Germline Polymorphisms in the Nuclear Receptors PXR and VDR as Novel Prognostic Markers in Metastatic Colorectal Cancer Patients Treated With FOLFIRI

Abstract

Nuclear receptors act as mediators of cancer-related inflammation and gene expression. They have a regulatory effect on genes encoding proteins related to drug adsorption, distribution, metabolism, and excretion. The aim of the present study was to highlight novel prognostic markers among polymorphisms in genes encoding for nuclear receptor proteins and inflammation-related cytokines in patients treated with a FOLFIRI regimen. This study included two independent cohorts comprising a total of 337 mCRC patients homogeneously treated with first-line FOLFIRI. Genotyping of 246 haplotype-tagging polymorphisms in 22 genes was performed using bead array technology. The NR1I2 (PXR)-rs1054190 and VDR-rs7299460 polymorphisms were significantly associated with patient overall survival (OS). A detrimental effect of the NR1I2 rs1054190-TT genotype on OS was observed in both the discovery and replication cohorts (HR = 6.84, P = 0.0021, q-value = 0.1278 and HR = 3.56, P = 0.0414, respectively). Patients harboring the NR1I2 rs1054190-TT genotype had a median OS of 9 months vs. 21 months in patients with C-allele (P < 0.0001 log-rank test). VDR rs7299460-T was consistently associated with a longer OS in both cohorts (discovery: HR = 0.61, P = 0.0075, q-value = 0.1535; replication: HR = 0.57, P = 0.0477). Patients with the VDR rs7299460-T allele had a median OS of 23 months compared to 18 months in those with the CC genotype (P = 0.0489, log-rank test). The NR1I2-rs1054190 polymorphism also had an effect on the duration of progression-free survival, consistent with the effect observed on OS. Two novel prognostic markers for mCRC treated with FOLFIRI were described and, if validated by prospective trials, have a potential application in the management of these patients.

IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm

“…(4) Developing a genetic score for OS prediction. Genetic markers identified in the previous steps were integrated with those already known to be associated with OS (i.e., NR1I2 -rs1054190, VDR -rs7299460) in the same study population [ 12 ], using the pooled dataset. For each polymorphism, point scores, according to the risk of death emerging from the Cox model including all genetic variants as covariates, were assigned to the presence of risk alleles, 0 otherwise.…”

“…The cancer-related inflammation response is also indicated to impact the efficacy of chemotherapy by regulating the inflammation-related transcriptional factors and in turn the expression of drug metabolic genes [ 8 , 9 , 10 ]. We have previously reported significant associations between genetic variants in inflammation-related transcriptional regulators and clinical outcome after administration of FOLFIRI (irinotecan, 5-FU, leucovorin) [ 11 , 12 , 13 ]. Particularly, pregnane X receptor (PXR; NR1I2 ) rs1054190 and vitamin D receptor ( VDR) rs7299460 polymorphisms emerged as prognostic markers of OS for metastatic CRC (mCRC) patients receiving FOLFIRI [ 12 ].…”

“…We have previously reported significant associations between genetic variants in inflammation-related transcriptional regulators and clinical outcome after administration of FOLFIRI (irinotecan, 5-FU, leucovorin) [ 11 , 12 , 13 ]. Particularly, pregnane X receptor (PXR; NR1I2 ) rs1054190 and vitamin D receptor ( VDR) rs7299460 polymorphisms emerged as prognostic markers of OS for metastatic CRC (mCRC) patients receiving FOLFIRI [ 12 ].…”

“…The primary aim was to identify novel genetic prognostic markers that could improve the pre-treatment identification of patients who may benefit from a first-line FOLFIRI administration. The secondary endpoint was to integrate these genetic markers related to the immune system with those related to the inflammation response (i.e., NR1I2 -rs1054190, VDR -rs7299460), that we previously identified in the same study population [ 12 ], to generate a genetic score of OS that could further improve the clinical management of patients with mCRC.…”

Germline and Somatic Pharmacogenomics to Refine Rectal Cancer Patients Selection for Neo-Adjuvant Chemoradiotherapy

“…DROSHA, double-stranded RNA-specific endoribonuclease; FGFR4, fibroblast growth factor receptor 4; HIF-1a, hypoxia inducible factor 1 subunit alpha; ICAM-1, intercellular adhesion molecule 1; IL-1, -6, -13, -17F, interleukin -1, -6, -13, -17F; mRNA, microRNA; SMAD-3, SMAD family member 3; VEGF, vascular endothelial growth factor. polymorphisms of proteins mediating inflammatory, angiogenic, hypoxia and cell adhesion phenomena were considered (Garziera et al, 2015;Garziera et al, 2017;Labriet et al, 2017;De Mattia et al, 2018a;De Mattia et al, 2018b;De Mattia et al, 2019;Labriet et al, 2019) (Figure 3). This is certainly a promising field of investigation in pharmacogenomics and this is proved by the number of studies published up to date analyzing different players and mediators of the complex inter-play between the microenvironment and the tumor tissue in determining the tumor response phenotype.…”