multivariate linear analysis. Results: After acute exercise, G2 showed an increase in oxidative stress biomarkers (P = .008), and both groups showed an increase in systolic BP (P < .001). Polymorphisms 894G > T and intron 4b/a had no association with nitrite and BP. However, −786T > C polymorphism showed an association with reduced systolic and diastolic BP (TT genotype) and increased diastolic BP (TC genotype). Higher TS level was also associated with lower BP. Conclusion: The maintenance of good TS levels may have a protective effect on cardiovascular risks regardless of the genetic profile.
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Marcuello, E., L. Pare, A. Altes, E. Del Rio, L. Sedano, A. Barnadas, and M. Baiget. "Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving 5-fluorouracil (FU)/oxaliplatin (OX) as first-line chemotherapy." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2509. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2509.
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2509 Background: Chemotherapy using oxaliplatin, 5-fluorouracil is known to be effective in the treatment of CRC patients. Optimization of this therapy is complicated due to wide variability in drug response that may be due to functional genomic polymorphisms in genes related to the drug target, to the metabolizing or to the DNA repair. We report the evaluation of polymorphisms in the TS, MTHFR (drug target) ERCC1, XPD and GSTP1 (repair enzymes) genes. Methods: We treated 109 CRC patients with a first line oxaliplatin/5-FU chemotherapeutic regimen. Genetic polymorphisms were determined by PCR based RFLP or by Real-Time PCR on an ABI PRISM 7000, using DNA from peripheral blood. The investigated polymorphisms were: TS (VNTR in the 5’ UTR, the 3R G>C SNP and the 1494del6), ERCC1 (Asn118Asn, 8092C>A, 19716 G>C), GSTP1 (Ile105Val) and XPD (Lys751Gln). Clinical response (CR), progression free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: The patients were classified according to the clinical risk assessment (CRA) defined by EORTC in three groups with different DFS (12, 9, 7 months; P= 0.008) and different OS (41,19,11 months; P= 0.0002). In the univariate analysis for CR, ERCC1 and XPD polymorphisms were significant (P=0.03, P= 0.047, respectively). After adjustment for the mentioned clinical risk assessment, only ERCC1 retained significance (P=0.037; HR: 4.2, C/C vs T/T). In the univariate analysis for PFS, only ERCC1 polymorphism was significant (P=0.034). After adjustment for the clinical risk, this genotype did not retained its significance (P=0.37). Finally, TS, ERCC1 and XPD polymorphisms were significant in the univariate analysis for overall survival, (P=0.032, P=0.003, P=0.016 respectively). Following the adjustement for the clinical risk, all three genotype variables retained significance (P=0.019, P=0.002, P= 0.024, respectively). Conclusions: i) The EORTC risk assessment classification was a very useful predictor of DFS and OS in our group of patients; ii) Germline genetic polymorphism of ERCC1 predicted response to FU/OX in CRC patients and iii) Polymorphisms in the TS, ERCC1 and XPD genes were good predictors of overall survival. No significant financial relationships to disclose.
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Scalco, Renata C., Ericka B. Trarbach, Edoarda V. A. Albuquerque, Thais K. Homma, Thais H. Inoue-Lima, Mirian Y. Nishi, Berenice B. Mendonca, and Alexander A. L. Jorge. "ESR1 polymorphism (rs2234693) influences femoral bone mass in patients with Turner syndrome." Endocrine Connections 8, no. 11 (November 2019): 1513–19. http://dx.doi.org/10.1530/ec-19-0398.
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Most patients with Turner syndrome (TS) need hormone replacement therapy because of hypergonadotropic hypogonadism; individual outcomes, however, are highly variable. Our objective was to assess the influence of five estrogen receptor 1 gene (ESR1) polymorphisms (rs543650, rs1038304, rs2046210, rs2234693 and rs9340799) on adult height, breast development, uterine volume and bone mineral density (BMD). We studied 91 TS patients from a tertiary hospital using adult estrogen dose. In our group, ESR1 rs2234693 was associated with femoral neck and total hip BMD, and it accounted for around 10% of BMD variability in both sites (P < 0.01). Patients homozygous for C allele in this polymorphism had significantly lower femoral neck BMD (0.699 ± 0.065 g/cm2 vs 0.822 ± 0.113 g/cm2, P = 0.008) and total hip BMD (0.777 ± 0.118 g/cm2 vs 0.903 ± 0.098 g/cm2, P = 0.009) than patients homozygous for T allele. The other four ESR1 polymorphisms were not able to predict any of the above estrogen therapy outcomes in an isolated manner. Patients homozygous for the haplotype GCG formed by polymorphisms rs543650, rs2234693 and rs9340799 had an even more significantly lower femoral neck BMD (0.666 ± 0.049 vs 0.820 ± 0.105 g/cm2, P = 0.0047) and total hip BMD (0.752 ± 0.093 vs 0.908 ± 0.097 g/cm2, P = 0.0029) than patients homozygous for haplotypes with a T allele in rs2234693. In conclusion, homozygosity for C allele in ESR1 rs2234693 and/or for GCG haplotype appears to be associated with lower femoral neck and total hip BMD. We believe that the identification of polymorphisms related to estrogen outcomes may contribute to individualization of treatment in TS.
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Dotor, Emma, Miriam Cuatrecases, María Martínez-Iniesta, Matilde Navarro, Felip Vilardell, Elisabeth Guinó, Laura Pareja, et al. "Tumor Thymidylate Synthase 1494del6 Genotype As a Prognostic Factor in Colorectal Cancer Patients Receiving Fluorouracil-Based Adjuvant Treatment." Journal of Clinical Oncology 24, no. 10 (April 1, 2006): 1603–11. http://dx.doi.org/10.1200/jco.2005.03.5253.
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Purpose The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. Patients and Methods One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. Results Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/–6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. Conclusion Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.
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Skibola, Christine F., Martyn T. Smith, Alan Hubbard, Barry Shane, Abby C. Roberts, Graham R. Law, Sara Rollinson, Eve Roman, Raymond A. Cartwright, and Gareth J. Morgan. "Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia." Blood 99, no. 10 (May 15, 2002): 3786–91. http://dx.doi.org/10.1182/blood.v99.10.3786.
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We previously reported that 2 polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic leukemia (ALL). In the present study, we have examined whether polymorphisms in other folate-metabolizing genes play a role in ALL susceptibility. Polymorphisms in methionine synthase (MS A2756G), cytosolic serine hydroxymethyltransferase (SHMT1 C1420T), and a double (2R2R) or triple (3R3R) 28-bp tandem repeat in the promoter region of thymidylate synthase (TS) were studied and found to modulate ALL risk. In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.25-0.91), whereas the 1420TT genotype conferred a 3.3-fold reduction in risk (OR = 0.31; 95% CI, 0.10-0.90). Similarly, TS 2R3R individuals exhibited a 2.8-fold reduction in ALL risk (OR = 0.36; 95% CI: 0.16-0.83), while the TS 3R3R genotype conferred an even greater level of protection (OR = 0.25; 95% CI, 0.08-0.78). However, no significant associations were evident for the MS 2756AG polymorphism (OR = 0.79; 95% CI, 0.38-1.7). In addition, potential interactions between theSHMT1 and TS or MS genes were observed. TS 3R3R individuals who were SHMT1 1420CT/TT had a 13.9-fold decreased ALL risk (OR = 0.072; 95% CI, 0.0067-0.77). Further, MS 2756AG individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in ALL risk (OR = 0.18; 95% CI, 0.05-0.63). This study suggests an important role for uracil misincorporation and resultant chromosomal damage in the pathogenesis of ALL, and that genetic interactions involving low penetrance polymorphisms in folate-metabolizing genes may increase ALL risk.
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Falandry, C., B. You, G. Milano, E. Chatelut, C. Rebischung, O. Glehen, D. Mille, et al. "Individual genotyping to optimize chemotherapy in metastatic colorectal cancer (MCRC): The COLOGEN trial." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2510. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2510.
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2510 Background: Thymidilate synthase (TS) and UGT1A1 genetic polymorphisms assessment helps to predict 5-FU efficacy and irinotecan toxicity - SN38 inactivation - respectively. We used this information to individualize MCRC first-line chemotherapy in the multi-centre COLOGEN trial. Methods: Were included first-line histologically proven MCRC patients (pts) aged 18–85, PS=2. Genotyping was performed on pts’ lymphocytes sampled at most 10 days before chemotherapy. Pts with 2R/2R or 2R/3R TS profile had subsequent UGT1A1 polymorphism determination. Those with 6/6 or 6/7 UGT1A1 profile received high dose bimonthly FOLFIRI (Irinotecan 260 mg/m2), whereas those with “defavorable” 7/7 polymorphism received standard FOLFIRI (Irinotecan 180 mg/m2). In pts with overexpressed TS (3R/3R), chemotherapy was left to investigator’s decision. Results: To date, 32 pts/65 planned have been included, aged 44 to 83 (mean: 65,2, median: 64). Six pts (19 %) had 3R/3R TS profile. Among those with 2R/2R or 2R/3R profile, 15 % (4/26) had defavorable 7/7 UGT1A1 profile. Median time for genotypic determination was 5 days for UGTA1 and 5 for TS. Treatment was: high-dose FOLFIRI, 23 pts (72 %); standard FOLFIRI ± bevacizumab, 3 pts (9 %); other regimens including capecitabine and/or oxaliplatin, 6 pts (16 %). Toxicities: we observed no toxic death. Serious adverse events were: febrile neutropenia (1, high dose FOLFIRI regimen) and grade 4 hypokaliemia (1, non FOLFIRI regimen). Eight patients over 70 years old and 3 over 80 received high-dose FOLFIRI without significant toxicity. Conclusions: Those preliminary results are the first ever reported on individual genotyping as a tool for treatment optimization in a multi-centre setting. This strategy appears clearly feasible and allows to safely intensify chemotherapy, even in elderly patients. No significant financial relationships to disclose.
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Price, R. A., R. S. Spielman, A. L. Lucena, J. A. Van Loon, B. L. Maidak, and R. M. Weinshilboum. "Genetic polymorphism for human platelet thermostable phenol sulfotransferase (TS PST) activity." Genetics 122, no. 4 (August 1, 1989): 905–14. http://dx.doi.org/10.1093/genetics/122.4.905.
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Abstract Platelet TS PST basal activity and thermal stability were measured in blood samples from 237 individuals in 50 nuclear families. Significant correlations were found among first degree relatives, confirming the previously reported familial aggregation of TS PST basal activity and thermal stability. Commingling analysis of basal TS PST activity provided evidence for multiple component distributions, and after transformation to remove skewness, segregation analysis supported a major gene hypothesis. For TS PST thermal stability, commingling analysis also provided evidence for multiple component distributions. However, segregation analyses were equivocal with regard to the presence of a major gene for thermal stability, since support for a major gene model depended on skewness. Bivariate commingling analysis, which examined thermal stability by simultaneously considering basal activity and activity after heating, suggested that genotypes, as defined by the inferred component distributions for TS PST activity, differ in thermal stability. A three-allele model is proposed as one hypothesis that may account for the combined results of basal activity and thermal stability. The results of this study indicate that a major gene polymorphism in conjunction with polygenic inheritance plays an important role in the regulation of both level of activity and thermal stability of this important drug-metabolizing enzyme in humans.
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Awan, Saad, Girijesh K. Patel, Anu Singh Maharjan, Gwendolyn A. McMillin, William R. Taylor, Sachin Pai, Arthur E. Frankel, et al. "Germline pharmacogenomics of thymidylate synthase gene in patients with gastrointestinal malignancies treated with fluoropyrimidines-based chemotherapy regimens." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 545. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.545.
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545 Background: Fluoropyrimidines are antimetabolites that target the S phase of the cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits thymidylate synthase (TS) enzyme, thus preventing DNA synthesis and ultimately cell death. While controversy exists in the literature, polymorphism in the promoter region of thymidylate synthase gene (TYMS) that decrease TS expression has been associated with increased fluoropyrimidines-associated toxicities. This study explored the association between polymorphism in the promoter region of TYMS gene and fluoropyrimidines-associated toxicities in patients with gastrointestinal malignancies with mixed racial background. Methods: Between 2011 and 2018, 126 patients were genotyped for TYMS. Patients with known high-risk dihydropyrimidine dehydrogenase gene variants were excluded. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institiute Common Terminology Criteria for Adverse Events (v 5.0). Fisher’s exact test was used for statistical analysis. Results: TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 toxicity (22%) while among patients with genotypes that predict decreased TS expression, 30 patients had grade 3-4 toxicities (42%) (P = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3-4 toxicity (P = 0.0039) and 15 out 40 patients (38%) with 2R/3RC and 3RC/3RC TYMS genotype had grade 3-4 toxicity (P = 0.1108). Among patients with 2R/2R TYMS, Caucasians represented 61% and African Americans represented 39%. Females represented 65% of the patients. Conclusions: Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3-4 fluoropyrimidines-associated toxicities.
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Kuramochi, H., K. Hayashi, G. Nakajima, H. Kamikozuru, and M. Yamamoto. "Evaluation of thymidylate synthase and ERCC1 mRNA levels as predictive markers in colorectal cancer patients treated with S-1 and oxaliplatin." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e15071-e15071. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15071.
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e15071 Background: Oxaliplatin has been widely used for the treatment of colorectal cancer. The mechanism of action of platinum compounds such as oxaliplatin is to bind to a DNA molecule in the form of a platinum-DNA-adduct. Excision repair cross complementation group 1 (ERCC1), which plays a major role in the nucleotide excision pathway, has a polymorphism in codon 118, and is reported to be associated with a resistance to platinum-based therapy. Thymidylate synthase (TS) and dehydropyrimidine dehydrogenase (DPD) are key enzymes of 5-FU metabolism and are well known to be associated with a response to 5-FU-based therapy. Methods: Twenty-one colorectal cancer patients (male:female = 7:14; median age, 65) treated with a combination of oxaliplatin and S-1 as a first-line therapy were analyzed for ERCC1 codon 118 polymorphism and the mRNA expression levels of TS, ERCC1, and DPD. Formalin-fixed paraffin- embedded surgical specimens were used and t-RNA and DNA were extracted. The mRNA expression levels were measured using real-time RT-PCR, and the polymorphism was analyzed using the allelic discrimination method together with real-time PCR. Results: No correlation was observed between ERCC1 codon118 polymorphism and any response to the chemotherapy. ERCC1 mRNA levels tended to be higher in the patients with wild-type homozygous alleles in codon 118 than in those with at least one mutant allele(1.19 vs.0.68: p= 0.15). Patients with both high TS and ERCC1 mRNA levels showed a significantly lower response rate than the others (25% vs. 67%, p=0.02). No relationship was seen between DPD mRNA expression levels and the response. Conclusions: The mRNA expression levels of TS and ERCC1 appear to be useful markers for the treatment of S-1 and oxaliplatin. No particular usefulness of ERCC1 codon 118 polymorphism was verified. No significant financial relationships to disclose.
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Jakobsen, Anders, Jens Nederby Nielsen, Niels Gyldenkerne, and Jan Lindeberg. "Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphism in Normal Tissue As Predictors of Fluorouracil Sensitivity." Journal of Clinical Oncology 23, no. 7 (March 1, 2005): 1365–69. http://dx.doi.org/10.1200/jco.2005.06.219.
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Purpose To analyze thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with respect to fluorouracil (FU) sensitivity. Patients and Methods The study included a retrospective analysis of 88 patients with metastatic colorectal cancer and a prospective trial with 51 patients also with measurable metastases. All patients were treated with FU and leucovorin. The analysis of gene polymorphism was performed on normal intestinal tissue and lymphocytes. Results The response rate was significantly higher in patients with TS 3R/3R or MTHFR 677 TT gene polymorphism compared with the other groups. The difference of response rate translated to a difference in time to progression. Similar results were observed in the retrospective analysis and the prospective confirmatory trial. Conclusion The analysis of gene polymorphism allows delineation of a group of patients (30%) with a response rate to a single drug of approximately 50%. This information should be used in the design of tailored treatment.
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Ishibashi, K., N. Okada, T. Ishiguro, M. Yokoyama, T. Miyazaki, M. Sano, H. Yamada, and H. Ishida. "Polymorphisms of GSTP1, GSTT1, GSTM1, MTHFR, TS, ERCC1, and ERCC2 in metastatic colorectal cancer treated by first-line mFOLFOX6 chemotherapy." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e14628-e14628. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14628.
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e14628 Background: It was reported that determining functional polymorphisms of genes involved in drug-metabolising pathways and DNA repair may be useful for predicting the response to 5-FU/oxaliplatin chemotherapy in Caucasian patients with metastatic colorectal cancer. This study was performed to examine whether determining these polymorphisms had any clinical value in Asian patients with colorectal cancer receiving 5-FU/oxaliplatin therapy. Methods: Genomic DNA was extracted from peripheral blood lymphocytes (n=25) or colonic mucosa (n=47) in Japanese patients with metastatic colorectal cancer who were receiving first-line therapy with the modified FOLFOX6 regimen followed by FOLFIRI (n=42). Polymorphisms of 5 genes involved in drug metabolism (glutathione S-transferase (GST) P1 (IIe 105 Val), GSTT1 deletion, and GSTM1 deletion, methylenetetrahydrofolate reductase (MTHFR) (Ala 677 Val), and a 6-base pair (bp) deletion in the 3’-untranslated region (UTR) of thymidylate synthase (TS)), and polymorphisms of two DNA repair genes (excision repair cross complementing group 1 (ERCC1): Asp 118 Asn and ERCC2: Lys 751 Gln) were assessed in these patients by PCR-RFLP or the invader technique. Correlations between polymorphisms of these genes and the response to therapy were evaluated. Results: The distribution of the genotypes of GSTP1, GSTT1, TS, ERCC1, and ERCC2 in the present Japanese patients (but not that of GSTM1 or MTHFR), differed significantly from the distribution of these genotypes in a Caucasian population. The response rate and progression-free survival were not correlated with any of the functional polymorphisms investigated. However, patients who had both alleles containing the 6-bp nucleotide fragment in the 3’UTR of TS showed significantly shorter overall survival than those who had at least one allele without the 6-bp nucleotide fragment (p=0.03). Conclusions: These results suggest that 3’UTR polymorphism of TS may be an important predictor of overall survival for Japanese patients with metastatic colorectal cancer receiving first-line 5-FU/oxaliplatin therapy. No significant financial relationships to disclose.
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Feng, Fu Juan, Dan Zhao, Xin Sui, and Xiao Yan Sun. "Study on Mating System of Pinus koraiensis in Natural Population Based on cpSSR Technology." Advanced Materials Research 183-185 (January 2011): 700–704. http://dx.doi.org/10.4028/www.scientific.net/amr.183-185.700.
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Chloroplast simple sequence repeat (cpSSR) technique was firstly used to study mating system of natural Pinus koraiensis population. Nine pairs of primers with clear spectrum bands, high stability and polymorphism were selected from 70 pairs of cpSSR primers to analyze the mating systems of 28 individuals. 14 polymorphic loci were detected in the nine pairs of primers. The multi-locus (tm) and single-locus (ts) outcrossing rate were 0.966 (SD=0.000) and 0.939 (SD=0.000), respectively, which were slightly higher than those of other tree species. The constant index (F=-0.035) was below zero, indicating the occurrence of excessive heterozygote. Moreover, inbreeding index (tm-ts=0.027; SD=0.000) was close to zero, indicating an insignificant inbreeding. MLDT analysis showed that multi-locus outcrossing rate differed from single-locus outcrossing rate in mating systems of 28 individuals, but the differences were not statistically significant.
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Duca, Lorena, Francesca Granata, Elena Di Pierro, Valentina Brancaleoni, Giovanna Graziadei, and Isabella Nava. "Associated Effect of SLC40A1 and TMPRSS6 Polymorphisms on Iron Overload." Metabolites 12, no. 10 (September 29, 2022): 919. http://dx.doi.org/10.3390/metabo12100919.
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Mutations in the ferroportin (FPN) gene SLC40A1 alter iron recycling and cause disturbances in iron homeostasis. The variants of TMPRSS6 contribute to the development of iron deficiencies. In this study, we determined the role of FPN and TMPRSS6 gene polymorphisms in the modulation of iron homeostasis based on biochemical parameters. PCR analysis and sequencing were performed to determine the single nucleotide polymorphisms (SNPs) SLC40A1 c.44–24G>C (rs1439816), SLC40A1 c.663T>C (rs2304704), and TMPRSS6 c.2207T>C (rs855791). Hemoglobin concentration and iron status were determined by standard procedures. We studied 79 iron-loaded individuals for SLC40A1 polymorphisms. Interestingly, 35/79 individuals with SLC40A1 SNPs also carried a TMPRSS6 c.2207T>C polymorphism. The biochemical values of the iron overloaded individuals were compared to those of the individuals carrying TMPRSS6 SNPs and the healthy individuals (wild-type group). The ferritin concentration, transferrin saturation % (TS%), and hemoglobin concentration were significantly higher in the participants with FPN SNPs than in the other three groups. The ferritin concentration and TS% were higher in participants with both SLC40A1 and TMPRSS6 SNPs than in the TMPRSS6 and wild-type groups, while hemoglobin concentration was significantly higher than that in the TMPRSS6 SNP group only. The participants with TMPRSS6 SNPs had significantly lower ferritin concentration, TS%, and hemoglobin concentration than all the other groups. SLC40A1 and TMPRSS6 SNPs might act in the opposite direction, preventing the development of severe iron overload, and the modulation of the iron status by TMPRSS6 SNPs might provide protection.
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Lee, Kyung-Hun, Hye Jung Chang, Sae-Won Han, Do-Youn Oh, Seock-Ah Im, Yung-Jue Bang, Sun Young Kim, et al. "Genetic polymorphisms and ethnic difference in outcome of adjuvant FOLFOX chemotherapy in Korean patients with colon cancer." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 623. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.623.
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623 Background: Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy. Methods: A total of 292 Korean patients (183 men and 109 women) from six hospitals in Korea were prospectively enrolled. Patients had resected stage III or high-risk stage II colon cancer and were treated with 12 cycles of adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) chemotherapy. 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) were analyzed from peripheral blood. TS genotype in 5’UTR was classified as ‘high’ (2R/3G, 3C/3G, and 3G/3G) or ‘low’ (2R/2R, 2R/3C, and 3C/3C). Results: Most patients (86.3%) received 12 complete cycles of FOLFOX chemotherapy. In contrast to previous studies in Caucasians, neutropenia (grade 3–4, 60.5%) was frequently observed in our Korean patients, whereas only 16.4% experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95% confidence interval (CI) 1.19–4.55] and ERCC1 19007TT (adjusted OR 4.58, 95% CI 1.20–17.40) genotypes. Patients harboring XRCC1 23885GG had lower risk of neuropathy (adjusted hazard ratio 0.56, 95% CI 0.32-0.99) and longer time to the onset of grade 2-4 neuropathy. MTHFR 677TT and XRCC1 23885GG genotype was also more prevalent in Koreans compared to Caucasians, and the difference of genotypic frequency could partly explain the ethnically different toxicity profile. After median 49.4 months of follow-up, there were 58 (19.9%) relapses and 19 (6.5%) deaths. TS ‘low’ genotype [adjusted hazard ratio (OR) 1.83, 95% CI 1.003–3.34] was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms. Conclusions: Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. These polymorphisms may explain the ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.
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Cole, Peter D., Traci M. Blonquist, Veena Vijayanathan, Donna S. Neuberg, Lynda M. Vrooman, Stephen E. Sallan, Lewis B. Silverman, and Yaron Finkelstein. "Homozygosity for the 2R Tandem Repeat Polymorphism in the Thymidylate Synthase (TS) Promoter Is Associated with Increased Risk for Bony Morbidity Among Children Treated for Acute Lymphoblastic Leukemia on DFCI Protocol 05-001." Blood 126, no. 23 (December 3, 2015): 251. http://dx.doi.org/10.1182/blood.v126.23.251.251.
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Abstract Introduction: Both fractures and avascular necrosis (AVN) of bone frequently complicate therapy for childhood acute lymphoblastic leukemia (ALL), resulting in significant pain and loss of function. Risk of bony morbidity has been associated with age >10 years and exposure to crucial components of leukemia therapy including corticosteroids, asparaginase, and methotrexate. To further define risk factors, we tested whether 19 common genetic polymorphisms were associated with bony morbidity among 637 children treated for ALL on Dana Farber Cancer Institute ALL Consortium protocol 05-001. Methods: Genomic DNA was isolated from peripheral blood or bone marrow collected at the time of remission. Nineteen candidate polymorphisms were selected a priori, targeting common variants within genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Single nucleotide polymorphisms were detected using PCR-based allelic discrimination assays. The number of 28bp nucleotide repeats within the 5' untranslated region of the gene for thymidylate synthase (TS) was assessed by PCR-product length analysis. The incidence of AVN and fracture were estimated by the cumulative incidence method identifying death and relapse as competing risks. Because the incidence of bony morbidity differed significantly between children above and below the age of 10 years, relationships between polymorphisms and bony morbidity were explored within these two age subgroups separately. Comparisons at the 0.10 significance level were modeled univariately and were considered in multivariable modeling using competing risks regression. Multivariable models for bony morbidity included sex, WBC at diagnosis, race, final risk group, and asparaginase randomization. Blood was collected during treatment for analysis of serum and RBC folate by HPLC. Results: Of the 637 patients tested, 627 achieved a complete remission and received post-induction therapy, of which 61 (9.7%) experienced AVN and 138 (22.0%) had ≥1 fracture. Both AVN and fracture were more common among those ≥10 years of age (22.9% AVN, 30.7% fracture) than younger children (5.5% AVN, p<0.0001 and 19.2% fracture, p=0.002). Homozygosity for the 2R TS polymorphism was observed in 129 (20.6%) of the 626 patients tested. This 2R/2R genotype was associated with a greater 5-year estimated incidence of AVN (11.6%; 95% CI 6.1-18.9%) than among those with 2R/3R or 3R/3R genotypes (4.1%, 95% CI 2.4-6.5%; p=0.0037; Figure [A]) among children < age 10, but not among older children. The increased risk of AVN in younger children remained significant in the multivariable risk regression model (adjusted hazard ratio 2.92; 95% CI 1.36-6.28; p=0.0059). Among children over age 10, this polymorphism was associated with an increased risk of bony fracture (multivariable HR 2.13; 95% CI 1.13-3.99; p=0.019; Figure [B]). No significant association was observed between bony morbidity and the other tested polymorphisms, including PAI-1 (rs6092), ABCB1 (rs1045642), and the vitamin D receptor Fok1 restriction site (rs228570) which have been previously linked to risk of AVN. Samples were available for analysis of serum and RBC folate at diagnosis (n=367), remission (n=347), 15 months post-remission (n=251), and at the conclusion of therapy (n=247). No significant association was observed between TS genotype and serum or RBC folate at any time point. Conclusions: Homozygosity for the 2R polymorphism in TS was associated with increased risk of bony morbidity among children treated for ALL. Interestingly, the impact of the polymorphism differed between those above the age of 10 years (associated with risk of fracture) and younger children (risk for AVN), suggesting that the pathophysiology of bony morbidity differs between these two age groups. This is the first report identifying a genetic risk factor for AVN specifically among children younger than 10 years, a group where AVN is significantly less frequent. This result suggests young children with ALL and the 2R/2R genotype should be monitored more closely for the development of AVN during therapy for ALL. Disclosures Silverman: Seattle Genetics, Inc.: Research Funding.
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PEHLIVAN, YAVUZ, BULENT GOGEBAKAN, SERDAR OZTUZCU, METIN OZGEN, GÖZDE YILDIRIM CETIN, RECEP BAYRAKTAR, BEYHAN CENGIZ, et al. "Association Between Thr21Met and Ser89Asn Polymorphisms of the Urotensin II Gene and Systemic Sclerosis." Journal of Rheumatology 39, no. 1 (November 1, 2011): 106–11. http://dx.doi.org/10.3899/jrheum.110509.
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Objective.Systemic sclerosis (SSc) is an autoimmune chronic fibrotic disorder. Urotensin II (U-II) is predominantly a vasoactive peptide with fibrotic and prothrombotic features. Like endothelin-1 (ET-1), U-II could play an important role in SSc pathogenesis. We evaluated the possible role of the U-II gene polymorphisms (Thr21Met and Ser89Asn) in the genetic susceptibility to SSc in a Turkish population.Methods.A total of 189 patients with SSc and 205 healthy controls were enrolled in our study. We analyzed the genotype and allele frequencies of the U-II (UTS2) gene polymorphisms Thr21Met and Ser89Asn in patients with SSc and in controls.Results.We found that the Thr21Met polymorphism of the UTS2 gene was markedly associated with the risk of developing SSc (p < 0.0001), but there was no relationship between the Ser89Asn polymorphism and SSc (p > 0.05). Two haplotypes (MS and TS) were markedly associated with SSc (p < 0.05). There were significant associations between the genotype and allele frequencies of UTS2 gene Thr21Met polymorphism and cases with diffuse or limited SSc, systemic or lung involvement, finger flexion deformity, pitting scars at the fingertips, positive anticentromere, or positive antitopoisomerase 1 antibody groups.Conclusion.Our study shows the association between Thr21Met, but not Ser89Asn, in the UTS2 gene and SSc. The results strongly suggest that this single-nucleotide polymorphism may be an important risk factor in the development of SSc, and a powerful indicator of severe skin and lung involvement in patients with SSc.
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Pappu, S. S., H. R. Pappu, C. A. Chang, A. K. Culbreath, and J. W. Todd. "Differentiation of Biologically Distinct Peanut Stripe Potyvirus Strains by a Nucleotide Polymorphism-Based Assay." Plant Disease 82, no. 10 (October 1998): 1121–25. http://dx.doi.org/10.1094/pdis.1998.82.10.1121.
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A necrotic strain of peanut stripe potyvirus (PStV-Ts) was used to design and test strain-differentiating oligonucleotides. The 3′ region of PStV-Ts, including a part of the NIb region, the complete coat protein (CP) gene, and the 3′-untranslated region, was cloned and sequenced. PStV-Ts had a high degree of sequence identity (92 to 95%) to the known non-necrotic (blotch) strains both at the nucleotide and amino acid sequence levels. Nucleotide sequence differences unique to the necrotic strain were identified when compared to the available non-necrotic isolates of PStV. Nucleotide polymorphism in the CP gene sequences was utilized in designing oligonucleotides that were specific to the necrotic strain, and were employed in an assay to differentiate the necrotic strain from non-necrotic. The 3′ end mismatch in the oligonucleotides contributed in particular to the differentiation of the strains. This approach facilitated rapid, sensitive, and reliable detection and differentiation of PStV strains.
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Schaerer, Dominic, Tanja K. Froehlich, Seid Hamzic, Steven M. Offer, Robert B. Diasio, Markus Joerger, Ursula Amstutz, and Carlo R. Largiadèr. "A Novel Nomenclature for Repeat Motifs in the Thymidylate Synthase Enhancer Region and Its Relevance for Pharmacogenetic Studies." Journal of Personalized Medicine 10, no. 4 (October 19, 2020): 181. http://dx.doi.org/10.3390/jpm10040181.
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Inhibition of thymidylate synthase (TS) is the primary mode of action for 5-fluorouracil (5FU) chemotherapy. TS expression is modulated by a variable number of tandem repeats in the TS enhancer region (TSER) located upstream of the TS gene (TYMS). Variability in the TSER has been suggested to contribute to 5FU-induced adverse events. However, the precise genetic associations remain largely undefined due to high polymorphism and ambiguity in defining genotypes. To assess toxicity associations, we sequenced the TSER in 629 cancer patients treated with 5FU. Of the 13 alleles identified, few could be unambiguously named using current TSER-nomenclature. We devised a concise and unambiguous systematic naming approach for TSER-alleles that encompasses all known variants. After applying this comprehensive naming system to our data, we demonstrated that the number of upstream stimulatory factor (USF1-)binding sites in the TSER was significantly associated with gastrointestinal toxicity in 5FU treatment.
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Zarate, R. N., J. Rodriguez, E. Bandres, N. Bitarte, N. Ramirez, M. Ponz, A. Chopitea, A. Viudez, and J. Garcia-Foncillas. "Predictive value of Ile105Val polymorphism of the gluthatione-S-transferase P1 in patients with metastatic colorectal cancer (m CRC) treated with the triplet combination of irinotecan, oxaliplatin, and capecitabine." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2544. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2544.
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2544 Background: Several phase I/II trials have shown that the triplet combination of oxaliplatin, irinotecan and capecitabine is a feasible and active in solid tumors. We aimed to investigate whether germline polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: The following genetic polymorphisms were analysed: glutathione S-transferase (GSTP1-Ile105Val, GSTT1 and GSTM1 deletion), TYMS (TS-5´UTR 2R/3R; TS-5´G/C; TS-3´UTR 6-bp deletion), MTHFR 1298A>C, UGT1A1, ERCC1, XPD. Polymorphisms from peripheral lymphocytes were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples for 63 out of 72 prospectively enrolled pts were tested for genomic analysis. Median age was 57 (32–78), median ECOG 1(0–2), median number of cycles administered 6 (1–13), median number of metastatic sites was 1 (1–4). M/F: 50/22. Risk according to Köhne classification was low (52.8% of pts), intermediate (26.4%) and high (8.3%). Overall response rate (ORR) was 62.5%. Median progression-free survival (PFS) was 9.87 months (95% CI; 7.6–12) and median overall survival was 24.6 months (95% CI; 19.5–29.7). A significant association was observed between MTHFR 1298A>C and haematological toxicity, with C/C genotype pts being at higher risk of grade 3–4 neutropenia (50% vs. 28%, p = 0.035) and leucopenia (50% vs. 15%, p = 0.04). Heterozygous and homozygous GSTP-105Val showed a significant superior response rate (80%) compared to only 40% in pts harbouring the GSTP1–105Ile/Ile genotype (p = 0.008, Fisher´s exact test). PFS was also adversely affected in pts with GSTP1–105Ile/Ile (5.2 months vs. 12.3 months in those pts with at least one GSTP1–105Val allele, p = 0.001). In the multivariate analysis, the relative risk for progression was 3.4 (95% CI; 1.3–9.1) for the GSTP1–105Ile/Ile genotype (p = 0.01). Conclusions: The GSTP1-Ile105Val polymorphism is a strong predictor of clinical outcome for XELOXIRI therapy in mCRC pts. No significant financial relationships to disclose.
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Kim, H., B. Seo, J. Kim, S. Oh, S. Lee, S. Kim, and H. Kwon. "Comprehensive analysis of Excision repair complementation group 1, Glutathione S-transferase, Thymidylate synthase, and Uridine diphosphate glucuronosyltransferase 1A1 polymorphisms predictive for treatment outcome in patients with advanced gastric cancer treated with FOLFOX or FOLFIRI." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e15580-e15580. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15580.
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e15580 Background: Pharmacogenetic advances in cancer chemotherapy have the potential to predict clinical benefit to particular regimens. Oxaliplatin and irinotecan have shown to be effective in the treatment of gastric cancer. We assessed whether single nucleotide polymorphisms (SNPs) in ERCC1, GST, TS, and UGT1A1predicted overall survival in gastric cancer patients receiving FOLFOX and/or FOLFIRI chemotherapy. Methods: Total genomic DNA was extracted from whole blood of patient. The PCR- restriction fragment length polymorphism (RFLP) method was applied to detect the known variant sites of ERCC1, GST, TS, and UGT1A1. Results: Response rate of FOLFOX (N=75) was 24%. Grade 3–4 neutropenia and neurotoxicity were observed 34.7% and 16%, respectively. TTP and OS of 1st line administration of FOLFOX (N=35) was 3.1 months (95% CI, 0.1–6.1 months) and 13.9 months (95% CI, 12.2–15.6 months). Only the GSTM1 positive genotype showed a significantly better time to progression (P=0.023). But significant genotype variation of TS, GST and ERCC1,which assumed to affect to activity of oxaliplatin was not observed to RR, toxicity, and overall survival. Response rate of FOLFIRI (N=74) was 23%. Grade 3–4 neutropenia and diarrhea were observed 55.4% and 9.5%, respectively. TTP and OS of 1st line administration of FOLFIRI (N=33) was 4.9 months (95% CI, 3.5–6.4 months) and 19.0 months (95% CI, 8.5–29.5months). Low expression type (2R/2R, 2R/3C, and 3C/3C) of TS was associated with high incidence of grade ≥3 neutropenia. But significant genotype variation of UGT1A1,which assumed to affect to toxicity of irinotecan was not observed to RR, toxicity, and survival. Conclusions: In this study, GSTM1 positive genotype showed a significantly better time to progression in the advanced gastric cancer treated with FOLFOX. Low expression type (2R/2R, 2R/3C, and 3C/3C) of TS was associated with high incidence of grade ≥3 neutropenia in the advanced gastric cancer treated with FOLFIRI. Well designed prospective trial will be clearly identifying relations between chemotherapy and genetic variations. No significant financial relationships to disclose.
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Pypa, L. V., I. V. Odarchuk, Yu M. Lysytsia, V. I. Ruda, and K. Yu Krenov. "Polymorphism of clinical manifestations, experience of diagnosis and treatment of multisystem inflammatory syndrome associated with COVID-19 in children." Modern pediatrics. Ukraine, no. 8(128) (December 28, 2022): 37–44. http://dx.doi.org/10.15574/sp.2022.128.37.
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Purpose - to analyze the literature data on possible variants of the course of pediatric multisystem inflammatory syndrome (PIMS-TS) in children; to describe our own experience in the diagnosis and treatment of some cases of PIMS-TS in children of different age groups; to present possible variants of clinical manifestations of the above disease; to draw attention to the need for early diagnosis and team care and treatment of such children. This novel clinical syndrome later identified as PIMS-TS temporally associated with SARS-CoV-2. In contrast with KD, PIMS-TS appears to occur in children at an older age with a predominance of gastrointestinal symptoms, hemodynamic instability, and myocardial dysfunction. However, the exact pathomechanism remains to be understood. Nevertheless, the post-viral immunological reaction is postulated to be the underlying mechanistic underpinnings. The paper describes the clinical course of the disease in a 5-year-old boy who complained of abdominal pain and hyperthermia, and the disease was masked by surgical pathology. The phenomena of intoxication syndrome, polyserositis, skin manifestations in the form of a polymorphic rash, hyperemia of the conjunctiva, swelling of the feet and hands increased in dynamics. The course of the disease in a 10-year-old girl who had symptoms of a viral infection is also described. However, upon going to the hospital, both children were diagnosed with a serious condition, they were hospitalized and given appropriate treatment. Therefore, the multifaceted nature of the PIMS-TS’ course underlines the need for early recognition and multispecialty care and management. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.
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Yongkiettrakul, Suganya, Fassou René Kolié, Darin Kongkasuriyachai, Jetsumon Sattabongkot, Wang Nguitragool, Namfon Nawattanapaibool, Chayanut Suansomjit, Saradee Warit, Niwat Kangwanrangsan, and Sureemas Buates. "Validation of PfSNP-LAMP-Lateral Flow Dipstick for Detection of Single Nucleotide Polymorphism Associated with Pyrimethamine Resistance in Plasmodium falciparum." Diagnostics 10, no. 11 (November 13, 2020): 948. http://dx.doi.org/10.3390/diagnostics10110948.
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The loop-mediated isothermal amplification coupled with lateral flow dipstick (PfSNP-LAMP-LFD) was recently developed to detect single nucleotide polymorphism (AAT → ATT), corresponding to substitution of asparagine to isoleucine at amino acid position 51 in the P. falciparumdhfr-ts gene associated with antifolate resistance. In this present study, the PfSNP-LAMP-LFD was validated on 128 clinical malaria samples of broad ranged parasite densities (10 to 87,634 parasites per microliter of blood). The results showed 100% accuracy for the detection of single nucleotide polymorphism for N51I mutation. Indeed, the high prevalence of N51I in the Pfdhfr-ts gene detected in the clinical samples is in line with reports of widespread antifolate resistant P. falciparum in Thailand. The relationship between enzyme choice and reaction time was observed to have an effect on PfSNP-LAMP-LFD specificity; however, the method yielded consistent results once the conditions have been optimized. The results demonstrate that PfSNP-LAMP-LFD is a simple method with sufficient sensitivity and specificity to be deployed in routine surveillance of antifolate resistance molecular marker and inform antimalarial management policy.
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Milano, G., M. Francoual, A. Bourgeon, D. Benchimol, M. Chazal, P. Laurent-Puig, T. André, C. Letoublon, F. N. Gilly, and M. C. Etienne-Grimaldi. "Multifactorial prospective study of tumoral factors related to disease-free survival (DFS) in colorectal cancer patients." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3604. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3604.
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3604 Background: There is still a need to identify faithful biological prognostic factors in colorectal cancer, particularly in stage 2, so as to decide upon adjuvant treatment. We thus conducted a prospective multicentric multifactorial study to this end. Methods: Primary colorectal tumors (30 stage 1, 119 stage 2, 107 stage 3) were prospectively collected in 256 patients undergoing total tumor resection (152 men, 104 women ; mean age 69, extremes 29–90). Adjuvant 5FU-based chemotherapy was administered in 92 patients. Median follow-up was 54 months (53 patients developed metastasis or recurrence). Tumors were analyzed for thymidylate synthase (TS), thymidine phosphorylase and dihydropyrimidine dehydrogenase expression (RT-PCR), TS activity (radioenzymatic assay), EGFR level (ligand-binding assay), VEGF (Elisa), DNA content and cell cycle (flow cytometry), p53 mutations (exon 4 to 8), microsatellite instability (bat 25, bat 26), EGFR genotype (CA repeats in intron 1 and -216G>T), TS genotype in 3’ (6 bp deletion) and 5’ (28 bp repeats including the G>C mutation), and methylenetetrahydrofolate reductase genotype (677C>T and 1298A>C). Results: With the exception of tumor TS expression (p = 0.034, the higher the expression, the better the DFS), none of the analyzed parameters were linked to DFS. In multivariate Cox analysis, tumor staging (p = 0.001) and TS expression (p = 0.062) were the sole factors associated to DFS. Focus on tumoral EGFR revealed large inter-patient variability (from 1 to 510 fmol/mg prot) with a significant influence of tumor localisation (p = 0.009, higher in proximal colon) and differentiation status (p = 0.01, higher in poorly differentiated tumors). EGFR within the tumors was 30 % lower than in adjacent normal mucosa (p<0.001). The longer the intron 1 CA repeats, the higher the tumor EGFR (p = 0.044). EGFR -216G>T polymorphism was linked to intron 1 polymorphism, although -216G>T did not influence EGFR levels. Conclusions: The present results underline the major impact of TS expression as a prognostic factor and provide new insights in the knowledge of EGFR in colorectal cancer. No significant financial relationships to disclose.
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Arrazubi, V., J. Suarez, D. Guerrero, K. Cambra, M. L. Gomez Dorronsoro, F. Arias, E. Balen, L. Teijeira, and R. Vera. "Polymorphisms of thymidylate synthase as prognostic factor in rectal cancer." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 433. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.433.
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433 Background: Neoadjuvant fluoropyrimidine-based chemotherapy (ChT) plus radiotherapy (Rt) is a standard approach for locally advanced rectal cancer. Polymorphisms of thymidylate synthase (TS), the target for fluoropyrimidines, are recognized prognostic factors in colon cancer. The aim of this study was to evaluate the prognostic value of the polymorphisms of TS in rectal cancer after neoadjuvant ChT plus Rt. Methods: We studied one-hundred consecutive patients with stage II/III rectal cancer between November 2001 and March 2009. Patients underwent surgery 6-8 weeks after neoadjuvant Rt (5,040 cGy) plus fluoropyrimidine-based ChT. DNA was extracted from paraffin embedded biopsies. TS1494del6 and 5′-28bp repeat +G/C SNP polymorphisms were determined. Results: Sixty-seven percent were men and median age was 67 years. ypT stage was: T0 9%, T1 2%, T2 27%, T3 60% and T4 2%; 32% had locoregional adenopathies. The median follow-up was 45 months and relapse occurred in 20% of patients. Polimorphisms could be determined in 98% of pt: -6bp/-6bp 10%, - 6bp/+6bp 39%, +6bp/+6bp 51% and 2R/2R 72%, 2R/3R 21%, 3R/3R 6%. The grade of pathological tumour regression was not associated with polymorphisms. Relapses occurred in 40% of patients -6bp/-6bp, 22% of patients -6bp/+6bp and 21% of patients +6bp/+6bp. The difference in disease- free survival (DFS) between the first and the third groups was stadistically significative (p=0.049). No relation between 5′-28bp repeat +G/C SNP polymorphism and DFS was found. Conclusions: Our data suggest that the TS1494del6 polimorphism may be an important prognosis factor in rectal cancer receiving neoadjuvant chemoradiotherapy. No significant financial relationships to disclose.
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Li, Mengdi, La Geng, Shanggeng Xie, Dezhi Wu, Lingzhen Ye, and Guoping Zhang. "Genome-Wide Association Study on Total Starch, Amylose and Amylopectin in Barley Grain Reveals Novel Putative Alleles." International Journal of Molecular Sciences 22, no. 2 (January 7, 2021): 553. http://dx.doi.org/10.3390/ijms22020553.
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The content and composition of starch in cereal grains are closely related to yield. Few studies have been done on the identification of the genes or loci associated with these traits in barley. This study was conducted to identify the genes or loci controlling starch traits in barley grains, including total starch (TS), amylose (AC) and amylopectin (AP) contents. A large genotypic variation was found in all examined starch traits. GWAS analysis detected 13, 2, 10 QTLs for TS, AC and AP, respectively, and 5 of them were commonly shared by AP and TS content. qTS-3.1, qAC-6.2 and qAP-5.1 may explain the largest variation of TS, AC and AP, respectively. Four putative candidate genes, i.e., HORVU6Hr1G087920, HORVU5Hr1G011230, HORVU5Hr1G011270 and HORVU5Hr1G011280, showed the high expression in the developing barley grains when starch accumulates rapidly. The examined 100 barley accessions could be divided into two groups based on the polymorphism of the marker S5H_29297679, with 93 accessions having allele GG and seven accessions having AA. Moreover, significantly positive correlation was found between the number of favorable alleles of the identified QTLs and TS, AC, AP content. In conclusion, the identified loci or genes in this study could be useful for genetic improvement of grains starch in barley.
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Li, Mengdi, La Geng, Shanggeng Xie, Dezhi Wu, Lingzhen Ye, and Guoping Zhang. "Genome-Wide Association Study on Total Starch, Amylose and Amylopectin in Barley Grain Reveals Novel Putative Alleles." International Journal of Molecular Sciences 22, no. 2 (January 7, 2021): 553. http://dx.doi.org/10.3390/ijms22020553.
Full textAbstract:
The content and composition of starch in cereal grains are closely related to yield. Few studies have been done on the identification of the genes or loci associated with these traits in barley. This study was conducted to identify the genes or loci controlling starch traits in barley grains, including total starch (TS), amylose (AC) and amylopectin (AP) contents. A large genotypic variation was found in all examined starch traits. GWAS analysis detected 13, 2, 10 QTLs for TS, AC and AP, respectively, and 5 of them were commonly shared by AP and TS content. qTS-3.1, qAC-6.2 and qAP-5.1 may explain the largest variation of TS, AC and AP, respectively. Four putative candidate genes, i.e., HORVU6Hr1G087920, HORVU5Hr1G011230, HORVU5Hr1G011270 and HORVU5Hr1G011280, showed the high expression in the developing barley grains when starch accumulates rapidly. The examined 100 barley accessions could be divided into two groups based on the polymorphism of the marker S5H_29297679, with 93 accessions having allele GG and seven accessions having AA. Moreover, significantly positive correlation was found between the number of favorable alleles of the identified QTLs and TS, AC, AP content. In conclusion, the identified loci or genes in this study could be useful for genetic improvement of grains starch in barley.
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Conradi, L., A. Bleckmann, M. Schirmer, T. Sprenger, K. Homayounfar, H. A. Wolff, H. Becker, B. M. Ghadimi, T. Beissbarth, and T. Liersch. "Biomarker study in rectal cancer patients after 5FU-based radiochemotherapy: Evaluation of the prognostic capacity of thymidylate synthase in pretreatment biopsies and resected adenocarcinoma." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 435. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.435.
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435 Background: Fluorouracil (5FU) remains the backbone of neoadjuvant radiochemotherapy (RCT) as well as adjuvant therapeutic strategies in multimodal treatment of rectal cancer patients. Due to its central role as the major target of 5FU thymidylate synthase (TS) is a promising biomarker in rectal cancer. We assessed TS in 208 patients with regard to its predictive/prognostic capacity for disease free DFS and overall cancer specific survival (CSS). Methods: 167 patients cUICC stages II (28%) and III (72%) received preoperative 5FU based RCT followed by total mesorectal excision (TME) A comparison group n = 41 received postoperative RCT after primary TME. All patients were treated after standardized protocols within phase-II/-III trials of the German Rectal Cancer Study Group. TS levels from pretreatment biopsies and corresponding resection specimens were assessed by immunohistochemical staining for their impact on DFS and CSS. Additionally, a TS gene polymorphism (28 bp repeat) was analysed in respect to intracellular protein expression levels and prognostic significance. Results: Patients with low TS expression in pre-treatment biopsies showed a correlation with impaired CSS (p = 0.015). After neoadjuvant RCT there was evidence of lymph node metastases ypUICC stage III in 32.6%. Complete histopathologically confirmed tumor regression TRG 4 was achieved in 16 patients (9.5%). During follow-up (median 57 months) patients with low intratumoral TS expression and positive nodal status were at high risk for local and/or distant metastatic recurrence (p = 0.040). Analysis of the 28bp repeat revealed a correlation of *3/*3 genotype with high TS expression in pretherapeutical biopsies (p = 0.05). Conclusions: TS represents a prognostic biomarker in locally advanced rectal cancer indicating an unfavourable outcome for patients with low TS expression and might help to adapt adjuvant therapy regimens by stratifying patients according to their risk for cancer recurrence. No significant financial relationships to disclose.
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Barcelos, Ana, Elisa Giovannetti, Robert de Jonge, Mina Maftouh, Pieter Griffioen, Axel R. Hanauske, and Godefridus J. Peters. "Polymorphisms correlated with the clinical outcome of locally advanced or metastatic colorectal cancer patients treated with ALIRI vs. FOLFIRI." Pteridines 24, no. 1 (June 1, 2013): 69–79. http://dx.doi.org/10.1515/pterid-2013-0021.
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AbstractLeucovorin-modulated 5-fluorouracil (5-FU) plus irinotecan (FOLFIRI) is the most common treatment of metastatic colorectal cancer (CRC). 5-FU inhibits thymidylate synthase (TS) and irinotecan topoisomerase I, leading to inhibition of DNA replication and repair. FOLFIRI efficacy suggested that other TS inhibitors might synergize with irinotecan, and Phase I/II studies for second-line treatment showed promising results of combinations with the multitargeted antifolate pemetrexed (PMX), which exerts its effects primarily via TS inhibition. However, a randomized Phase II trial of PMX + irinotecan (ALIRI) showed similar efficacy and safety, but significantly shorter progression-free survival (PFS) compared with FOLFIRI in locally advanced or metastatic CRC. In our previous aCGH study, we evaluated genome-wide copy number variations, whereas in the current study we evaluated relationships between functional polymorphisms and PFS. Candidate polymorphisms were studied by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) (TSER-2R/3R) or Taqman-PCR (MTHFR-1958G>A, MTR-2756A>G, MTHFR-1298A>C, SHMT1-1420C>T, ATIC-347C>G, AMPD-134C>T, MTRR-66A>G and SLC-19A180G>A) in 84 patients (40 FOLFIRI, 44 ALIRI). The Kaplan-Meier method was used to plot PFS, and the log-rank test to compare curves. At univariate analysis the homozygous variants of both MTR-2756A>G and SHMT1-1420C>T were associated with significantly shorter PFS. Conversely, a significantly longer PFS (7.3 months) was observed when ATIC-347C>G CC+CG genotypes were grouped vs. GG. At multivariate analysis the genotypes MTR-2756A>G AA+AG, SHMT1-1420C>T TT+CT and ATIC-347C>G CC+CG emerged as significant predictors for PFS. Because MTR, SHMT1 and ATIC are all involved in folate pathways, we further explored the effect of a combination of their risk genotypes on PFS, showing that patients carrying two risk genotypes had a significantly shorter PFS (3.9 months, p<0.001). The correlations of polymorphisms in genes with clinical outcome underscore the importance of a candidate gene-based approach. Ultimately, the validation of the role of these polymorphisms in prospective multicenter trials might optimize currently available treatments in selected CRC patients (e.g., FOLFIRI) or PMX-based treatments in other tumor types.
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Malovrh, Špela, Tanja Kunej, Milena Kovač, and Peter Dovč. "The microRNA gene <i>bta-mir-2313</i> in cattle: an atlas of regulatory elements and an association analysis with growth and carcass traits in the Slovenian Simental cattle breed." Archives Animal Breeding 61, no. 3 (July 11, 2018): 271–78. http://dx.doi.org/10.5194/aab-61-271-2018.
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Abstract. MicroRNAs (miRNA) are a class of non-coding RNAs important in posttranscriptional regulation of target genes. Regulation requires complementarity between the target mRNA and the miRNA region responsible for their recognition and binding, also called the seed region. Previous studies have proven that expression profiles and genetic variations of miRNA genes (miR-SNP; SNP – single nucleotide polymorphism) and their target sites (miR-TS-SNPs) have an impact on phenotypic variation and disease susceptibility in human, animal models, and livestock. MicroRNA-associated polymorphisms therefore represent biomarker potential for phenotypic traits in livestock. Effects of miRNA gene polymorphisms on phenotypic traits have been studied in several animal species but much less in cattle. The aim of the present study was therefore to analyze the genetic variability in the bta-mir-2313 gene and test associations with growth and carcass traits of the Slovenian Simmental cattle breed. Additionally, validated and predicted genomic information related to the miRNA gene bta-mir-2313 has been obtained and presented as an atlas of miRNA regulatory elements. Sanger sequencing has been used for biomarker development and genotyping of 145 animals of Slovenian dual-purpose Simmental cattle. Out of nine known polymorphisms located within pre-miRNA regions, one mature miRNA seed SNP was polymorphic in the Slovenian Simmental cattle breed. An additional three polymorphisms were identified within the flanking pri-miRNA regions. There was no significant effect of polymorphisms on 18 tested fattening and carcass traits; however, validated polymorphisms could now be tested in association with other traits in other cattle populations. The microRNA gene bta-mir-2313 warrants further genetic and functional analyses since it overlaps with a large number of quantitative trait loci (QTL), has over 3100 predicted targets and highly polymorphic mature seed regions, and is located within protein-coding gene GRAMD1B, previously associated with production traits in cattle. Mature miRNA seed SNPs present important genomic loci for functional studies because they could affect the gain/loss of downstream targets and should be systematically studied in cattle.
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Taylor, Michael D., James Perry, Magdalena C. Ƶlatescu, Anat O. Stemmer-Rachamimov, L. C. Ang, Yasushi Ino, Michael Schwartz, Laurence E. Becker, David N. Louis, and J. Gregory Cairncross. "The hPMS2 exon 5 mutation and malignant glioma." Journal of Neurosurgery 90, no. 5 (May 1999): 946–50. http://dx.doi.org/10.3171/jns.1999.90.5.0946.
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✓ Patients with Turcot syndrome (TS) are predisposed to colon tumors and primary brain tumors, typically glioblastomas or medulloblastomas. The authors describe a patient with TS featuring a known germline mutation of exon 5 of the hPMS2 mismatch repair gene who developed two metachronous glioblastomas, both with distinct oligodendroglial features. Molecular genetic analysis revealed allelic loss of chromosome 19q in the patient's second tumor but no allelic loss of chromosome 1p. Prominent microsatellite instability was also found in this tumor, consistent with a germline mismatch repair defect. Because this patient had an unusual underlying condition and his tumor had a unique histological appearance for TS, it was hypothesized that this genetic defect may predispose to malignant gliomas with oligodendroglial features. The authors therefore evaluated whether sporadic glioblastomas and oligodendrogliomas undergo mutations of this region of the hPMS2 gene. However, single-strand conformation polymorphism analysis of hPMS2 exon 5 failed to reveal mutations in 20 sporadic glioblastomas and 16 sporadic oligodendroglial gliomas. Thus, although it is possible that the germline hPMS2 exon 5 mutation may predispose to glioblastomas with an oligodendroglial component, the same genetic defect is not commonly involved in sporadic oligodendrogliomas or glioblastomas.
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Weekes, C., S. Nallapareddy, A. Jimeno, M. Hidalgo, D. Laheru, M. A. Rudek, S. Baker, C. Redlinger, K. Murphy, and W. Messersmith. "Single nucleotide polymorphisms of TSER, ATM, RecQ1 genes association with survival in pancrease cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e14590-e14590. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14590.
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e14590 Background: Pancreatic cancer (PaCa) is the 4th leading cause of cancer-related mortality in the U.S . We tried to determine whether ATM, RecQ1 gene polymorphisms correlate with gemcitabine (G) and TSER gene polymorphism with capecitabine (C) response and over all survival(OS). We also tested the hypothesis that PaCa pts homozygous for the S/S variant of the TSER will have a higher 6-month survival with C compared to historical controls. TS expression is regulated by a polymorphism in the TSER and has been shown that pts with S/S variant have high response rate and increased toxicity in colon cancer pts. ATM and recQ1 genes are involved with DNA damage response and repair and correlate with G response. Methods: DNA isolated from peripheral blood samples in 82 pts with Stage IV pancreatic cancer was tested for the TSER, ATM and RecQ1 gene polymorphisms. All patients were treated with G 1,000mg/m2 wkly for 3/4 wks. Pts homozygous for the S/S variant were treated with C, 2,000 mg/m2/day for 14 /21days. Pts were evaluated for response to therapy according to the RECIST. Results: 16 pts (19.5%) were positive for S/S variant of TSER, but only 4 (4.8%) were treated. The reasons for declining treatment were geographic, logistic or progression issues. Only 1 pt was evaluable, receiving at least 3 cycles of C . All pts needed dose reductions due to toxicities. Grade 3 hand foot syndrome, diarrhea and vomiting were dose limiting toxicities. No complete or partial responses were seen. The pt who received 3 cycles came off study due to progressive disease and the other 3 pts came of the study due to toxicities. TSER polymorphism was correlated to OS and only S/S variant was significant with a trend towards improved OS by log rank test and Kaplan Meier plot. ATM and RecQ1 gene polymorphisms subtypes did not correlate with G response and OS ( not statistically significant). Conclusions: Our study represents an initial effort to apply pharmacogenetics to PaCa therapy. 19.5% of pts had the S/S variant of the TSER polymorphism, but only 4.8% enrolled. C administration was associated with excess toxicity. The toxicities observed in this study appear to outweigh the benefit of using C in this pt population. There is no correlation between ATM and RecQ1 genotypes with OS. However the sample size is too small to draw conclusions. [Table: see text]
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de Jonge, Robert, Jan Hendrik Hooijberg, Bertrand D. van Zelst, Gerritz Jansen, Christine H. van Zantwijk, Gert Jan L. Kaspers, Frits G. J. Peters, Yaddanapudi Ravindranath, Rob Pieters, and Jan Lindemans. "Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia." Blood 106, no. 2 (July 15, 2005): 717–20. http://dx.doi.org/10.1182/blood-2004-12-4941.
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Abstract We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI50, cont) or short-term (3 hours; TSI50, short) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI50, cont. In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL. (Blood. 2005;106:717-720)