Polymorphisms in
            <i>Slco1B3</i>
            and
            <i>Nr1I2</i>
            as Genetic Determinants of Hematotoxicity of Carboplatin and Paclitaxel Combination

Mbatchi, Litaty; Schmitt, Antonin; Thomas, Fabienne; Cazaubon, Yoann; Robert, J.; Lumbroso, Serge; Brouillet, Jean‐Paul; Pourquier, Philippe; Chatelut, Étienne; Boyer, Jean-Christophe; Evrard, Alexandre

doi:10.2217/pgs.15.84

Cited by 14 publications

(6 citation statements)

References 36 publications

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“…These evidences supported the notion of explaining drug action by the biological functions of drug-related genes [ 39 ]. Therefore, other carboplatin-related genes involved in hematopoietic cell lineage may provide new research routes with regard to the underlying toxicological mechanisms of carboplatin, such as finding polymorphisms associated with hematotoxicity [ 40 ] and differential gene expression involved in hematopoietic lineage [ 41 ]. Experimental validation of these genes will be required to further elucidate the roles they play in the hematologic context.…”

Section: Discussionmentioning

confidence: 99%

Carboplatin-induced hematotoxicity among patients with non-small cell lung cancer: Analysis on clinical adverse events and drug-gene interactions

Cheng

et al. 2016

Oncotarget

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In order to clarify the risk of hematotoxicity of carboplatin, we inspected 19901 case reports of non-small cell lung cancer patients that were submitted to the FDA Adverse Event Reporting System (FAERS) between January 2004 and December 2015. These comprised 3907 cases which were treated with carboplatin and 15994 cases which were treated with other therapies in the absence of carboplatin. By comparison, carboplatin cases were significantly more likely to report anemia (OR = 2.27, 95% CI 1.85-2.78, P = 5.04×10−15), neutropenia (OR = 2.27, 95% CI 1.76-2.92, P = 2.39×10−10), and thrombocytopenia (OR = 2.38, 95% CI 1.84-3.08, P = 5.60×10−11). We further explored published evidences and found 205 human genes interacting with carboplatin. Functional analysis corroborated that these genes were significantly enriched in the biochemical pathway of hematopoietic cell lineage (adjusted P = 6.02×10−11). This indicated that carboplatin could profoundly affect the development of blood cells. Given the early awareness of the hematologic risks, great caution should be exercised in prescribing carboplatin to non-small cell lung cancer patients. And functional enrichment analysis on carboplatin-related genes warranted subsequent research with regard to the underlying toxicological mechanisms.

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Section: Discussionmentioning

confidence: 99%

Carboplatin-induced hematotoxicity among patients with non-small cell lung cancer: Analysis on clinical adverse events and drug-gene interactions

Cheng

et al. 2016

Oncotarget

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“…An assessment of polymorphisms (SNPs) in SLCO1B3 revealed that a number of variants were associated with anti-cancer drug and immunosuppressant drug response or toxicity (see https://www.pharmgkb.org/gene/PA35844/variantAnnotation). For example, patients who are carriers of the T allele of rs4149117 (OATP1B3-Ser112Ala, c.334T>G), were 19% less sensitive to thrombocytopenia from carboplatin/paclitaxel treatment, than the homozygotes for the G allele 65 . SLCO1B3 699GG (rs7311358, OATP1B3-Met233Ile, c.699G>A) and 344TT (rs4149117) genotypes are also associated with non-response to imatinib in patients with chronic myeloid leukemia 66 .…”

Section: Polymorphisms In Other Drug Transporters With Less Evidencementioning

confidence: 99%

Influence of Transporter Polymorphisms on Drug Disposition and Response: A Perspective From the International Transporter Consortium

Yee

Brackman

Ennis

et al. 2018

Clin Pharma and Therapeutics

110

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Advances in genomic technologies have led to a wealth of information identifying genetic polymorphisms in membrane transporters, specifically how these polymorphisms affect drug disposition and response. This review describes the current perspective of the International Transporter Consortium (ITC) on clinically important polymorphisms in membrane transporters. ITC suggests that, in addition to previously recommended polymorphisms in ABCG2 (BCRP) and SLCO1B1 (OATP1B1), polymorphisms in the emerging transporter, SLC22A1 (OCT1), be considered during drug development. Collectively, polymorphisms in these transporters are important determinants of interindividual differences in the levels, toxicities, and response to many drugs.

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“…The effect of SLCO1B3 variation on chemotherapy‐induced toxicities is poorly understood. A SLCO1B3 variant rs4149117 (c.334T>C, p.Ser112Pro), which is in a complete LD with rs7311358 in our data and European population, 31 has been found to reduce, increase, or not affect the risk for toxicities 7,32,33 . Similarly, the mechanism explaining our finding of a reduced risk of severe adverse effects associated with the rs7311358 remains elusive.…”

Section: Discussionmentioning

confidence: 51%

Toxicity and therapy outcome associations in LIG3, SLCO1B3, ABCB1, OPRM1 and GSTP1 in high‐grade serous ovarian cancer

Deng

Laasik

Salminen

et al. 2023

Basic Clin Pharma Tox

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Adverse effects are the major limiting factors in combinatorial chemotherapies. To identify genetic associations in ovarian cancer chemotherapy‐induced toxicities and therapy outcomes, we examined a cohort of 101 patients receiving carboplatin‐paclitaxel treatment with advanced high‐grade serous ovarian cancers. Based on literature and database searches, we selected 19 candidate polymorphisms, designed a multiplex single nucleotide polymorphism‐genotyping assay and applied Cox regression analysis, case–control association statistics and the log‐rank Mantel−Cox test. In the Cox regression analysis, the SLCO1B3 rs1052536 AA‐genotype was associated with a reduced risk of any severe toxicity (hazard ratio = 0.35, p = 0.023). In chi‐square allelic test, the LIG3 rs1052536 T‐allele was associated with an increased risk of neuropathy (odds ratio [OR] = 2.79, p = 0.031) and GSTP1 rs1695 G allele with a poorer response in the first‐line chemotherapy (OR = 2.65, p = 0.026). In Kaplan–Meier survival analysis, ABCB1 rs2032582 TT‐genotype was associated with shorter overall survival (uncorrected p = 0.025) and OPRM1 rs544093 GG and GT genotypes with shorter platinum‐free interval (uncorrected p = 0.027) and progression‐free survival (uncorrected p = 0.012). Results suggest that SLCO1B3 and LIG3 variants are associated with the risk of adverse effects in patients receiving carboplatin‐paclitaxel treatment, the GSTP1 variant may affect the treatment response and ABCB1 and OPRM1 variants may influence the prognosis.

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Polymorphisms in Slco1B3 and Nr1I2 as Genetic Determinants of Hematotoxicity of Carboplatin and Paclitaxel Combination

Abstract: Our results revealed the importance of SLCO1B3 and NR1I2 in the sensitivity to carboplatin/paclitaxel thrombocytopenia.

Cited by 14 publications

References 36 publications

Carboplatin-induced hematotoxicity among patients with non-small cell lung cancer: Analysis on clinical adverse events and drug-gene interactions

Carboplatin-induced hematotoxicity among patients with non-small cell lung cancer: Analysis on clinical adverse events and drug-gene interactions

Influence of Transporter Polymorphisms on Drug Disposition and Response: A Perspective From the International Transporter Consortium

Toxicity and therapy outcome associations in LIG3, SLCO1B3, ABCB1, OPRM1 and GSTP1 in high‐grade serous ovarian cancer

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