title: Role of NR1I2 (pregnane X receptor) polymorphisms in head and neck squamous cell carcinoma.
abstract: The pregnane X receptor (PXR) is a transcription factor regulating genes involved not only in pharmacokinetics but also in chemotherapy resistance and cancer progression. The significance of PXR for survival of head and neck squamous cell carcinoma (HNSCC) patients is unknown so far. Single nucleotide polymorphisms (SNPs) in the PXR-encoding NR1I2 gene influence receptor functionality and inducibility by ligands and thus modulate expression and activity of its target genes. In this study, seven SNPs in the NR1I2 gene were investigated for an association with PXR protein expression and survival of HNSCC patients. Genotyping was conducted using hybridisation probe format methodology. PXR protein expression was quantified by immunohistochemistry of tissue microarray samples of HNSCC biopsies. Genotypes were correlated to PXR protein expression by a linear model regressing on the continuous gene expression value and a Cox model regressing on overall survival times. Haplotype analysis was performed by reconstruction of haplotypes from genotype information according to the expectation-maximisation algorithm. Of all tested SNPs, rs1054190 and rs1054191 allele variants tended to correlate with a reduced protein expression score of PXR (p = 0.088). Four haplotypes, each consisting of two SNPs, rs3814055/rs1054190 and rs3814055/rs1054191 as well as rs1523127/rs1054190 and rs1523127/rs1054191, showed a significant reduction of the PXR expression score (p = 0.049 and p = 0.032). However, neither allele variants nor haplotypes influenced overall survival of the respective patients. Certain NR1I2 SNPs showed an impact on PXR protein expression in HNSCC but did not influence overall survival times, questioning their value as prognostic biomarkers.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Tasmin
authors.initials: T
authors.lastname: Reuter
authors.affiliation: Experimental Neurosurgery Research, Department of Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.|Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Warta
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Theile
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Meid
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rigalli
authors.affiliation: Tissue Bank of the National Center for Tumour Diseases (NCT) Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.|Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 244, 69120, Heidelberg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Mogler
authors.affiliation: Tissue Bank of the National Center for Tumour Diseases (NCT) Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.|Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 244, 69120, Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Department of Medical Oncology, National Center for Tumour Diseases, University of Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.|Hamamatsu Tissue Imaging and Analysis Center, BIOQUANT, University of Heidelberg, Im Neuenheimer Feld 267, 69120, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 244, 69120, Heidelberg, Germany.|Hamamatsu Tissue Imaging and Analysis Center, BIOQUANT, University of Heidelberg, Im Neuenheimer Feld 267, 69120, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Plinkert
authors.affiliation: Experimental Neurosurgery Research, Department of Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.|Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dyckhoff
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. johanna.weiss@med.uni-heidelberg.de.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism
chemical_list: C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid
keywords: Genotype/phenotype correlation; Head and neck squamous cell carcinoma; NR1I2 polymorphism; Pregnane X receptor