WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• SLCO1B3 is an influx transporter located at the hepatocyte basolateral membrane and it is involved in the uptake of a broad range of drug substrates including docetaxel.• The pharmacogenetics of SLCO1B3 is not well characterized and previous in vivo and in vitro studies reported conflicting results with regards to the functional effects of the limited number of SLCO1B3 polymorphisms that were studied. • Docetaxel displays a wide interindividual variability in its pharmacokinetics and pharmacodynamics and an understanding of SLCO1B3 pharmacogenetics might provide clinical benefits in guiding docetaxel dosing. WHAT THIS STUDY ADDS• The SLCO1B3 gene was comprehensively screened in the local healthy Asian populations (n = 168). A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15 haplotype-tag SNPs (htSNPs) were identified. These htSNPs were profiled in a cohort of Chinese nasopharyngeal cancer (NPC) patients (n = 50).• Genotypic-phenotypic analysis showed that a haplotypic construct comprising of four variants [IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA] was the critical determinant of docetaxel disposition.• This study suggests that the comprehensive screening and haplotypic linkage analysis of SLCO1B3 can better elucidate its pharmacogenetic effects on interpatient variability of docetaxel and other putative drug substrates. Further studies are warranted in cancer patients belonging to other ethnic groups. AIMSTo completely screen the SLCO1B3 gene in three distinct healthy Asian populations (Chinese, Malay and Indian, n = 168) and investigate the influence of haplotype-tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients. METHODSGenomic DNA of individuals was screened for SLCO1B3 polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK. RESULTSA strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15-htSNPs were identified. The SLCO1B3 haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (P = 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration-time curve (AUC(0,•)): r 2 = 29% and 22%, respectively]. Patients harbouring the GAG*347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,•) of docetaxel compared with patients harbouring the reference haplotype, GGA*347wt (P = 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the re...
Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for Hepatocellular Carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across TNM stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.
Several nuclear receptors are being increasingly recognized for their role as master xenosensors. Among them, CAR-RXRα heterodimer, as encoded by NR1I3 and NR2B1, responds to the presence of drug compounds and regulates the transcription of a wide array of genes involved in their disposition. To investigate the frequency distribution and linkage disequilibrium patterns of NR1I3 and NR2B1 genetic variations, these genes were screened in 168 healthy local Asian subjects, namely Chinese, Malays, and Indians (n=56 subjects each). A total of 38 and 88 SNPs were identified in NR1I3 and NR2B1, respectively. Among them, there were 13 and 43 novel SNPs present at low allelic frequencies (<10%) in NR1I3 and NR2B1, respectively. Notably, the genetic variations in the NR1I3 and NR2B1 genes were mainly confined to the introns whilst the exons were highly conserved across the ethnic populations. Indians harboured distinct frequency distributions from Chinese and Malays in both genes. Based on the linkage disequilibrium patterns of both genes, a number of tag-SNPs were selected for each population (n=8-13 for NR1I3; n=12-18 for NR2B1). In-silico prediction analyses revealed a number of possible functional SNPs. Our data would be valuable for future pharmacogenetic studies on the drug substrates of CAR-RXRα target genes.
HNF4α (encoded by gene NR2A1) is a dominant transcriptional regulator of various drug disposition genes. It forms a circuitry of molecular cross-talk with other nuclear receptors such as PXR and CAR to synergistically initiate transcription. This study reports on the frequency, linkage disequilibrium pattern and tag-SNP selection of NR2A1 polymorphisms in three local Asian populations, namely Chinese, Malays and Indians (n = 56 subjects each). A total of 69 polymorphisms were identified in the genomic region of NR2A1, of which thirty-three were novel polymorphisms with low allelic frequencies (<0.02). The exonic region of NR2A1 was highly conserved with only 4 novel and 1 reported SNPs identified at low allelic frequencies of less than 0.02. Based on the criteria of MAF ≥ 0.05 and R(2) ≥ 0.80, there were 19, 20 and 22 tag-SNPs selected to represent the genetic polymorphisms of NR2A1 in Chinese, Malays and Indians, respectively. In-silico predictions suggested that some of these polymorphic variants may exert functional effects through affecting the binding sites of transcription and splicing factors. Our study provides valuable information on the genetic variability of NR2A1 which would be useful for pharmacogenetics studies in the local Asian populations.
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