DRD2

Gene Summary

Gene:DRD2; dopamine receptor D2
Aliases: D2R, D2DR
Location:11q23
Summary:This gene encodes the D2 subtype of the dopamine receptor. This G-protein coupled receptor inhibits adenylyl cyclase activity. A missense mutation in this gene causes myoclonus dystonia; other mutations have been associated with schizophrenia. Alternative splicing of this gene results in two transcript variants encoding different isoforms. A third variant has been described, but it has not been determined whether this form is normal or due to aberrant splicing. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:D(2) dopamine receptor
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DRD2 (cancer-related)

Murata Y, Nishioka M, Bundo M, et al.
Comprehensive DNA methylation analysis of human neuroblastoma cells treated with blonanserin.
Neurosci Lett. 2014; 563:123-8 [PubMed] Related Publications
Blonanserin is a second-generation antipsychotic drug for schizophrenia. The pharmacological actions of blonanserin are shown to be the antagonism of dopamine receptor 2 and serotonin receptors. However, its molecular mechanisms in brain cells have not been fully characterized. Accumulating evidence suggests that antipsychotic drugs and mood stabilizers show epigenetic effects on a wide range of genes in animal and cellular models. We performed genome-wide DNA methylation analysis targeting 479,814 CpG sites of cultured human neuroblastoma cells administered with blonanserin. We found that 3,057 CpG sites showed statistically significant changes in DNA methylation at two different doses of blonanserin (1.36 nM and 13.6 nM). These included hypermethylated CpG sites that were enriched in genes related to axonogenesis and cell morphogenesis involved in neuron differentiation. We also showed that the global effect on DNA methylome depends on the concentration of the drug. With a high dose of blonanserin, the overall methylation levels across all CpG sites significantly increased. These increases in DNA methylation were prominent in the CpG sites distant from promoter regions. We further examined DNA methylation changes in specific genes implicated for the actions of antipsychotic drugs, such as the dopamine receptor 2 (DRD2) gene and the serotonin receptor 2A (HTR2A) gene. We observed that CpG sites that were located within DRD2 and HTR2A genes were significantly hypermethylated by blonanserin. The DNA methylation changes induced by the treatment with blonanserin will be useful for understanding its pharmacological actions at the cellular level.

Komatsu S, Ichikawa D, Hirajima S, et al.
Clinical impact of predicting CCND1 amplification using plasma DNA in superficial esophageal squamous cell carcinoma.
Dig Dis Sci. 2014; 59(6):1152-9 [PubMed] Related Publications
BACKGROUND: This study was designed to evaluate the clinical benefit of predicting the cyclin D1 (CCND1) status using cell-free plasma DNA in superficial esophageal squamous cell carcinoma (ESCC) patients.
METHODS: The ratio of the CCND1 (11q13) dosage to the DRD2 (11q22-23) dosage (C/D ratio) as the CCND1 copy number was evaluated. This study was divided into three steps: (1) demonstration of the feasibility, (2) evaluation of whether the plasma C/D ratio assay could monitor tumor dynamics, and (3) a validation study in 63 consecutive superficial ESCC (pTis-T1) patients and 40 healthy volunteers.
RESULTS: (1) The plasma C/D ratio was significantly higher (p = 0.0369) in superficial ESCC patients than in the controls in a preliminary test. (2) The high plasma C/D ratio appeared to reflect the tumor levels of the CCND1 status and was reduced in postoperative plasma samples (p = 0.1154) and samples following endoscopic resection (p = 0.0845). (3) Validation analysis revealed that the plasma C/D ratio was significantly higher in superficial ESCC patients than in controls (p < 0.0001). The frequency of recurrence was significantly higher (p = 0.0198), and recurrence-free survival was significantly shorter (p = 0.0075) in patients with a high plasma C/D ratio. Moreover, a high C/D ratio was shown to be an independent risk factor for recurrence on multivariate analysis [p = 0.0334; odds ratio 10.58 (range 1.203-93.23)].
CONCLUSION: The prediction of CCND1 amplification by plasma DNA may be a new complementary clinical biomarker for recurrence in patients with superficial ESCC.

Jiang X, Konkalmatt P, Yang Y, et al.
Single-nucleotide polymorphisms of the dopamine D2 receptor increase inflammation and fibrosis in human renal proximal tubule cells.
Hypertension. 2014; 63(3):e74-80 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
The dopamine D2 receptor (D2R) negatively regulates inflammation in mouse renal proximal tubule cells (RPTCs), and lack or downregulation of the receptor in mice increases the vulnerability to renal inflammation independent of blood pressure. Some common single-nucleotide polymorphisms (SNPs; rs6276, rs6277, and rs1800497) in the human DRD2 gene are associated with decreased D2R expression and function, as well as high blood pressure. We tested the hypothesis that human RPTCs (hRPTCs) expressing these SNPs have increased expression of inflammatory and injury markers. We studied immortalized hRPTCs carrying D2R SNPs and compared them with cells carrying no D2R SNPs. RPTCs with D2R SNPs had decreased D2R expression and function. The expressions of the proinflammatory tumor necrosis factor-α and the profibrotic transforming growth factor-β1 and its signaling targets Smad3 and Snail1 were increased in hRPTC with D2R SNPs. These cells also showed induction of epithelial mesenchymal transition and production of extracellular matrix proteins, assessed by increased vimentin, fibronectin 1, and collagen I a1. To test the specificity of these D2R SNP effects, hRPTC with D2R SNPs were transfected with a plasmid encoding wild-type DRD2. The expression of D2R was increased and that of transforming growth factor-β1, Smad3, Snail1, vimentin, fibronectin 1, and collagen I a1 was decreased in hRPTC with D2R SNPs transfected with wild-type DRD2 compared with hRPTC-D2R SNP transfected with empty vector. These data support the hypothesis that D2R function has protective effects in hRPTCs and suggest that carriers of these SNPs may be prone to chronic renal disease and high blood pressure.

van der Pas R, Feelders RA, Gatto F, et al.
Preoperative normalization of cortisol levels in Cushing's disease after medical treatment: consequences for somatostatin and dopamine receptor subtype expression and in vitro response to somatostatin analogs and dopamine agonists.
J Clin Endocrinol Metab. 2013; 98(12):E1880-90 [PubMed] Related Publications
CONTEXT: Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D₂R) and somatostatin receptor subtype 5 (sst₅). The sst₂ expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst₂-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease.
OBJECTIVE: Our objective was to compare sst and D₂R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion.
PATIENTS AND DESIGN: Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles.
MAIN OUTCOME MEASURES: We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells.
RESULTS: The sst₂ mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst₅ and D₂R mRNA expression or in sst₂, sst₅, and D₂R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; -30.5% ± 10.4%) was less potent than pasireotide (n = 5 out of 6; -47.0% ± 4.2%) and cabergoline (n = 3 out of 4; -41.9% ± 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2.
CONCLUSIONS: After achieving normocortisolism induced by medical therapy, cortisol-mediated sst₂ downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with respect to in vitro inhibition of ACTH secretion. Whether sustained normocortisolism induced by medical therapy induces re-expression of functional sst₂ protein in corticotroph adenomas and whether this increases the ACTH-lowering potency of octreotide remains to be established.

Saveanu A, Sebag F, Guillet B, et al.
Targeting dopamine receptors subtype 2 (D2DR) in pheochromocytomas: head-to-head comparison between in vitro and in vivo findings.
J Clin Endocrinol Metab. 2013; 98(12):E1951-5 [PubMed] Related Publications
CONTEXT: Dopamine subtype 2 receptors (D2DRs) are overexpressed in pheochromocytomas (PHEOs). D2DR-expressing tumors can be visualized by iodine-123 labeled iodobenzamide (¹²³I-IBZM) single-photon emission computed tomography (SPECT).
OBJECTIVE: The hypothesis of this study was that D2DR high expression in PHEOs would allow in vivo visualization through ¹²³I-IBZM SPECT. The present prospective pilot study aims to evaluate the performance of ¹²³I-IBZM SPECT in PHEOs and to correlate the tumor uptake with D2DR expression in tumor samples after surgery. SETTING, MATERIALS, AND METHODS: Ten unrelated patients with PHEOs were evaluated, prior to adrenalectomy, with ¹²³I-IBZM SPECT (whole body scan at 4 and 24 h after the injection; and SPECT centered on the abdomen at 24 h). D2DR mRNA and protein expressions were evaluated in all tumors by quantitative real-time RT-PCR and immunohistochemistry, respectively.
MAIN OUTCOME MEASURE: Intensity of tumoral uptake of ¹²³I-IBZM was measured.
RESULTS: All PHEOs express D2DR mRNA (ranging from 2.1 to 14.7 copy/copy β-glucuronidase) and protein (immunostaining score: moderate or strong in 9 of 10 cases). However, none of the patients (0%) showed an increased tumor uptake of ¹²³I-IBZM.
CONCLUSIONS: These results suggest that ¹²³I-IBZM is not a useful radiopharmaceutical in the detection and characterization of PHEOs despite D2DR expression. Our findings and data from the related literature may support different hypotheses to explain the failure of D2DR targeting by ¹²³I-IBZM.

Flores KG, Erdei E, Luo L, et al.
A pilot study of genetic variants in dopamine regulators with indoor tanning and melanoma.
Exp Dermatol. 2013; 22(9):576-81 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Many people frequently tan indoors despite being aware of the increased risk of melanoma. Ultraviolet radiation is hypothesized to modify biological reward pathways, for example, through the dopamine neurotransmitter system, to reinforce tanning behaviour. In this pilot study, we relied on questionnaire and DNA data from a recently completed case-control study to examine 67 single-nucleotide polymorphisms (SNPs) and related haplotypes in five dopamine receptor and drug metabolism genes in relation to indoor tanning among controls. We also examined the association between individual SNPS and likelihood of melanoma, adjusting for or stratifying on indoor tanning status. In candidate and haplotype gene analyses, variants only in the DRD2 dopamine receptor and ANKK1 signalling genes were positively associated with indoor tanning use among controls; only associations for ANKK1 remained statistically significant (P < 0.05) after adjustment. Several SNPs in ANKK1 and DRD2 associated with indoor tanning among controls were also found to be associated with increased risk of melanoma. Upon stratifying for indoor tanning status, one ANKK1 SNP was positively associated with melanoma among non-tanners, while three DRD2 SNPS were positively associated with melanoma among tanners or non-tanners, depending on the SNP. These alleles represent important genomic regions to further explore addictive tanning behaviour.

Sheikhpour M, Ahangari G, Sadeghizadeh M, Deezagi A
A novel report of apoptosis in human lung carcinoma cells using selective agonist of D2-like dopamine receptors: a new approach for the treatment of human non-small cell lung cancer.
Int J Immunopathol Pharmacol. 2013 Apr-Jun; 26(2):393-402 [PubMed] Related Publications
In our previous study, a relationship between low expression of D2-like dopamine receptor genes and non-small cell lung cancer (NSCLC) disease was found. In this new research, by using selective agonist of these receptors, Bromocriptine (BR), we attempted to activate D2-like expression and apoptotic induction in a selective cell line of NSCLC. In addition, the relationship of apoptotic response of human lung carcinoma cells to BR and D2- dopamine receptor genes is investigated. Human lung cancer (QU-DB) cells were treated by five doses of BR at 48 h and cell viability was determined by MTT assay. The gene expression pattern of D2-like dopamine receptor Genes was studied by Real Time PCR. Nuclear morphology of cells was monitored by DAPI flourescent staining then induction of DNA fragmentation by BR was shown in an agarose gel. Finally, the detection and quantification of apoptosis and its differentiation from necrosis was carried out by using Annecxin-V-Fluos Staining. In this study, it is demonstrated that BR inhibited the proliferation of human lung cancer cells and induced apoptosis in them. In addition, the probable relationship between D2-dopamine receptor genes expression and the development of apoptosis was found. In conclusion, BR is responsible for induction of apoptosis in human lung cancer cells and can be used in treatment of these tumoric cells. In addition, normal expression of D2 dopamine receptors was associated with apoptotic effect of BR on these cells.

Katoh M
Functional proteomics, human genetics and cancer biology of GIPC family members.
Exp Mol Med. 2013; 45:e26 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
GIPC1, GIPC2 and GIPC3 consist of GIPC homology 1 (GH1) domain, PDZ domain and GH2 domain. The regions around the GH1 and GH2 domains of GIPC1 are involved in dimerization and interaction with myosin VI (MYO6), respectively. The PDZ domain of GIPC1 is involved in interactions with transmembrane proteins [IGF1R, NTRK1, ADRB1, DRD2, TGFβR3 (transforming growth factorβ receptor type III), SDC4, SEMA4C, LRP1, NRP1, GLUT1, integrin α5 and VANGL2], cytosolic signaling regulators (APPL1 and RGS19) and viral proteins (HBc and HPV-18 E6). GIPC1 is an adaptor protein with dimerizing ability that loads PDZ ligands as cargoes for MYO6-dependent endosomal trafficking. GIPC1 is required for cell-surface expression of IGF1R and TGFβR3. GIPC1 is also required for integrin recycling during cell migration, angiogenesis and cytokinesis. On early endosomes, GIPC1 assembles receptor tyrosine kinases (RTKs) and APPL1 for activation of PI3K-AKT signaling, and G protein-coupled receptors (GPCRs) and RGS19 for attenuation of inhibitory Gα signaling. GIPC1 upregulation in breast, ovarian and pancreatic cancers promotes tumor proliferation and invasion, whereas GIPC1 downregulation in cervical cancer with human papillomavirus type 18 infection leads to resistance to cytostatic transforming growth factorβ signaling. GIPC2 is downregulated in acute lymphocytic leukemia owing to epigenetic silencing, while Gipc2 is upregulated in estrogen-induced mammary tumors. Somatic mutations of GIPC2 occur in malignant melanoma, and colorectal and ovarian cancers. Germ-line mutations of the GIPC3 or MYO6 gene cause nonsyndromic hearing loss. As GIPC proteins are involved in trafficking, signaling and recycling of RTKs, GPCRs, integrins and other transmembrane proteins, dysregulation of GIPCs results in human pathologies, such as cancer and hereditary deafness.

Athanasoulia AP, Sievers C, Uhr M, et al.
The effect of the ANKK1/DRD2 Taq1A polymorphism on weight changes of dopaminergic treatment in prolactinomas.
Pituitary. 2014; 17(3):240-5 [PubMed] Related Publications
Treatment with dopamine agonists in patients with prolactinomas has been associated with weight loss in short term studies. However, long-term studies on weight changes are lacking. Taq1A is a restriction fragment length polymorphism considered as a gene marker for the DRD2 gene. The presence of at least one A1 allele is linked to reduced brain dopaminergic activity due to reduced receptor binding and lower density of the dopamine 2 receptor. We aimed at testing the hypothesis that the dopaminergic treatment in prolactinoma patients leads to sustained weight loss and that the presence of diminished weight loss response under dopamine agonists is associated with the minor A1 allele of Taq1A.We included n = 44 patients (17 male and 27 female, 26 macroadenomas and 18 microadenomas) with prolactinomas treated with dopamine agonists. Outcome measures were weight and body mass index (BMI) change under dopaminergic treatment after 2 years with regard to Taq1A status and sex. We observed that the dopaminergic treatment leads to a significant mean weight loss of 3.1 ± 6.25 kg after 2 years. Regarding Taq1A polymorphisms, 21 patients were carriers of at least one A1 allele and 23 patients had a genotype of A2/A2. However, the presence of the A1 allele was neither associated with the mean BMI at baseline nor with an altered weight loss response under dopamine agonist therapy. Our results implicate that the dopaminergic treatment leads to a sustained weight loss in patients with prolactinomas after 2 years. However, there was no association to the A1 allele of Taq1A, observation that needs to be analysed in larger cohorts.

Yacqub-Usman K, Duong CV, Clayton RN, Farrell WE
Preincubation of pituitary tumor cells with the epidrugs zebularine and trichostatin A are permissive for retinoic acid-augmented expression of the BMP-4 and D2R genes.
Endocrinology. 2013; 154(5):1711-21 [PubMed] Related Publications
Retinoic acid (RA)-induced expression of bone morphogenetic protein-4 (BMP-4) inhibits in vitro and in vivo cell proliferation and ACTH synthesis in corticotroph-derived tumor cells. Reduced expression of BMP-4 in this adenoma subtype is associated with epigenomic silencing, and similar silencing mechanisms are also associated with the RA-responsive dopamine D2 receptor (D2R) in somatolactotroph cells. We now show that preincubation with the epidrugs zebularine and trichostatin A is obligate and permissive for RA-induced expression of the BMP-4 and the D2R genes in pituitary tumor cells. Combined epidrug challenges are associated with marginal reduction in CpG island methylation. However, significant change to histone tail modifications toward those associated with expression-competent genes is apparent, whereas RA challenge alone or in combined incubations does not have an impact on these modifications. Epidrug-mediated and RA-augmented expression of endogenous BMP-4 increased or decreased cell proliferation and colony-forming efficiency in GH3 and AtT-20 pituitary tumor cells, respectively, recapitulating recent reports of challenges of these cells with exogenous ligand. The specificity of the BMP-4-mediated effects was further supported by knock-down experiments of the BMP-4 antagonist noggin (small interfering RNA [siRNA]). Knock-down of noggin, in the absence and the presence of epidrugs, induced and augmented BMP-4 expression, respectively. In cell proliferation assays, challenge with either epidrugs or siRNA led to significant increase in cell numbers at the 72-hour time point; however, in siRNA-treated cells coincubated with epidrugs, a significant increase was apparent at the 48-hour time point. These studies show the potential of combined drug challenges as a treatment option, where epidrug renders silenced genes responsive to conventional therapeutic options.

Gordiev M, Engstrom PF, Khasanov R, et al.
Genetic analysis of polymorphisms in dopamine receptor and transporter genes for association with smoking among cancer patients.
Eur Addict Res. 2013; 19(2):105-11 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Smoking among Russian cancer patients may be related to variations in the DRD2/ANKK1 (Taq1), DRD4 (exon III VNTR), and SLC6A3 genes.
METHODS: Seven hundred fifty patients provided smoking history and DNA.
RESULTS: Current smokers were more likely to be DRD2 A2 allele carriers versus nonsmokers (former/never smokers; 69 vs. 56%; OR = 1.69; 95% CI 1.13-2.53, p = 0.01) and former smokers (69 vs. 59%; OR = 1.54; 95% CI 0.97-2.46, p = 0.07). Ever smokers (current/former smokers) were more likely to be DRD2 A2 allele carriers versus never smokers (65 vs. 55%; OR = 1.50; 95% CI 1.00-2.27, p = 0.05). The risk of current smoking among DRD2 A2 allele carriers was present if the DRD4 short allele was also present (OR = 1.76; 95% CI 1.12-2.78, p = 0.02), and the risk of ever smoking among DRD2 A2 allele carriers was present if the DRD4 short allele was also present (OR = 1.62; 95% CI 1.02-2.55, p = 0.04). DRD2 A2 allele carriers had a shorter period of previous abstinence versus DRD2 A1 carriers (p = 0.02). Effects were not statistically significant when controlling for multiple comparisons.
CONCLUSIONS: The DRD2 A2 allele may increase the risk of smoking among cancer patients, convergent with studies using non-Western samples. However, additional replication is needed.

Cuny T, Mohamed A, Graillon T, et al.
Somatostatin receptor sst2 gene transfer in human prolactinomas in vitro: impact on sensitivity to dopamine, somatostatin and dopastatin, in the control of prolactin secretion.
Mol Cell Endocrinol. 2012; 355(1):106-13 [PubMed] Related Publications
OBJECTIVE: As prolactinomas fail to respond to dopamine agonist (DA) in 10-20% of cases, we hypothesized that somatostatin subtype 2 receptor (sst2) overexpression in DA-resistant prolactinomas may enhance suppression of prolactine (PRL) using chimeric agonist (dopastatin) that simultaneously binds sst2 and the dopamine subtype 2 receptor (D2DR).
DESIGN AND METHODS: PRL suppression by octreotide, sst5 agonist, sst2-D2DR agonist (BIM-23A760 dopastatin) and cabergoline was assessed in primary cultures of seven DA-resistant prolactinomas overexpressing sst2.
RESULTS: sst2 was effectively overexpressed via adenoviral expression in prolactinomas (38.1±7.4 vs. 0.1±0.1 copy/copy β-Gus) and induced octreotide sst2-mediated PRL suppression that remained lower than that induced by DA. BIM-23A760 inhibited PRL similarly to cabergoline both in the control and sst2-expressing cells. Antagonist experiments confirmed predominant dopaminergic effect in dopastatin activity.
CONCLUSION: sst2 was successfully overexpressed in prolactinomas. However BIM-23A760 was unable to enhance PRL suppression underlining a predominant dopaminergic contribution in its action.

Kato M, Inoshita N, Sugiyama T, et al.
Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas.
Endocr J. 2012; 59(3):221-8 [PubMed] Related Publications
There are two main subtypes of GH-producing pituitary adenoma: densely granulated (DG-type) and sparsely granulated (SG-type). Despite the difference in drug responsiveness between the two subtypes, their molecular mechanisms remain unknown. The aim of this study is to evaluate the differential expression of genes related to drug responsiveness between the two subtypes of somatotroph adenoma, and their relationship to the clinical characteristics. Eighty-two acromegaly patients (44 DG-type, 38 SG-type) were studied retrospectively. Clinical characteristics were compared between the two subtypes. Among them, 36 tumor tissue specimens (19 DG-type, 17 SG-type) were available for investigation of the expression of SSTR2, SSTR5 and D2R that are reported to be involved in drug responsiveness by realtime RT-PCR. Protein level was evaluated by immunohistochemical study. Patients with SG-type adenomas were younger in age and showed greater GH suppression by octreotide, but not by bromocriptin, and bigger in size and more invasiveness than DG-type adenomas. The mRNA expression of SSTR2 in DG-type adenomas were greater than those in SG-type adenomas and showed significantly positive correlation with GH suppression by octreotide. There was positive correlation between mRNA and protein levels of SSTR2. These data suggested that the differences of responsiveness to octreotide between DG- and SG-type adenomas are based on the expression levels of SSTR2.

Shimazu S, Shimatsu A, Yamada S, et al.
Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels.
Eur J Endocrinol. 2012; 166(3):383-90 [PubMed] Related Publications
OBJECTIVE: Dopamine agonists normalize prolactin (PRL) levels and reduce tumour size in responsive prolactinoma. However, several cases have shown resistance to dopamine agonists upon initial treatment. Infrequently, prolactinoma initially responds, but then becomes refractory to prolonged treatment (secondary resistance). We investigated the possible mechanisms of resistance to dopamine agonists.
SUBJECTS AND METHODS: Twelve cases of prolactinoma were surgically resected and classified according to the responsiveness of PRL levels and tumour size to dopamine agonists: good responders (n = 5), poor responders (n = 5), or secondary resistance (n = 2). We examined the expression of dopamine D(2) receptor (D(2)R) isoform (short: D(2)S and long: D(2)L) mRNA and protein. We investigated DNA methylation patterns in the promoter region of the DRD2 gene.
RESULTS: The predominant D(2)R isoform expressed in prolactinoma was D(2)L. Levels of D(2)L mRNA were significantly lower in secondary resistance and poor responders than in good responders. Expression of D(2)R protein was variable among cases. Almost no CpG sites of the DRD2 gene promoter region were methylated.
CONCLUSION: Resistance of prolactinoma to dopamine agonists is correlated with a reduction in D(2)L isoform mRNA levels. Silencing of the DRD2 gene by methylation in the promoter region is unlikely to play a role in dopamine agonist resistance in prolactinoma.

Su Z, Wang C, Wu J, et al.
Expression of dopamine 2 receptor subtype mRNA in clinically nonfunctioning pituitary adenomas.
Neurol Sci. 2012; 33(2):275-9 [PubMed] Related Publications
Dopamine receptor agonists (DAs) can reduce hormone release and tumor mass in the majority of prolactinomas, whereas such effects are controversial in clinically nonfunctioning pituitary adenomas (NFPAs). Whether expression of dopamine 2 receptor (D2R) is different in subgroups of NFPAs has not been fully elucidated. We assessed and compared D2R subtype (long: D2L and short: D2S) mRNA levels in subgroups of NFPAs by real-time reverse transcriptase polymerase chain reaction (RT-PCR). For both D2L and D2S mRNA, there were no significant differences among them. Only 21.6% of NFPAs showed relatively high D2R mRNA levels; furthermore, histopathological subtypes of those cases with relatively high D2R expression were gonadotropinomas and null-cell adenomas. These data suggest that DAs are effective only for a small proportion of NFPAs, and relatively high D2R expression may more possibly happen to a subset of gonadotropinomas and null-cell adenomas.

Gabalec F, Beranek M, Netuka D, et al.
Dopamine 2 receptor expression in various pathological types of clinically non-functioning pituitary adenomas.
Pituitary. 2012; 15(2):222-6 [PubMed] Related Publications
Clinically non-functioning pituitary adenomas account for about one-third of pituitary tumors. The majority of them are pathologically classified as gonadotropinomas or null-cell adenomas without hormonal expression. The rest represent silent corticotroph adenomas and plurihormonal tumors. Conservative therapy with dopamine agonists is effective in some cases only depending on the expression of dopamine 2 receptors (D2R). The aim of this study was to quantitatively estimate D2R expression in clinically non-functioning pituitary adenomas and correlate the results with adenoma type according to pathological classification. Out of the 87 adenomas investigated, 63 expressed gonadotropins, 7 were silent corticotroph adenomas, 7 were plurihormonal tumors, and only 6 did not express any pituitary hormone on immunohistochemical investigation. With the use of the reverse transcriptase PCR technique, D2R mRNA was expressed in all adenomas with very heterogeneous quantity. The expression was very low in corticotroph adenomas (relative median quantity after normalization to housekeeping gene 0.01) and lower in plurihormonal tumors (median 0.4) than in gonadotroph (median 1.3) and null-cell adenomas (median 1.9). The difference between corticotroph adenomas and plurihormonal tumors in comparison with other pathological types was statistically significant. The expression of D2R did not depend on the presence or absence of gonadotropins. We conclude that D2R expression is very low in corticotroph adenomas and significantly lower in plurihormonal tumors. The positivity of gonadotropins does not predict the D2R quantity.

Laugsand EA, Fladvad T, Skorpen F, et al.
Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids.
Eur J Cancer. 2011; 47(11):1682-91 [PubMed] Related Publications
BACKGROUND: This study investigates whether demographical, disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain.
METHODS: Cancer patients receiving opioids were included from 17 centres in 11 European countries. Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales. In stratified regression models including demographical and disease-related factors as covariates, 96 single nucleotide polymorphisms (SNPs) in 16 candidate genes related to opioid- or nausea/vomiting signalling pathways (ABCB1, OPRM1, OPRK1, ARRB2, STAT6, COMT, CHRM3, CHRM5, HRH1, DRD2, DRD3, TACR1, HTR3A, HTR3B, HTR3C, CNR1) were analysed for association with nausea and vomiting.
FINDINGS: Age, body mass index, Karnofsky Performance Status, gender, use of antiemetics, type of opioid, type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids (p<0.01). The SNPs were rs1176744, rs3782025 and rs1672717 in HTR3B; rs165722, rs4680 and rs4633 in COMT; rs10802789 and rs685550 in CHRM3. Only the SNP rs1672717 in HTR3B passed the Benjamini-Hochberg criterion for a 10% false discovery rate.
INTERPRETATION: Clinical characteristics and SNPs within the HTR3B, COMT and CHRM3 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids. This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain.

Klepstad P, Fladvad T, Skorpen F, et al.
Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients.
Pain. 2011; 152(5):1139-45 [PubMed] Related Publications
Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed.

Tani Y, Sugiyama T, Izumiyama H, et al.
Differential gene expression profiles of POMC-related enzymes, transcription factors and receptors between non-pituitary and pituitary ACTH-secreting tumors.
Endocr J. 2011; 58(4):297-303 [PubMed] Related Publications
The differential gene expression of proopiomelanocortin (POMC)-related processing enzymes, transcription factors, and receptors responsible for ACTH secretion between non-pituitary and pituitary ACTH-secreting tumors remains obscure. This study was attempted to determine the gene expression profiles of transcription factors (Tpit, NeuroD1 and IKZF1), proprotein convertase (PC) 1/3 and PC2, and several key receptors linked to ACTH secretion, including corticotrophin releasing hormone receptor (CRHR1), vasopressin receptor 1b (V1bR), somatostatin receptor (SSTR) subtype-2, -5 and dopamine receptor type 2 (D2R) in non-pituitary and pituitary ACTH-secreting tumors. Surgical tissue specimens from carcinoid tumors causing ectopic ACTH syndrome (EAS: n=4) and pituitary tumors causing Cushing's disease (CD: n=13), were subjected to real-time RT-PCR for measurements of each mRNA levels. POMC and CRHR1 mRNA levels in CD were far greater than those in EAS, whereas IKZF1, PC2, SSTR-2 and -5 mRNA levels in EAS were significantly greater than those in CD. NeuroD1, Tpit, PC1/3, V1bR and D2R mRNA levels were comparable between EAS and CD. In conclusion, differential gene expression profiles revealed more abundant mRNA expression in EAS than in CD of 1) IKZF1 with its potential implication of cell differentiation and hormone secretion, 2) PC2 with its possible enhanced processing activity of mature ACTH, and 3) SSTR-2 and -5 with their potential therapeutic application of more selective agonists in EAS patients.

Gatto F, Barbieri F, Castelletti L, et al.
In vivo and in vitro response to octreotide LAR in a TSH-secreting adenoma: characterization of somatostatin receptor expression and role of subtype 5.
Pituitary. 2011; 14(2):141-7 [PubMed] Related Publications
Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of pituitary adenomas. Medical therapy with somatostatin analogues (SSAs) effectively reduces TSH secretion in approximately 80% of patients and induces shrinkage in about 45% of tumors. According with previous data, resistance to SSA treatment might be due to heterogeneity in somatostatin receptors (SSTRs) expression. We report the case of TSHoma in a 41-year-old man treated with octreotide LAR that caused a dramatic decrease of TSH and thyroid hormones and tumor shrinkage already after 3 months of pre-surgical therapy. In search of potential molecular determinants of octreotide effectiveness, we measured, in primary cultures from this tumor, SSTR and dopamine D2 receptor (D2R) expression, and octreotide and/or cabergoline effects on TSH secretion and cell proliferation. SSTR5 and D2R expression was higher than SSTR2. Octreotide significantly inhibited TSH secretion more effectively than cabergoline (P<0.001), whereas the combined treatment was comparable with cabergoline alone. Similarly, octreotide resulted more effective than cabergoline on cell proliferation, while the combination did not show any additive or synergistic effects. In conclusion, the significant antisecretive and antiproliferative effect of octreotide in this patient might be related to the high expression of SSTR5, in the presence of SSTR2. After reviewing the literature, indeed, in line with previous observations, we hypothesize that SSTR5/SSTR2 ratio in TSHomas may represent a useful marker in predicting the outcome of therapy with SSAs. The role of D2R should be further explored considering that the presence of D2R can influence SSTRs functionality.

Nishioka H, Tamura K, Iida H, et al.
Co-expression of somatostatin receptor subtypes and estrogen receptor-α mRNAs by non-functioning pituitary adenomas in young patients.
Mol Cell Endocrinol. 2011; 331(1):73-8 [PubMed] Related Publications
The expression by non-functioning adenomas (NFoma) of somatostatin receptor (SSTR) subtypes and estrogen receptor (ERα) is poorly understood. Consequently, the mRNAs of SSTR subtypes (SSTR) 1, 2, 3, and 5, dopamine receptor (D2R), and ERα were measured by real-time quantitative RT-PCR in 59 NFomas and 50 functioning adenomas; the latter included 30 GH-secreting adenomas (GHomas) and 20 prolactinomas (PRLomas). NFomas expressed higher levels of SSTR3 than functioning adenomas but had lower levels of SSTR2, SSTR5 and D2R mRNAs than GHomas. Their ERα levels were higher than those of GHomas. The SSTR subtype mRNA levels in NFomas correlated significantly with each other; there was also a good correlation between the SSTR subtypes and ERα in NFomas. These correlations were largely only observed in younger patients (<50 years). The present study describes the differential expression of SSTR subtypes in the largest number of NFoma patients studied thus far, and further proposes possible involvements of SSTR3 and estrogen in the pathophysiology of NFomas.

Takeshita H, Ichikawa D, Komatsu S, et al.
Prediction of CCND1 amplification using plasma DNA as a prognostic marker in oesophageal squamous cell carcinoma.
Br J Cancer. 2010; 102(9):1378-83 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: We aimed to develop a new biomarker to predict cyclin D1 (CCND1) status using plasma DNA in oesophageal squamous cell carcinoma (ESCC) patients.
METHODS: We evaluated the ratio of the CCND1 (11q13) dosage to the dopamine receptor D2 (DRD2; 11q22-23) dosage (C/D ratio) as CCND1 copy number. This study was divided into three steps: (1) Determination of a cutoff value for the C/D ratio in test scale; (2) Comparison of the C/D ratio in between plasma samples and cancer tissues in ESCC patients showing high plasma C/D ratio; (3) Validation study of the clinical application of the plasma C/D ratio as a diagnostic and prognostic marker, by comparing with clinicopathologic factors in 96 ESCC patients.
RESULTS: The plasma C/D ratio was significantly higher in the ESCC group than the controls (P=0.0134). A high plasma C/D ratio reflected the tumour C/D ratio, and significantly correlated with a poorer prognosis (P=0.0186). Moreover, the high C/D ratio was found to be an independent prognostic factor on multivariate analysis (P=0.0266; hazard ratio 5.988).
CONCLUSION: Prediction of CCND1 amplification using plasma DNA is thought to be a promising prognostic biomarker in ESCC patients.

Sangrajrang S, Sato Y, Sakamoto H, et al.
Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case-control study in Thai women.
Breast Cancer Res Treat. 2010; 123(3):885-93 [PubMed] Related Publications
Dietary folate as well as polymorphic variants in one-carbon metabolism genes may modulate risk of breast cancer through aberrant DNA methylation and altered nucleotide synthesis and repair. Alcohol is well recognized as a risk factor for breast cancer, and interactions with one-carbon metabolism has also been suggested. The purpose of this study is to test the hypothesis that genetic polymorphisms in the folate and alcohol metabolic pathway are associated with breast cancer risk. Twenty-seven single nucleotide polymorphisms (SNPs) in the MTR, MTRR, MTHFR, TYMS, ADH1C, ALDH2, GSTP1, NAT1, NAT2, CYP2E1 DRD2, DRD3, and SLC6A4 were genotyped. Five hundred and seventy patients with histopathogically confirmed breast cancer and 497 controls were included in the present study. Association of genotypes with breast cancer risk was evaluated using multivariate logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (95% CI). Increased risk was observed for homozygotes at the MTR SNPs (rs1770449 and rs1050993) with the OR = 2.21 (95% CI 1.18-4.16) and OR = 2.24 (95% CI 1.19-4.22), respectively. A stratified analysis by menopausal status indicated the association between the NAT2 SNP (rs1799930) and breast cancer was mainly evident in premenopausal women (OR 2.70, 95% CI 1.20-6.07), while the MTRR SNP (rs162049) was significant in postmenopausal women (OR 1.61, 95% CI 1.07-2.44). Furthermore, SNPs of the genes that contribute to alcohol behavior, DRD3 (rs167770), DRD2 (rs10891556), and SLC6A4 (rs140701), were also associated with an increased risk of breast cancer. No gene-gene or gene-environment interactions were observed in this study. Our results suggest that genetic polymorphisms in folate and alcohol metabolic pathway influence the risk of breast cancer in Thai population.

Filopanti M, Lania AG, Spada A
Pharmacogenetics of D2 dopamine receptor gene in prolactin-secreting pituitary adenomas.
Expert Opin Drug Metab Toxicol. 2010; 6(1):43-53 [PubMed] Related Publications
IMPORTANCE OF THE FIELD: Dopamine-agonists are the treatment of choice of prolactin-secreting pituitary adenomas (PRL-omas). Their actions on D2 dopamine receptor (DRD2) and the clinical outcome may be affected by polymorphisms.
AREAS COVERED IN THIS REVIEW: PRL-omas are well-differentiated endocrine tumors expressing DRD2. The dopamine-agonist cabergoline (CB), normalizes prolactin and reduces tumor size in about 80 - 90% of patients. DRD2 polymorphisms correlate with neuropsychiatric disorders, in particular alcoholism and schizophrenia. This review describes the DRD2 polymorphisms, their functional effects, and their impact on susceptibility and response to dopamine-agonists treatment. Searching PubMed database for pertinent articles we found that some DRD2 polymorphisms, particularly TaqIA, TaqIB and NcoI, are associated with different receptor binding in brain areas. One study carried out in patients with PRL-omas found a correlation between NcoI and TaqIA and resistance to CB. In particular, resistant patients had higher prevalence of NcoI-T allele than the responsive patients, while the commonest haplotype (having TaqIA2 allele) was associated with better response.
WHAT THE READER WILL GAIN: This review deals with the connection between DRD2 polymorphisms and PRL-oma treatment and suggests hypotheses for further studies.
TAKE HOME MESSAGE: Only one study was carried out to analyze the role of DRD2 polymorphisms in PRLomas response to CB. Further studies, including pituitary and hypothalamus in vivo determination of DRD2 binding according to DRD2 genotypes, investigation of possible post-receptorial mechanisms involved, as well as population studies in collaboration with psychiatrists and neurologists, are needed.

Hoenicka J, Quiñones-Lombraña A, España-Serrano L, et al.
The ANKK1 gene associated with addictions is expressed in astroglial cells and upregulated by apomorphine.
Biol Psychiatry. 2010; 67(1):3-11 [PubMed] Related Publications
BACKGROUND: TaqIA, the most widely analyzed genetic polymorphism in addictions, has traditionally been considered a gene marker for association with D2 dopamine receptor gene (DRD2). TaqIA is located in the coding region of the ANKK1 gene that overlaps DRD2 and encodes a predicted kinase ANKK1. The ANKK1 protein nonetheless had yet to be identified. This study examined the ANKK1 expression pattern as a first step to uncover the biological bases of TaqIA-associated phenotypes.
METHODS: Northern blot and quantitative reverse-transcriptase polymerase chain reaction analyses were performed to analyze the ANKK1 mRNA. To study ANKK1 protein expression, we developed two polyclonal antibodies to a synthetic peptides contained in the putative Ser/Thr kinase domain.
RESULTS: We demonstrate that ANKK1 mRNA and protein were expressed in the adult central nervous system (CNS) in human and rodents, exclusively in astrocytes. Ankk1 mRNA level in mouse astrocyte cultures was upregulated by apomorphine, suggesting a potential relationship with the dopaminergic system. Developmental studies in mice showed that ANKK1 protein was ubiquitously located in radial glia in the CNS, with an mRNA expression pick around embryonic Day 15. This time expression pattern coincided with that of the Drd2 mRNA. On induction of differentiation by retinoic acid, a sequential expression was found in human neuroblastoma, where ANKK1 was expressed first, followed by that of DRD2. An opposite time expression pattern was found in rat glioma.
CONCLUSIONS: Spatial and temporal regulation of the expression of ANKK1 suggest an involvement of astroglial cells in TaqIA-related neuropsychiatric phenotypes both during development and adult life.

Clague J, Cinciripini P, Blalock J, et al.
The D2 dopamine receptor gene and nicotine dependence among bladder cancer patients and controls.
Behav Genet. 2010; 40(1):49-58 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Multiple twin, family, and genetic studies have rendered substantial evidence supporting an association between hereditary factors and smoking initiation and maintenance. To investigate further the relationships between the DRD2 genotypes, cigarette use and nicotine dependence, we examined the prevalence of polymorphisms in the TaqIA (A1 and A2) and the TaqIB (B1 and B2) alleles among a series of 608 non-Hispanic White bladder cancer patients and 608 matched controls. Among ever-smoking controls, A1 and B1 genotypes exhibited a greater smoking intensity and were significantly younger at the age of initiation than A2A2 or B2B2 genotypes (two-sided P < 0.05). Among former smoking cases, persons with the A1 genotypes exhibited significantly higher mean pack-years and years of smoking, and were younger at the age of initiation than were persons with the A2A2 genotype (two-sided P < 0.05). Additionally, current smokers with the A1 genotypes reported fewer quit attempts than those with the A2A2 genotype (two-sided P < 0.01). The present study suggests that the DRD2 alleles A1 and B1 confer greater vulnerability to tobacco use.

Bhattacharya N, Roy A, Roy B, et al.
MYC gene amplification reveals clinical association with head and neck squamous cell carcinoma in Indian patients.
J Oral Pathol Med. 2009; 38(10):759-63 [PubMed] Related Publications
BACKGROUND: Amplification of the MYC gene is reported to be associated with the development of head and neck squamous cell carcinoma (HNSCC). This study is focused to analyze the correlation between MYC gene amplification and various clinicopathological features and outcome in a cohort of 49 dysplastic and 187 primary head and neck lesions.
METHODS: MYC gene amplification was assessed by differential polymerase chain reaction using primer sets from the MYC gene as target locus and DRD2 gene as the control locus.
RESULT: The MYC gene amplification was detected in a total of 23.7% (56/236) head and neck lesions comprising 14.2% (7/49) dysplastic lesions and 26% (49/187) HNSCC samples. The clinicopathological association study between MYC gene amplification with the different clinical parameters like sex, tumor stage, tumor differentiation, lymph node status, tobacco habit and HPV 16/18 status determined significant association of MYC amplification with tumor progression (P = 0.009). Kaplan Meier analysis revealed MYC gene has no prognostic significance on survival in HNSCC.
CONCLUSION: In conclusion, our results suggest that MYC gene amplification is associated with tumor progression in HNSCC.

Tateno T, Kato M, Tani Y, et al.
Differential expression of somatostatin and dopamine receptor subtype genes in adrenocorticotropin (ACTH)-secreting pituitary tumors and silent corticotroph adenomas.
Endocr J. 2009; 56(4):579-84 [PubMed] Related Publications
Somatostatin analogs and dopamine agonists are clinically used for medical therapy of functioning pituitary tumors, such as growth hormone- and prolactin-secreting tumors, however, their effects on ACTH-secreting tumors are controversial. This study was aimed to determine whether somatostatin receptor (SSTR) subtype (1-5) and dopamine receptor type 2 (D2R) are differentially expressed in pituitary tumors causing Cushing's disease (CD), silent corticotroph adenoma (SCA), and non-functioning pituitary tumor (NFT). Tissue specimens were obtained from 35 pituitary tumors during transsphenoidal surgery. The steady-state mRNA levels of SSTR1-5 and D2R genes were determined by real-time reverse-transcription polymerase chain reaction. Both SSTR1 and 2 mRNA levels in SCA were greater than CD, while SSTR1 mRNA levels, but not SSTR2, in SCA were also greater than NFT. SSTR5 mRNA levels in CD were greater than SCA, but did not differ between NFT and SCA. SSTR4 mRNA expression was undetectable. D2R mRNA levels were markedly lower in CD and SCA than in NFT. The present study suggests that somatostatin analogs more selective for SSTR5 and for SSTR1 and/or 2may have the therapeutic potential for medical treatment of CD and SCA, respectively, whereas clinical application of dopamine agonists selective for D2R is very limited in either CD or SCA.

Hsieh YY, Chang CC, Bau DT, et al.
The p21 codon 31*C- and DRD2 codon 313*T-related genotypes/alleles, but not XRCC1 codon 399, hOGG1 codon 326, and DRD1-48 polymorphisms, are correlated with the presence of leiomyoma.
Fertil Steril. 2009; 91(3):869-77 [PubMed] Related Publications
OBJECTIVE: To investigate whether the gene polymorphisms for p21, X-ray repair cross-complementing group 1 (XRCC1), human 8-oxoguanine glycosylase 1 (hOGG1), and dopamine D1 and D2 receptors (DRD1, -2) are associated with leiomyoma susceptibility.
DESIGN: Prospective study.
SETTING: Departments of gynecology and genetics in a medical center.
PATIENT(S): Women were divided into two groups: leiomyoma (n = 120) and nonleiomyoma (n = 112).
INTERVENTION(S): The p21 codon 31, XRCC1 codon 399, hOGG1 codon 326, DRD1-48, and DRD2 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions (Blp I, MspI, Fnu4HI, Dde I, and NcoI, respectively).
MAIN OUTCOME MEASURE(S): Genotypes and allelic frequencies.
RESULT(S): The p21 codon 31(*)C- and DRD2 codon 313(*)T-related genotypes/alleles were associated with the presence of leiomyomas. The proportions of p21(*)CC/CA/AA and DRD2(*)CC/CT/TT in both groups were 27.5/68.3/4.2% and 12.5/51.7/35.8% (leiomyoma); and 14.3/51.8/33.9% and 33.9/40.2/25.9% (nonleiomyoma). XRCC1, hOGG1, and DRD1 were not correlated with the presence of leiomyomas. XRCC1(*)GG/GA/AA, hOGG1(*)TT/TA/AA, and DRD1(*)GG/GA/AA were 54.2/37.5/8.3%, 36.7/44.2/19.1%, and 3.3/25.8/70.8% (leiomyoma); and 48.2/47.3/4.5%, 43.6/41/15.4%, and 3.6/25/71.4% (nonleiomyoma).
CONCLUSION(S): The p21 codon 31(*)C- and DRD2 codon 313(*)T-related genotypes/alleles were associated with the presence of leiomyoma. XRCC1, hOGG1, and DRD1 were not correlated with leiomyoma development.

Murphy G, Cross AJ, Sansbury LS, et al.
Dopamine D2 receptor polymorphisms and adenoma recurrence in the Polyp Prevention Trial.
Int J Cancer. 2009; 124(9):2148-51 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Epidemiological evidence suggests that obesity may be causally associated with colorectal cancer. Dopamine and the dopaminergic reward pathway have been implicated in drug and alcohol addiction as well as obesity. Polymorphisms within the D2 dopamine receptor gene (DRD2) have been shown to be associated with colorectal cancer risk. We investigated the association between DRD2 genotype at these loci and the risk of colorectal adenoma recurrence in the Polyp Prevention Trial. Odds ratios (OR) and 95% confidence intervals (CI) for risk of adenoma recurrence were calculated using unconditional logistic regression. Individuals with any, multiple (>or=2) or advanced adenoma recurrence after 4 years were compared to those without adenoma recurrence. Variation in intake of certain dietary components according to DRD2 genotype at 3 loci (rs1799732; rs6277; rs1800497) was also investigated. The DRD2 rs1799732 CT genotype was significantly associated with all adenoma recurrence (OR: 1.30; 95% CI: 1.01, 1.69). The rs1800497 TT genotype was also associated with a significantly increased risk of advanced adenoma recurrence (OR: 2.40; 95% CI: 1.11, 5.20). The rs1799732 CT and rs1800497 TT genotypes were significantly associated with adenoma recurrence in the Polyp Prevention Trial. Increased risk of adenoma recurrence as conferred by DRD2 genotypes may be related to difference in alcohol and fat intake across genotypes.

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