Genetic Variants in the Vitamin D Receptor Are Associated with Advanced Prostate Cancer at Diagnosis: Findings from the Prostate Testing for Cancer and Treatment Study and a Systematic Review

Chen, Lina; Smith, George Davey; Evans, David M.; Cox, Angela; Lawlor, Debbie A.; Donovan, Jenny; Wei, Yuan; Day, Ian N.M.; Martin, Richard M.; Lane, Athene; Rodriguez, Santiago; Davis, Michael J.; Zuccolo, Luisa; Collin, Simon M.; Hamdy, Freddie C.; Neal, David E.; Lewis, Sarah J.

doi:10.1158/1055-9965.epi-09-0544

Cited by 63 publications

(44 citation statements)

References 44 publications

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“…The actions of 1,25(OH) 2 D are mediated via the vitamin D receptor gene (VDR) [10], which is usually expressed in cells involved in calcium homeostasis, but it is also expressed in other cells, including the prostate [10]. A recent genetic association study and meta-analysis of 13 studies found an association between three VDR polymorphisms (BsmI, ApaI, and TaqI) and prostate cancer grade [48]: ApaI-a and BsmIb increased the risk of a high grade, TaqI-t was protective. These polymorphisms modulate the activity of the VDR and therefore may modulate a protective effect of 1,25(OH) 2 D with aggressive prostate cancers.…”

Section: Discussionmentioning

confidence: 99%

Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose–response meta-analysis

Gilbert

Martin

Beynon

et al. 2011

Cancer Causes Control

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Section: Discussionmentioning

confidence: 99%

Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose–response meta-analysis

Gilbert

Martin

Beynon

et al. 2011

Cancer Causes Control

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138

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“…[42] Furthermore, different kinds of chronic diseases and cancers seem to be associated with variations in the structure or functionality of the vitamin D receptor (VDR). [43][44][45][46] Vitamin D exerts its effects through interaction with its intracellular receptor (VDR), encoded by a gene located on chromosome 12; several singlenucleotide polymorphisms (SNPs) have been identified in the sequence of the gene encoding for VDR. The distribution of SNPs in this gene is different among human populations, and so a specific SNP that is common in one geographical or ethnic group may be less represented in another.…”

Section: Introductionmentioning

confidence: 99%

C-Reactive Protein Levels and Vitamin D Receptor Polymorphisms as Markers in Predicting Cachectic Syndrome in Cancer Patients

et al. 2012

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Background and Objective: In patients with advanced cancer, cachexia correlates with low performance status and poor quality of life. In addition, cachexia may be associated with reduced response to chemoradiotherapy and a poor prognosis in cancer patients. Nearly all forms of cachexia are closely associated with chronic inflammation and elevated levels of inflammatory and pro-inflammatory circulating factors, including C-reactive protein (CRP), which is considered a valid laboratory and clinical marker. Among the different pathways involved in the production of inflammatory cytokines and chemokines, the vitamin Dvitamin D receptor (VDR) axis plays a fundamental role.In this study, we explore the possible association between CRP and key factors pertaining to the vitamin D axis -in particular, VDR gene polymorphisms -in cancer patients with cachexia. Although certain tumor types are more commonly associated with cachexia, even within the same tumor type there are significant differences in the extent and duration of cachexia. Such variations may be due to polymorphisms of the VDR gene that could lead to cachexia-prone genotypes or to cachexia-resistant genotypes. Identification of such genotypes could be very helpful in the management of cancer patients. Methods: Forty-three cancer patients were recruited by the Nutritional Unit of the Prato Hospital. Data on age, gender, type of cancer, stage of cancer, and nutritional assessment, as well as transferrin, ferritin, albumin, and CRP levels, were collected. Genomic DNA was extracted from peripheral blood leukocytes and amplified by polymerase chain reaction. BsmI, ApaI, TaqI, and FokI polymorphisms of the VDR gene were investigated using the respective restriction enzymes. For the different VDR polymorphisms, the absence or presence of the restriction sites were designated with capital or small letters, respectively. For example, for the BsmI polymorphism, the presence of the undigested fragment identified the B allele, whereas the presence of the digested fragment identified the b allele. Results: Cancer patients with cachexia have higher CRP levels compared with non-cachectic cancer patients, independently from the genotype. In cachectic patients, the presence of specific VDR BsmI and TaqI alleles was associated with higher CRP levels. In particular, the VDR b and T alleles were more frequent in cachectic cancer patients with elevated CRP levels than in cachectic patients with normal CRP levels. Conclusion: From these results, we hypothesize that there is an association between BsmI and TaqI VDR gene polymorphisms and the cachectic syndrome. In particular, we propose that in cancer patients, the concomitance of b and T alleles with elevated CRP levels may represent an early clinical predictor for the development of a more aggressive form of cachexia.

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“…These men then underwent testing in PSA-testing clinics. From the results, 2000 PCa cases and 2000 controls were randomly selected to form one of the largest PCa case control studies in the world (15,16 ).…”

Section: Information About the Protect Studymentioning

confidence: 99%

Very Low PSA Concentrations and Deletions of the KLK3 Gene

et al. 2013

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BACKGROUND Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression. METHODS We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing. RESULTS We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations. CONCLUSIONS The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.

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Genetic Variants in the Vitamin D Receptor Are Associated with Advanced Prostate Cancer at Diagnosis: Findings from the Prostate Testing for Cancer and Treatment Study and a Systematic Review

Cited by 63 publications

References 44 publications

Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose–response meta-analysis

Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose–response meta-analysis

C-Reactive Protein Levels and Vitamin D Receptor Polymorphisms as Markers in Predicting Cachectic Syndrome in Cancer Patients

Very Low PSA Concentrations and Deletions of the KLK3 Gene

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