Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary objective of this review is to explore the hypothesis that folate insufficiency may be important in the pathogenesis of squamous cell carcinomas of the head and neck (SCCHN) and that folate repletion may be an effective component of chemoprevention. The main results are that folate insufficiency disrupts DNA global and specific gene methylation patterns such that the activity of certain tumor suppressor genes such as p16 and possibly p53 may be lost. Folate pool imbalance and impaired repair mechanisms may contribute to DNA instability and strand breaks. Sensitive methods exist for identification of individuals with folate insufficiency in contrast to the relatively insensitive conventional serum or red cell folate assays with broad "normal" ranges. The impact of folate supplementation can thus be quantified. Folate imbalance may result from alterations in folate cellular uptake by the reduced folate carrier (RFC) and/or the folate receptor (FR) and polymorphisms in enzymes important in folate retention such as folylpolyglutamate synthetase and in folate modification such as methylene tetrahydrofolate reductase (MTHFR). Known predisposing factors for SCCHN such as alcohol and tobacco carcinogens may influence folate balance. Folate supplementation may reduce primary or secondary risk of cancer. Formal studies of folate sufficiency in persons at risk for or diagnosed and treated for SCCHN are needed to define the role of folate supplementation in the prevention of these cancers.
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PMID:The role of folates in squamous cell carcinoma of the head and neck. 1573 17

Although colorectal cancer has the third highest cancer mortality rate, the treatment remains far from optimized with patients showing variable responses to standard treatment. Molecular differences in pharmacologically relevant genes may contribute to the variability in response. This study used Taqman PCR to investigate the expression of 24 5-fluorouracil (5-FU) pathway genes in colorectal cancer using paired nontumor and tumor sample from 52 patients with Dukes' C colon cancer. In comparing tumor versus nonmalignant tissue, 14 of the 24 genes showed significant variation in gene expression. For 11 of these same genes (FPGS, DHFR, GGH, NME1, NME2, RRM2, UMPH2, UNG, UMPS, TP53, and TK1), a significant proportion of the patients showed an over expression of the particular gene in tumor tissue with a tumor-to-nonmalignant (T/N) ratio >1.2, whereas one gene (DPYD) showed the converse with a large number of patients showing a lower expression in the tumor tissue (T/N < 0.8). Multiple gene correlations for the genes of the 5-FU pathway were found with the Spearman rank correlation of >0.6 (all P > 0.001), suggesting possible coregulation mechanisms. Hierarchical clustering analysis created at least three groups of genes, which were consistent with groupings by the other statistical methods. Additionally, the hierarchical clustering showed two distinct groups of patients based on their gene expression. These variations in gene expression could provide valuable insights for optimizing treatment selection for patients with colorectal cancer.
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PMID:Variance in the expression of 5-Fluorouracil pathway genes in colorectal cancer. 1581 41

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.
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PMID:Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia. 3189 51