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Genetic polymorphisms of the adenosine triphosphate-binding cassette transporters (ABCG2, ABCB1) and gefitinib toxicity.

ABSTRACT: The purpose of this study is to investigate associations between allelic variations of ABCG2 and ABCB1 with skin toxicity, diarrhea, liver injury and interstitial lung disease (ILD) in gefitinib-treated patients. A prospective clinical study of 83 Japanese patients with non-small-cell lung cancer was performed. Polymorphic loci in ABCG2 and ABCB1 were genotyped, and their effects on gefitinib toxicities were evaluated. ABCG2 34G>A was statistically associated with occurrence of skin rash; 13 (42%) of the 32 patients with at least one variant ABCG2 34G>A allele (G/A and A/A) developed grade 2 or worse skin rash, whereas only 10 (19%) of 51 patients homozygous for the reference allele (G/G) for the wild-type sequence for both alleles did so (P=0.046). There was no significant association between severe toxicities and polymorphisms of ABCG2 421C>A nor ABCB1 3435C>T. The results suggested that ABCG2 34G>A would be useful for predicting grade 2 or worse skin rash.

SUBMITTER: Tamura M

PROVIDER: S-EPMC4831258 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Genetic polymorphisms of the adenosine triphosphate-binding cassette transporters (ABCG2, ABCB1) and gefitinib toxicity.

Tamura Mariko M Kondo Masashi M Horio Mihoko M Ando Maki M Saito Hiroshi H Yamamoto Masashi M Horio Yoshitsugu Y Hasegawa Yoshinori Y

Nagoya journal of medical science 20120201 1-2

The purpose of this study is to investigate associations between allelic variations of ABCG2 and ABCB1 with skin toxicity, diarrhea, liver injury and interstitial lung disease (ILD) in gefitinib-treated patients. A prospective clinical study of 83 Japanese patients with non-small-cell lung cancer was performed. Polymorphic loci in ABCG2 and ABCB1 were genotyped, and their effects on gefitinib toxicities were evaluated. ABCG2 34G>A was statistically associated with occurrence of skin rash; 13 (42 ...[more]

PMID: 22515119

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Project description:AbstractAberrant expression of adenosine triphosphate-binding cassette subfamily C (ABCC), one of the largest superfamilies and transporter gene families of membrane proteins, is associated with various tumors. However, its relationship with liver hepatocellular carcinoma (LIHC) remains unclear.We used the Oncomine, UALCAN, Human Protein Atlas, GeneMANIA, GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), TIMER, and Kaplan-Meier Plotter databases. On May 20, 2021, we searched these databases for the terms ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC10, ABCC11, ABCC12, ABCC13, and "liver cancer." The exposure group comprised LIHC patients, and the control group comprised normal patients (those with noncancerous liver tissue). All patients shown in the retrieval language search were included. We compared the mRNA expression of these proteins in LIHC and control patients to examine the potential role of ABCC1-13 in LIHC.Relative to the normal liver tissue, mRNA expression of ABCC1/2/3/4/5/6/10 was significantly upregulated (P < .001), and that of ABCC9/11 significantly downregulated (both P < .001), in LIHC. ABCC mRNA expression varied with gender (P < .05), except for ABCC11-13; with tumor grade (P < 0.05), except for ABCC7/12/13; with tumor stage (P < .05), except for ABCC11-13; and with lymph node metastasis status (P < .05), except for ABCC7/8/11/12/13. Based on KEGG enrichment analysis, these genes were associated with the following pathways: ABC transporters, Bile secretion, Antifolate resistance, and Peroxisome (P < .05). Except for ABCC12/13, the ABCCs were significantly associated with B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration (P < .05). High mRNA expression of ABCC1/4/5/8 (P < .05) and low expression of ABCC6/7/9/12/13 (P < .05) indicated poor prognosis. Prognostic significance was indicated for ABCC2/13 for both men and women (P < .05); for ABCC1/6/12/13 for tumor grades 1-3 (P < .05); for ABCC5/11/12/13 for all tumor stages (P < .05); for ABCC1/11/12/13 for American Joint Committee on Cancer T stages 1-3 (P < .05); and for ABCC1/5/6/13 for vascular invasion. None showed prognostic significance for microvascular invasion (P < .05).We identified ABCC1/2/3/4/5/6/9/10/11 as potential diagnostic markers, and ABCC1/4/5/6/7/8/9/12/13 as prognostic markers, of LIHC. Our future work will promote the use of ABCCs in the diagnosis and treatment of LIHC.

Project description:Strawberry (Fragaria × ananassa Duch) are sensitive to salt stress, and breeding salt-tolerant strawberry cultivars is the primary method to develop resistance to increased soil salinization. However, the underlying molecular mechanisms mediating the response of strawberry to salinity stress remain largely unknown. This study evaluated the salinity tolerance of 24 strawberry varieties, and transcriptomic and metabolomic analysis were performed of 'Sweet Charlie' (salt-tolerant) and 'Benihoppe' (salt-sensitive) to explore salt tolerance mechanisms in strawberry. Compared with the control, we identified 3412 differentially expressed genes (DEGs) and 209 differentially accumulated metabolites (DAMs) in 'Benihoppe,' and 5102 DEGs and 230 DAMs in 'Sweet Charlie.' DEGs Gene Ontology (GO) enrichment analyses indicated that the DEGs in 'Benihoppe' were enriched for ion homeostasis related terms, while in 'Sweet Charlie,' terms related to cell wall remodeling were over-represented. DEGs related to ion homeostasis and cell wall remodeling exhibited differential expression patterns in 'Benihoppe' and 'Sweet Charlie.' In 'Benihoppe,' 21 ion homeostasis-related DEGs and 32 cell wall remodeling-related DEGs were upregulated, while 23 ion homeostasis-related DEGs and 138 cell wall remodeling-related DEGs were downregulated. In 'Sweet Charlie,' 72 ion homeostasis-related DEGs and 275 cell wall remodeling-related DEGs were upregulated, while 11 ion homeostasis-related DEGs and 20 cell wall remodeling-related DEGs were downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed only four KEGG enriched pathways were shared between 'Benihoppe' and 'Sweet Charlie,' including flavonoid biosynthesis, phenylalanine metabolism, phenylpropanoid biosynthesis and ubiquinone, and other terpenoid-quinone biosynthesis. Integrating the results of transcriptomic and metabolomics analyses showed that adenosine triphosphate-binding cassette (ABC) transporters and flavonoid pathway genes might play important roles in the salt stress response in strawberry, and DAMs and DEGs related to ABC transporter and flavonoid pathways were differentially expressed or accumulated. The results of this study reveal that cell wall remodeling and ABC transporters contribute to the response to salt stress in strawberry, and that related genes showed differential expression patterns in varieties with different salt tolerances. These findings provide new insights into the underlying molecular mechanism of strawberry response to salt stress and suggest potential targets for the breeding of salt-tolerant strawberry varieties.

Project description:Background: ABCG2 and ABCB1 are genes related to the pharmacokinetics of sunitinib and have been associated with its toxicity and efficacy. However, the results have been controversial. This study aimed to evaluate the associations of ABCG2 and ABCB1 polymorphisms with sunitinib-induced toxicity and efficacy in renal cell carcinoma (RCC) by meta-analysis. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for studies investigating the associations of the ABCG2 rs2231142 polymorphism with sunitinib-induced toxicity and the associations of the ABCB1 rs1128503 and ABCB1 rs2032582 polymorphisms with sunitinib-induced toxicity and clinical outcomes. The associations were evaluated by effect size (ES) with 95% confidence intervals (CIs). Results: Eight and five studies were included in the toxicity and efficacy analysis, respectively, including a total of 1081 RCC patients. The ABCG2 rs2231142 A allele was associated with an increased risk of sunitinib-induced thrombocytopenia and hand-foot syndrome (HFS) in Asians (ES = 1.65, 95% CI = 1.15-2.36, p = 0.006; ES = 1.52, 95% CI = 1.02-2.27, p = 0.041). However, the ABCG2 rs2231142 polymorphism was not associated with sunitinib-induced hypertension or neutropenia (ES = 1.09, 95% CI = 0.69-1.73, p = 0.701; ES = 0.87, 95% CI = 0.57-1.31, p = 0.501). Compared with the C allele, the ABCB1 rs1128503 T allele was associated with a decreased risk of sunitinib-induced hypertension but worse progression-free survival (PFS) (ES = 0.44, 95% CI = 0.26-0.77, p = 0.004; ES = 1.36, 95% CI = 1.07-1.73, p = 0.011). There was no significant association between the T allele or C allele of ABCB1 rs1128503 and overall survival (OS) (ES = 0.82, 95% CI = 0.61-1.10, p = 0.184). The ABCB1 rs2032582 T allele was associated with worse PFS than the other alleles (ES = 1.46, 95% CI = 1.14-1.87, p = 0.003), while there was no significant association between the T allele or other alleles and sunitinib-induced hypertension, HFS, or OS (ES = 0.77, 95% CI = 0.46-1.29, p = 0.326; ES = 1.02, 95% CI = 0.65-1.62, p = 0.919; ES = 1.32, 95% CI = 0.85-2.05, p = 0.215). Conclusion: The results indicate that the ABCG2 rs2231142 polymorphism may serve as a predictor of sunitinib-induced thrombocytopenia and HFS in Asians, while the ABCB1 rs1128503 polymorphism may serve as a predictor of sunitinib-induced hypertension, and both the ABCB1 rs1128503 and rs2032582 polymorphisms may serve as predictors of PFS in RCC. These results suggest a possible application of individualized use of sunitinib according to the genetic background of patients.

Dataset Information

Genetic polymorphisms of the adenosine triphosphate-binding cassette transporters (ABCG2, ABCB1) and gefitinib toxicity.

Publications

Genetic polymorphisms of the adenosine triphosphate-binding cassette transporters (ABCG2, ABCB1) and gefitinib toxicity.

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