Cumulative Association of Five Genetic Variants with Prostate Cancer

Zheng, S. Lilly; Sun, Jielin; Wiklund, Fredrik; Smith, Shelly G.; Stattin, Pär; Li, Ge; Adami, Hans Olov; Hsu, Fang Chi; Zhu, Yi; Bälter, Katarina; Kader, A. Karim; Turner, Aubrey R.; Liu, Wennuan; Bleecker, Eugene R.; Meyers, Deborah A.; Duggan, David; Carpten, John D.; Chang, Bao Li; Isaacs, William B.; Xu, Jianfeng; Grönberg, Henrik

doi:10.1056/nejmoa075819

Cited by 571 publications

(564 citation statements)

References 15 publications

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“…The other three populations were from our collaborative research group, including a hospital-based case series from the JHH, and two populationbased studies based on the National Prostate Cancer Register of Sweden; a case-control study; CAncer Prostate in Sweden (CAPS) (41,26), and a case series of PCa patients treated for localized PCa (PROCAP) (42,43).…”

Section: Methodsmentioning

confidence: 99%

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

Zheng

Isaacs

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 × 10−8 under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non–organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.

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Section: Methodsmentioning

confidence: 99%

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

Zheng

Isaacs

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…[6][7][8][9][10][11][12][13] In this study, by combining the number of risk alleles at eight susceptibility loci, each having rather small allelic OR, it became possible to distinguish high and low risk groups with up to 60-fold difference in the genetic predisposition to SLE. However, it should be noted that the model proposed in this study is, at this point, not sufficient for the purpose of predicting disease onset or identifying a high-risk group that requires preventive intervention.…”

Section: Association Between Cumulative Risk Allele Number and Clinicmentioning

confidence: 99%

“…Such an approach has been employed in type 2 diabetes, 6,7 cholesterol levels and cardiovascular diseases, 8,9 prostate cancer 10 and rheumatic diseases such as gout, 11 rheumatoid arthritis 12 and systemic sclerosis. 13 Our group has been intensively working on the susceptibility genes to SLE in a Japanese population.…”

Section: Introductionmentioning

confidence: 99%

Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

et al. 2011

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Although large-scale studies established many susceptibility genes to systemic lupus erythematosus (SLE), effect of each gene is not sufficiently large to be used alone to identify individuals with strong genetic predisposition. In this study, we analyzed the cumulative number of risk alleles at eight established susceptibility loci, HLA-DRB1, IRF5, STAT4, BLK, TNFAIP3, TNIP1, FCGR2B and TNFSF13, in 282 Japanese female SLE and 222 healthy female controls. The average number of risk alleles was significantly increased in SLE (8.07 ± 1.60) than healthy controls (7.02 ± 1.64) (P¼1.63Â10 À12 ). Significant gene-gene interaction was not detected. When the subjects carrying seven risk alleles were used as a reference, the odds ratio (OR) for individuals carrying 10 and 11-13 risk alleles were 4.17 (95% confidence interval (CI) 1.89-9.19, P¼0.0002) and 8.77 (95% CI 1.92-40.0, P¼0.0016), respectively. In contrast, subjects with p4 risk alleles were significantly decreased in SLE (OR 0.15, CI 0.03-0.67, P¼0.007). The proportion of the patients with neurologic disorder was significantly increased in those carrying X10 risk alleles than those with o10 (OR 2.30, CI 1.09-4.83, P¼0.025). This study suggested that the cumulative number of risk alleles may efficiently distinguish groups with high and low genetic predisposition to SLE and its severe manifestation.

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“…Recent findings indicate that genetic variants may predispose to more aggressive prostate cancer [3][4][5], which is supported by epidemiological studies that propose genetic background influences cancer prognosis [6][7][8]. Recent genome-wide association studies (GWAS) revealed numerous genetic variants associated with prostate cancer risk, although only little discriminatory ability was shown for fatal forms of the disease [9].…”

Section: Introductionmentioning

confidence: 94%

The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration

Fraga

Ribeiro

Príncipe

et al. 2014

European Journal of Cancer

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KEYWORDS Androgen deprivation therapy Hypoxia inducible factor 1 alpha Metastasis Prostate cancer Single nucleotide polymorphismAbstract The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

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Cumulative Association of Five Genetic Variants with Prostate Cancer

Abstract: SNPs in five chromosomal regions plus a family history of prostate cancer have a cumulative and significant association with prostate cancer.

Cited by 571 publications

References 15 publications

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration

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