Association of STAT-3 rs1053004 and VDR rs11574077 With FOLFIRI-Related Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

Elena De Mattia, Erika Cecchin, Marcella Montico, Adrien Labriet, Chantal Guillemette, Eva Dreussi, Rossana Roncato, Alessia Bignucolo, Angela Buonadonna, Mario D'Andrea, Luigi Coppola, Sara Lonardi, Eric Lévesque, Derek Jonker, Félix Couture, Giuseppe Toffoli

Research output: Contribution to journalArticle

Abstract

Pharmacogenomics has largely been applied to the personalization of irinotecan-based treatment, focusing mainly on the study of genetic variants in adsorption, distribution, metabolism, and excretion (ADME) genes. The transcriptional control of ADME gene expression is mediated by a set of nuclear factors responding to cancer-related inflammation, which could have pharmacological implications. The aim of the present study was to uncover novel genetic predictors of neutropenia and gastrointestinal toxicity risk among 246 haplotype-tagging polymorphisms in 22 genes encoding inflammation-related cytokines and transcriptional regulators of ADME genes. The study comprised overall more than 400 metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI, grouped in a discovery and a replication cohorts. A concordant protective effect of STAT-3 rs1053004 polymorphism against the risk of grade 3-4 gastrointestinal toxicity was observed in both the cohorts of patients (OR = 0.51, p = 0.045, q = 0.521 and OR = 0.39, p = 0.043, respectively). VDR rs11574077 polymorphism was demonstrated to affect both irinotecan biliary index (BI) and glucuronidation ratio (GR) by a pharmacokinetic analysis. This effect was consistent with an increased risk of grade 3-4 gastrointestinal toxicity in the discovery cohort (OR = 4.46, p = 0.010, q = 0.305). The association was not significant in the replication cohort (OR = 1.44, p = 0.601). These findings suggest an effect of STAT-3 and VDR polymorphisms on FOLFIRI-related gastrointestinal toxicity. If prospectively validated as predictive markers, they could be used to improve the clinical management of mCRC.

Original languageEnglish
Pages (from-to)367
JournalFrontiers in Pharmacology
Volume9
DOIs
Publication statusPublished - 2018

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irinotecan
Adsorption
Colorectal Neoplasms
Genes
Inflammation
Pharmacogenetics
Neutropenia
Haplotypes
Pharmacokinetics
Pharmacology
Cytokines
Gene Expression
Neoplasms
Therapeutics

Cite this

@article{eb6c576bd9644605958dda3b68db9dbb,
title = "Association of STAT-3 rs1053004 and VDR rs11574077 With FOLFIRI-Related Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients",
abstract = "Pharmacogenomics has largely been applied to the personalization of irinotecan-based treatment, focusing mainly on the study of genetic variants in adsorption, distribution, metabolism, and excretion (ADME) genes. The transcriptional control of ADME gene expression is mediated by a set of nuclear factors responding to cancer-related inflammation, which could have pharmacological implications. The aim of the present study was to uncover novel genetic predictors of neutropenia and gastrointestinal toxicity risk among 246 haplotype-tagging polymorphisms in 22 genes encoding inflammation-related cytokines and transcriptional regulators of ADME genes. The study comprised overall more than 400 metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI, grouped in a discovery and a replication cohorts. A concordant protective effect of STAT-3 rs1053004 polymorphism against the risk of grade 3-4 gastrointestinal toxicity was observed in both the cohorts of patients (OR = 0.51, p = 0.045, q = 0.521 and OR = 0.39, p = 0.043, respectively). VDR rs11574077 polymorphism was demonstrated to affect both irinotecan biliary index (BI) and glucuronidation ratio (GR) by a pharmacokinetic analysis. This effect was consistent with an increased risk of grade 3-4 gastrointestinal toxicity in the discovery cohort (OR = 4.46, p = 0.010, q = 0.305). The association was not significant in the replication cohort (OR = 1.44, p = 0.601). These findings suggest an effect of STAT-3 and VDR polymorphisms on FOLFIRI-related gastrointestinal toxicity. If prospectively validated as predictive markers, they could be used to improve the clinical management of mCRC.",
author = "{De Mattia}, Elena and Erika Cecchin and Marcella Montico and Adrien Labriet and Chantal Guillemette and Eva Dreussi and Rossana Roncato and Alessia Bignucolo and Angela Buonadonna and Mario D'Andrea and Luigi Coppola and Sara Lonardi and Eric L{\'e}vesque and Derek Jonker and F{\'e}lix Couture and Giuseppe Toffoli",
year = "2018",
doi = "10.3389/fphar.2018.00367",
language = "English",
volume = "9",
pages = "367",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - Association of STAT-3 rs1053004 and VDR rs11574077 With FOLFIRI-Related Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

AU - De Mattia, Elena

AU - Cecchin, Erika

AU - Montico, Marcella

AU - Labriet, Adrien

AU - Guillemette, Chantal

AU - Dreussi, Eva

AU - Roncato, Rossana

AU - Bignucolo, Alessia

AU - Buonadonna, Angela

AU - D'Andrea, Mario

AU - Coppola, Luigi

AU - Lonardi, Sara

AU - Lévesque, Eric

AU - Jonker, Derek

AU - Couture, Félix

AU - Toffoli, Giuseppe

PY - 2018

Y1 - 2018

N2 - Pharmacogenomics has largely been applied to the personalization of irinotecan-based treatment, focusing mainly on the study of genetic variants in adsorption, distribution, metabolism, and excretion (ADME) genes. The transcriptional control of ADME gene expression is mediated by a set of nuclear factors responding to cancer-related inflammation, which could have pharmacological implications. The aim of the present study was to uncover novel genetic predictors of neutropenia and gastrointestinal toxicity risk among 246 haplotype-tagging polymorphisms in 22 genes encoding inflammation-related cytokines and transcriptional regulators of ADME genes. The study comprised overall more than 400 metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI, grouped in a discovery and a replication cohorts. A concordant protective effect of STAT-3 rs1053004 polymorphism against the risk of grade 3-4 gastrointestinal toxicity was observed in both the cohorts of patients (OR = 0.51, p = 0.045, q = 0.521 and OR = 0.39, p = 0.043, respectively). VDR rs11574077 polymorphism was demonstrated to affect both irinotecan biliary index (BI) and glucuronidation ratio (GR) by a pharmacokinetic analysis. This effect was consistent with an increased risk of grade 3-4 gastrointestinal toxicity in the discovery cohort (OR = 4.46, p = 0.010, q = 0.305). The association was not significant in the replication cohort (OR = 1.44, p = 0.601). These findings suggest an effect of STAT-3 and VDR polymorphisms on FOLFIRI-related gastrointestinal toxicity. If prospectively validated as predictive markers, they could be used to improve the clinical management of mCRC.

AB - Pharmacogenomics has largely been applied to the personalization of irinotecan-based treatment, focusing mainly on the study of genetic variants in adsorption, distribution, metabolism, and excretion (ADME) genes. The transcriptional control of ADME gene expression is mediated by a set of nuclear factors responding to cancer-related inflammation, which could have pharmacological implications. The aim of the present study was to uncover novel genetic predictors of neutropenia and gastrointestinal toxicity risk among 246 haplotype-tagging polymorphisms in 22 genes encoding inflammation-related cytokines and transcriptional regulators of ADME genes. The study comprised overall more than 400 metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI, grouped in a discovery and a replication cohorts. A concordant protective effect of STAT-3 rs1053004 polymorphism against the risk of grade 3-4 gastrointestinal toxicity was observed in both the cohorts of patients (OR = 0.51, p = 0.045, q = 0.521 and OR = 0.39, p = 0.043, respectively). VDR rs11574077 polymorphism was demonstrated to affect both irinotecan biliary index (BI) and glucuronidation ratio (GR) by a pharmacokinetic analysis. This effect was consistent with an increased risk of grade 3-4 gastrointestinal toxicity in the discovery cohort (OR = 4.46, p = 0.010, q = 0.305). The association was not significant in the replication cohort (OR = 1.44, p = 0.601). These findings suggest an effect of STAT-3 and VDR polymorphisms on FOLFIRI-related gastrointestinal toxicity. If prospectively validated as predictive markers, they could be used to improve the clinical management of mCRC.

U2 - 10.3389/fphar.2018.00367

DO - 10.3389/fphar.2018.00367

M3 - Article

C2 - 29706892

VL - 9

SP - 367

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

ER -