Evidence for two independent prostate cancer risk–associated loci in the HNF1B gene at 17q12

Sun, Jielin; Zheng, S. Lilly; Wiklund, Fredrik; Isaacs, Sarah D.; Purcell, Lina D.; Gao, Zhengrong; Hsu, Fang Chi; Kim, Seong-Tae; Liu, Wennuan; Zhu, Yi; Stattin, Pär; Adami, Hans Olov; Wiley, Kathleen E.; Dimitrov, Latchezar; Sun, Jing; Li, Tao; Turner, Aubrey R.; Adams, Tamara S.; Adolfsson, Jan; Johansson, Jan; Lowey, James; Trock, Bruce J.; Partin, Alan W.; Walsh, Patrick C.; Trent, Jeffrey M.; Duggan, David; Carpten, John D.; Chang, Bao Li; Grönberg, Henrik; Isaacs, William B.; Xu, Jianfeng

doi:10.1038/ng.214

Cited by 150 publications

(137 citation statements)

References 17 publications

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“…Our finding differs from the two dozen PCa risk-associated SNPs discovered to date from GWAS (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although the associations for some SNPs, such as those at 8q24, were stronger among patients with aggressive PCa in some studies when each type of case is compared versus unaffected controls (35,36), these SNPs were not associated with PCa aggressiveness in any of the studies when patients with more or less aggressive PCa were directly compared.…”

Section: Discussioncontrasting

confidence: 54%

“…Recent breakthroughs in genome-wide association studies (GWAS) have led to the discovery of more than two dozen reported SNPs that are associated with PCa risk by comparing men with or without PCa using case-control study designs (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Unfortunately, none of these PCa risk-associated SNPs consistently distinguish risk for more or less aggressive cancer (26)(27)(28), nor are they associated with prostate cancer-specific mortality (29).…”

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confidence: 99%

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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: Discussioncontrasting

confidence: 54%

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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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“…[4][5][6] PCa is one of the common cancers with a large genetic component, as up to 42% of the risk could be explained by inheritance from studies about twins. 7 Genome-wide association studies (GWAs) have identified 46 susceptibility loci associated with PCa [8][9][10][11][12][13][14][15][16][17][18][19][20] that individually contribute to a small increase in PCa risk, but which taken together, could explain more than 25% of the excess of PCa familial risk. 13 Although present in only 1%-2% of sporadic PCa cases [21][22][23] germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of PCa (8.6-fold in men f65 years).…”

Section: Introductionmentioning

confidence: 99%

The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

131

105

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One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men f65 years). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2 gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.

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“…Several studies have also identified numerous SNPs in the HNF1B gene as being associated with the risk of cancers of the ovary and prostate glands (Kao et al, 2012;Chornokur et al, 2013), indicating that genetic variation in HNF1B might play an important role in the etiology of numerous cancers. Genomewide association studies have reported the HNF1B rs4430796 (A>G) polymorphism to be associated with a risk of prostate cancer (Gudmundsson et al, 2007;Sun et al, 2008;Liu et al, 2011;Zhou et al, 2011;Zhang et al, 2012;Chan et al, 2013;Rojas et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of the association between the HNF1B rs4430796 (A>G) polymorphism and risk of prostate cancer based on case-control studies

Zhao¹,

Liang²,

Jiang³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Genome-wide studies have reported an association between the HNF1B rs4430796 (A>G) polymorphism and prostate cancer risk, but results have been inconsistent and recent meta-analyses have been inadequate. This study aimed to integrate previous results and explore the validity of this association. Electronic searches for all relevant publications through May 18, 2014, were conducted across several databases. Additional studies were identified manually, and only the most recent or complete were used in this meta-analysis. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Seven eligible case-control studies were identified, incorporating a total of 14,049 patients and 12,674 controls. Overall, we found that the rs4430796 (A>G) polymorphism had a Furthermore, in the stratified analysis, there were significantly decreased risks among studies with population-and hospital-based controls. In the subgroup analysis by ethnicity, significantly decreased risks were also found among Caucasians, Americans, and Asians. Our results suggested that the HNF1B rs4430796 (A>G) polymorphism decreased the risk of prostate cancer. In the future, additional and larger studies on patients from across of the world might be required to validate our findings.

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Evidence for two independent prostate cancer risk–associated loci in the HNF1B gene at 17q12

Cited by 150 publications

References 17 publications

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

The role of BRCA1 and BRCA2 in prostate cancer

Meta-analysis of the association between the HNF1B rs4430796 (A>G) polymorphism and risk of prostate cancer based on case-control studies

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