The table below is from a paper titled Influence of genetic polymorphisms in the

Question

The table below is from a paper titled Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma link: https://www.synapse.koreamed.org/search.php?where=aview&id=10.5045/br.2016.51.1.50&code=3072BR&vmode=FULL#ArticleGotoNagivator.

For the table below, create a figure legend for it, and specifically explain how this figure shows that only the SNP (single nuclear polymorphism) at SLC19A1 is medically relevant (this was one of the major conclusions of the paper)

Table 7. Analysis of SNPs and methotrexate-induced toxicity Liver toxicity Kidney toxicity Mucositis Gene SNPss: Grade 2 2Grade 3 ORP Grade 2 2Grade 3 OR p 95% CI S Grade 2 2Grade 3 95% CI ORP 95% CI ATIC 347 (N-27) CC 1.0 0 0.63 CG/GG 5 (56 44 0.31 0.22 0.06-1.64 8 (89) 1 11 1.0 1.0 0.08-12.76 9 (100) 0 (0) 0.83 0.53 0.68-1.03 CC MTHFR 677 (N=35) 0.152 0.07 CT/TT 8 (31) 18 (69 13 1.00 0.22-5.67 22 (85) 4 15) 1.18 0.553 1.00-1.39 22 (85) (15) 1.18 0.55 1.00-1.39 MTHFR 1298 AA 0.67 0 0.67 AC/CC 6 (38 10 (63) 0.52 0.48 0.13-2.17 15 (94) 1 (6) 0.4 0.62 0.04-4.26 15 94) 1 (6 0.40 0.62 0.04-4.26 3 SLC19A1 1.0 0.01 9 7 0 GA/AA 10 (34) 19 (66) 0.27 0.39 0.03-2.53 26 (90) 3 (10) 0.81 1.0 0.07-9.01 28 (97) 3) 0.06 0.03 0.01-0.69

Explanation / Answer

High-dose methotrexate (MTX) with leucovorin (5-formyltetrahydrofolic acid) rescue in combination with doxorubicin and a platinum agent has served as a cornerstone of neoadjuvant chemotherapy for osteosarcoma. High-dose MTX treatment is associated with various toxicities, including toxicities of central nervous system (CNS), liver, kidney, bone marrow and gastrointestinal system, particularly oral mucosa. Various studies have reported that several pharmacokinetic parameters, including a high plasma MTX concentration and prolonged exposure to high levels of MTX, were associated with the development of high-dose MTX-induced toxicities . However, MTX levels exhibit significant inter-individual variability, and acute toxicity after high-dose MTX is often unexpected and not typically dose dependent; thus, it is difficult to predict who will develop a more serious adverse response to high-dose MTX. Folate pathway genes are involved in the metabolism of MTX and are very polymorphic. Numerous pharmacogenetic studies have reported that single nucleotide polymorphisms (SNPs) alter the activity or expression of folate pathway enzymes, which may influence the response to and toxicity caused by MTX in various malignancies and autoimmune diseases.

However, comparatively few data are available regarding associations between various genetic polymorphisms of the folate pathway genes and pediatric osteosarcoma. We hypothesized that polymorphisms of the folate pathway genes may influence plasma concentrations of MTX and MTX-induced toxicity in pediatric patients with osteosarcoma. Among various candidate SNPs in folate pathway genes, SNPs in solute carrier family 19, member1 (SLC19A1), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (ATIC) are potential biomarkers that confer susceptibility to MTX. In this study, we retrospectively examined whether SLC19A1 80G>A, MTHFR 677C>T, MTHFR 1298A>C, and ATIC 347C>G polymorphisms affected plasma MTX concentrations and susceptibility to high-dose MTX-induced toxicity in Korean pediatric patients with osteosarcoma.

Use and importance of SNPs

Variations in the DNA sequences of humans can affect how humans develop diseases and respond to pathogens, chemicals, medication, vaccines, and other agents. SNPs are also thought to be key enablers in realizing the concept of personalized medicine. However, their greatest importance in biomedical research is for comparing regions of the genome between cohorts (such as matched cohorts with and without a disease).

SLC19A1:

SNPs in solute carrier family 19, member1 (SLC19A1), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (ATIC) are potential biomarkers that confer susceptibility to MTX. In this study, we retrospectively examined whether SLC19A1 80G>A, MTHFR 677C>T, MTHFR 1298A>C, and ATIC 347C>G polymorphisms affected plasma MTX concentrations and susceptibility to high-dose MTX-induced toxicity in Korean pediatric patients with osteosarcoma.

Results of the analysis about the associations between the candidate gene SNPs and development of grade 3 or 4 toxicities are described in . SLC19A1 80G>A had a lower risk of developing severe mucositis (OR, 0.06; P=0.026; 95% CI, 0.005-0.693). Any of the remaining SNPs did not show significant correlations with severe liver and kidney toxicity or mucositis.

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