The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Howard L Mcleod - One of the best experts on this subject based on the ideXlab platform.
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polymorphism in the thymidylate synthase promoter Enhancer Region in colorectal cancer
International Journal of Oncology, 2001Co-Authors: Sharon Marsh, J A Mckay, Jim Cassidy, Howard L McleodAbstract:Thymidylate synthase (TS) is an important target for chemotherapy drugs such as 5-fluorouracil and raltitrexed. Over-expression of TS has been linked to chemotherapy resistance. A polymorphic tandem repeat sequence in the 5' untranslated Region (5'UTR) of the human TS gene (TSER) has been shown to influence TS expression. The presence of a triple tandem repeat (TSER*3) increases in vitro TS expression compared to a double tandem repeat (TSER*2) and is associated with higher in vivo tumor TS activity. The polymorphism of this promoter Enhancer Region has not been extensively studied in patients with cancer and may represent a possible mechanism of intrinsic resistance to TS inhibitors. In this study, PCR analysis of genomic DNA from 121 patients with colorectal cancer demonstrated 29% of patients were homozygous for TSER*3, 16% were homozygous for TSER*2 and 55% were heterozygous. In 44/45 microdissected tumors the TS Enhancer genotype was identical between paired samples of colorectal tumor and normal tissue. In 24 patients receiving a bolus/infusion 5-fluorouracil (5FU) regimen for metastatic colorectal cancer, 22% of non-responders to chemotherapy were homozygous for TSER*2 compared with 40% of responders. Median survival dropped from 16 months for homozygous TSER*2 to 12 months for homozygous TSER*3. This is consistent with previous studies where higher TS expression was associated with poor response to TS inhibitors. Prospective analysis of the influence of the TS polymorphism on patient outcome is warranted.
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novel thymidylate synthase Enhancer Region alleles in african populations
Human Mutation, 2000Co-Authors: Sharon Marsh, Howard L Mcleod, Margaret M Ameyaw, Jessie Githanga, A A Indalo, David OforiadjeiAbstract:Thymidylate synthase (TS) regulates the production of DNA synthesis precursors and is an important target of cancer chemotherapy. A polymorphic tandem repeat sequence in the Enhancer Region of the TS promoter was previously described, where the triple repeat gives higher in vitro gene expression than a double repeat. We recently identified ethnic differences in allele frequencies between Caucasian and Asian populations. We now describe assessment of genotype and allele frequencies of the TS polymorphism in 640 African (African American, Ghanaian and Kenyan) and Caucasian (UK, USA) subjects. The double and triple repeat were the predominant alleles in all populations studied. The frequency of the triple repeat allele was similar between Kenyan (49%), Ghanaian (56%), African American (52%), American Caucasian (54%) and British Caucasian (54%) subjects. However, two novel alleles contained 4 and 9 copies of the tandem repeat. These novel alleles were found at a higher allele frequency in African populations (Kenyan 7%, Ghanaian 3%, African American 2%) than Caucasians (UK 1%, USA 0%). The novel alleles identified in this study decrease in frequency with Western migration, while the common alleles are relatively stable. This is a unique example suggesting the influence of multiple selection pressures within individual populations. Hum Mutat 16:528, 2000.
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ethnic variation in the thymidylate synthase Enhancer Region polymorphism among caucasian and asian populations
Genomics, 1999Co-Authors: Sharon Marsh, Elaina Susan Renata Collieduguid, Xiehe Liu, Howard L McleodAbstract:Thymidylate synthase (TS) regulates the production of DNA synthesis precursors and is an important target of cancer chemotherapy. A tandem repeat sequence in a TS promoter Enhancer Region (TSER) was recently identified. Polymorphic variation affected in vitro expression levels of the gene. We evaluated the influence of ethnicity on TSER genotype. Allele frequency was similar in Caucasian and Southwest Asian subjects. However, homozygous triple repeat subjects were twice as common in Chinese subjects (67%) than in Caucasian subjects (38%). This demonstrates significant ethnic variation in a TS gene regulatory element which may have significant impact on pyrimidine homeostasis and drug therapy.
Jia Chen - One of the best experts on this subject based on the ideXlab platform.
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polymorphism in the thymidylate synthase promoter Enhancer Region and risk of colorectal adenomas
Cancer Epidemiology Biomarkers & Prevention, 2004Co-Authors: Jia Chen, Charles Kyte, Wendy Chan, James G Wetmur, Charles S Fuchs, Edward GiovannucciAbstract:Thymidylate synthase (TS), a key one-carbon metabolizing gene, encodes an enzyme that converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. We recently reported that a promoter polymorphism in TS modified the risk of colorectal cancer as well as the survival rate after the disease. To explore whether TS may play an important role in colorectal carcinogenesis early in the multistaged pathogenic pathway, we investigated the relation between the TS promoter polymorphism and risk of colorectal adenoma in a nested case-control study within the prospective Health Professionals Follow-up Study. We ascertained the TS genotype from 373 incident colorectal adenoma cases and 720 control subjects. Although there was no overall association between the TS promoter polymorphism and adenoma risk, we observed a significant TS-alcohol interaction (P for interaction = 0.009); relative to low alcohol consumers with the 2R/2R genotype, those with high alcohol consumption (>30 g/d) were not at elevated risk if they had the 2R/2R genotype [relative risk (RR), 0.80; 95% confidence interval (95% CI), 0.34-1.90], but were at higher risk if they had the 2R/3R genotype (RR, 1.70; 95% CI, 0.87-3.31), and at the highest risk (RR, 3.16; 95% CI, 1.50-6.63) if they had the 3R/3R genotype. In addition, a significant interaction was observed between the TS promoter polymorphism and the 677C > T polymorphism of methylenetetrahydrofolate reductase (MTHFR; P for interaction = 0.007). These findings lend additional support that one-carbon metabolism is an important process in pathogenesis of colorectal cancer.
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polymorphism in the thymidylate synthase promoter Enhancer Region modifies the risk and survival of colorectal cancer
Cancer Epidemiology Biomarkers & Prevention, 2003Co-Authors: Jia Chen, Charles Kyte, Wendy Chan, James G Wetmur, David J Hunter, Meir J Stampfer, Rebecca Mosig, Jacob SelhubAbstract:Thymidylate synthase (TS) converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. It is also the target for 5-flurorouracil, the most common chemotherapy agent for treatment of colorectal cancer (CRC). We designed a nested case-control study within the prospective Physicians' Health Study to investigate whether TS polymorphisms independently predict risk of CRC and simultaneously the overall survival after the disease in the same population. We also investigated influences of this polymorphism on plasma folate and homocysteine levels. The study consists of 270 incident CRC and 454 control subjects. Risk of CRC was estimated by use of conditional multiple logistic regression analysis. Survival was analyzed by Cox proportional hazards regression analysis. Compared with the TS 3R/3R genotype, the multivariate-adjusted risk ratio was 0.86 (0.59-1.25) for the 2R/3R genotype and 0.59 (0.36-0.98) for the 2R/2R genotype with P for trend of 0.03. The TS 2R/2R genotype was also associated with better survival, although the results were not significant. Compared with those with either the 3R/3R or 2R/3R genotypes, the age-adjusted hazard ratio for the 2R/2R genotype was 0.57 (0.30-1.07). Individuals with the 2R/2R genotype had significantly lower plasma folate levels than those with the 3R/3R genotype, whereas their plasma homocysteine levels were unaffected by the TS promoter polymorphism. The deletion polymorphism at the TS 3'-untranslated Region did not influence the CRC risk and survival, nor did it modify the plasma folate and total homocysteine levels. Given that individuals with high plasma folate had a better survival outcome with a hazard ratio of 0.68 (0.45-1.03) compared with those with low plasma folate, we conclude that the TS promoter polymorphism may modify both the risk and the survival of CRC; however, these effects do not appear to be mediated through its modulation of biological folate levels.
Hany Elsaleh - One of the best experts on this subject based on the ideXlab platform.
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a polymorphism in the Enhancer Region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5 fluorouracil
British Journal of Cancer, 2001Co-Authors: Barry Iacopetta, Fabienne Grieu, David Joseph, Hany ElsalehAbstract:High levels of thymidylate synthase (TS) expression have been associated with poor survival of colorectal cancer (CRC) patients to 5-fluorouracil (5-FU)-based chemotherapy. Recent evidence suggests that a polymorphism within the Enhancer Region of the TS gene promoter can influence TS expression, with the triple repeat homozygote (3R/3R) being associated with significantly higher tumour TS levels than either the double repeat homozygote (2R/2R) or heterozygotes (2R/3R). In the present study we investigated whether TS genotype was associated with the degree of survival benefit from chemotherapy in 221 Dukes' C stage CRC patients. Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30-1.25, P = 0.18), whereas those with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52-0.82, P = 0.005). These results demonstrate that a polymorphism within the TS gene, probably through its effect on TS expression levels, can influence the survival benefit obtained by CRC patients from 5-FU-based chemotherapy.
Sharon Marsh - One of the best experts on this subject based on the ideXlab platform.
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polymorphism in the thymidylate synthase promoter Enhancer Region in colorectal cancer
International Journal of Oncology, 2001Co-Authors: Sharon Marsh, J A Mckay, Jim Cassidy, Howard L McleodAbstract:Thymidylate synthase (TS) is an important target for chemotherapy drugs such as 5-fluorouracil and raltitrexed. Over-expression of TS has been linked to chemotherapy resistance. A polymorphic tandem repeat sequence in the 5' untranslated Region (5'UTR) of the human TS gene (TSER) has been shown to influence TS expression. The presence of a triple tandem repeat (TSER*3) increases in vitro TS expression compared to a double tandem repeat (TSER*2) and is associated with higher in vivo tumor TS activity. The polymorphism of this promoter Enhancer Region has not been extensively studied in patients with cancer and may represent a possible mechanism of intrinsic resistance to TS inhibitors. In this study, PCR analysis of genomic DNA from 121 patients with colorectal cancer demonstrated 29% of patients were homozygous for TSER*3, 16% were homozygous for TSER*2 and 55% were heterozygous. In 44/45 microdissected tumors the TS Enhancer genotype was identical between paired samples of colorectal tumor and normal tissue. In 24 patients receiving a bolus/infusion 5-fluorouracil (5FU) regimen for metastatic colorectal cancer, 22% of non-responders to chemotherapy were homozygous for TSER*2 compared with 40% of responders. Median survival dropped from 16 months for homozygous TSER*2 to 12 months for homozygous TSER*3. This is consistent with previous studies where higher TS expression was associated with poor response to TS inhibitors. Prospective analysis of the influence of the TS polymorphism on patient outcome is warranted.
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novel thymidylate synthase Enhancer Region alleles in african populations
Human Mutation, 2000Co-Authors: Sharon Marsh, Howard L Mcleod, Margaret M Ameyaw, Jessie Githanga, A A Indalo, David OforiadjeiAbstract:Thymidylate synthase (TS) regulates the production of DNA synthesis precursors and is an important target of cancer chemotherapy. A polymorphic tandem repeat sequence in the Enhancer Region of the TS promoter was previously described, where the triple repeat gives higher in vitro gene expression than a double repeat. We recently identified ethnic differences in allele frequencies between Caucasian and Asian populations. We now describe assessment of genotype and allele frequencies of the TS polymorphism in 640 African (African American, Ghanaian and Kenyan) and Caucasian (UK, USA) subjects. The double and triple repeat were the predominant alleles in all populations studied. The frequency of the triple repeat allele was similar between Kenyan (49%), Ghanaian (56%), African American (52%), American Caucasian (54%) and British Caucasian (54%) subjects. However, two novel alleles contained 4 and 9 copies of the tandem repeat. These novel alleles were found at a higher allele frequency in African populations (Kenyan 7%, Ghanaian 3%, African American 2%) than Caucasians (UK 1%, USA 0%). The novel alleles identified in this study decrease in frequency with Western migration, while the common alleles are relatively stable. This is a unique example suggesting the influence of multiple selection pressures within individual populations. Hum Mutat 16:528, 2000.
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ethnic variation in the thymidylate synthase Enhancer Region polymorphism among caucasian and asian populations
Genomics, 1999Co-Authors: Sharon Marsh, Elaina Susan Renata Collieduguid, Xiehe Liu, Howard L McleodAbstract:Thymidylate synthase (TS) regulates the production of DNA synthesis precursors and is an important target of cancer chemotherapy. A tandem repeat sequence in a TS promoter Enhancer Region (TSER) was recently identified. Polymorphic variation affected in vitro expression levels of the gene. We evaluated the influence of ethnicity on TSER genotype. Allele frequency was similar in Caucasian and Southwest Asian subjects. However, homozygous triple repeat subjects were twice as common in Chinese subjects (67%) than in Caucasian subjects (38%). This demonstrates significant ethnic variation in a TS gene regulatory element which may have significant impact on pyrimidine homeostasis and drug therapy.
Jacob Selhub - One of the best experts on this subject based on the ideXlab platform.
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polymorphism in the thymidylate synthase promoter Enhancer Region modifies the risk and survival of colorectal cancer
Cancer Epidemiology Biomarkers & Prevention, 2003Co-Authors: Jia Chen, Charles Kyte, Wendy Chan, James G Wetmur, David J Hunter, Meir J Stampfer, Rebecca Mosig, Jacob SelhubAbstract:Thymidylate synthase (TS) converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. It is also the target for 5-flurorouracil, the most common chemotherapy agent for treatment of colorectal cancer (CRC). We designed a nested case-control study within the prospective Physicians' Health Study to investigate whether TS polymorphisms independently predict risk of CRC and simultaneously the overall survival after the disease in the same population. We also investigated influences of this polymorphism on plasma folate and homocysteine levels. The study consists of 270 incident CRC and 454 control subjects. Risk of CRC was estimated by use of conditional multiple logistic regression analysis. Survival was analyzed by Cox proportional hazards regression analysis. Compared with the TS 3R/3R genotype, the multivariate-adjusted risk ratio was 0.86 (0.59-1.25) for the 2R/3R genotype and 0.59 (0.36-0.98) for the 2R/2R genotype with P for trend of 0.03. The TS 2R/2R genotype was also associated with better survival, although the results were not significant. Compared with those with either the 3R/3R or 2R/3R genotypes, the age-adjusted hazard ratio for the 2R/2R genotype was 0.57 (0.30-1.07). Individuals with the 2R/2R genotype had significantly lower plasma folate levels than those with the 3R/3R genotype, whereas their plasma homocysteine levels were unaffected by the TS promoter polymorphism. The deletion polymorphism at the TS 3'-untranslated Region did not influence the CRC risk and survival, nor did it modify the plasma folate and total homocysteine levels. Given that individuals with high plasma folate had a better survival outcome with a hazard ratio of 0.68 (0.45-1.03) compared with those with low plasma folate, we conclude that the TS promoter polymorphism may modify both the risk and the survival of CRC; however, these effects do not appear to be mediated through its modulation of biological folate levels.