Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu, Haibo; Zhuang, Wei; Wu, Ting; Xin, Shuang; Lin, Chih-Wen; Ruan, Honglian; Zhu, Xia; Huang, Min; Li, J. L.; Hou, Xue; Zhou, Zhiwei; Wang, X. D.

doi:10.1038/tpj.2017.40

Cited by 20 publications

(22 citation statements)

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“…Imatinib mesylate is a TKI that inhibits the BCR-ABL, c-Kit and PDGFR tyrosine kinases. 2 Imatinib is mainly used in the treatment of chronic myeloid leukaemia (CML) and GISTs. In addition to cancer cells, the tyrosine kinase enzymes of non-cancer cells also get inhibited.…”

Section: Discussionmentioning

confidence: 99%

Imatinib-induced haematuria necessitating drug discontinuation

Hemakumar

Pavithran

2020

Journal of Onco-Nephrology

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Gastrointestinal stromal tumours are rare neoplasms of the gastrointestinal tract that are mesenchymal in origin. The introduction of tyrosine kinase inhibitors resulted in significant improvement in survival of patients with gastrointestinal stromal tumour even in advanced disease conditions. A 43-year-old adult male who is a known case of gastrointestinal stromal tumour of the stomach, on adjuvant therapy with imatinib, presented with a history of gross haematuria of several episodes as well as persistent microhaematuria and was evaluated for the same. He was investigated for all possible causes, but all were negative. The patient was advised to withhold imatinib. Haematuria resolved 1 month after stopping imatinib. Then it was rechallenged. He had recurrence of symptoms, so it was discontinued. In view of the temporal relation of haematuria and administration of imatinib, a diagnosis of imatinib-induced haematuria was made.

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Section: Discussionmentioning

confidence: 99%

Imatinib-induced haematuria necessitating drug discontinuation

Hemakumar

Pavithran

2020

Journal of Onco-Nephrology

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“…OCT1 is primarily expressed in hepatocytes and the hepatic excretion of drugs will be influenced by the lower functioning haplotypes. Qiu et al and Singh et al showed that rs6383369 (F160L) and rs628031 (M480V) reduced the clearance of imatinib [49,52]. In OCT1, the loss-of-function genetic variants showed lower uptake activity in all reported polymorphisms for metformin and imatinib, and also showed a decreased clearance of morphine.…”

Section: Genetic Polymorphisms In the Oct1 Gene (Slc22a1)mentioning

confidence: 99%

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

Zazuli

Duin

Jansen

et al. 2020

IJMS

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A considerable number of drugs and/or their metabolites are excreted by the kidneys through glomerular filtration and active renal tubule secretion via transporter proteins. Uptake transporters in the proximal tubule are part of the solute carrier (SLC) superfamily, and include the organic cation transporters (OCTs). Several studies have shown that specific genetic polymorphisms in OCTs alter drug disposition and may lead to nephrotoxicity. Multiple single nucleotide polymorphisms (SNPs) have been reported for the OCT genes (SLC22A1, SLC22A2 and SLC22A3), which can influence the proteins’ structure and expression levels and affect their transport function. A gain-in-function mutation may lead to accumulation of drugs in renal proximal tubule cells, eventually leading to nephrotoxicity. This review illustrates the impact of genetic polymorphisms in OCTs on renal drug disposition and kidney injury, the clinical significances and how to personalize therapies to minimize the risk of drug toxicity.

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“…Case-control study demonstrated that G risks allele at SNP rs27437 in SLC22A5 gene was associated with colorectal cancer risk (69). Study on GIST patients suggested that investigation on minor allele of SLC22A5 may assist to optimise imatinib therapy (70,71).…”

Section: Slc22a5mentioning

confidence: 99%

Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

Feng

Zhang

et al. 2020

Preprint

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Abstract BackgroundDiffuse gastric cancer (DGC) is known as gastric cancer with diffuse type morphology. Early onset DGC is an indicator of suspicious hereditary diffuse gastric cancer (HDGC). HDGC patient are often less sensitive to chemotherapy and suffer from highly invasive late stage malignancy with poor prognosis. Such hereditary cancer syndrome is closely related to deleterious CDH1 germline variant. In addition, potential pathogenic germline variants in other candidate genes were also observed in HDGC families. However, the profile of gastric cancer (GC) susceptibility gene in Chinese HDGC patients is yet to be elucidated.MethodsTo investigate gastric cancer susceptibility genes in Chinese gastric cancer patients, we collected peripheral blood samples from 29 patients fulfilled both HDGC clinical diagnosis and genetic testing criteria updated on 2015 by IGCLC. Genomic DNA was extracted from peripheral blood followed by Whole Exome Sequencing (WES) with average sequencing depth of at least 100X. Gastric cancer predisposing SNV and Indel candidates were filtered based on population allele frequencies in public nucleotide polymorphism databases and pathogenic variant filtering process was performed to identify potential gastric cancer predisposing variant candidates. Immunohistochemistry was conducted on biopsies from patient who carries potential pathogenic CDH1 germline variant.ResultsIn general, 336296 germline non-synonymous variants were detected from 29 GC patients. According to the pathogenic variant filtering process, 25 germline variant candidates in 22 genes were identified as gastric cancer predisposing variant candidates. In addition, a novel splice-site variant, c.2165-1G>A (NM_004360.4), in CDH1 was detected in a Chinese early-onset HDGC patient who developed ovarian metastasis. Furthermore, IHC analysis on the ovarian cancer tissue from this patient demonstrated weakly to moderate staining of E-cadherin compared with positive control. Moreover, another two variants, CTNNA1 c.1975_1976del (NM_001903.2), APC c.-19+1G>A (NM_001127511.2), were suspicious of gastric cancer predisposing variants.ConclusionsThis study suggested that CDH1 c.2165-1G>A may act as a gastric cancer predisposing variant. In addition, to further investigate molecular mechanisms of early-onset gastric cancer, one may consider 22 genes observed in this study. Furthermore, the inconclusive results in this study warrant future investigation on gastric cancer susceptibility gene discovery that cohort selection may require more stringent conditions.

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Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Cited by 20 publications

References 50 publications

Imatinib-induced haematuria necessitating drug discontinuation

Imatinib-induced haematuria necessitating drug discontinuation

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

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