Multiple loci on 8q24 associated with prostate cancer susceptibility

Olama, Ali Amin Al; Kóte-Jarai, Zsofia; Giles, Graham G.; Guy, Michelle; Morrison, Jonathan J.; Severi, Gianluca; Leongamornlert, Daniel; Tymrakiewicz, Malgorzata; Jhavar, Sameer; Saunders, Ed; Hopper, John L.; Southey, Melissa C.; Muir, Kenneth; English, Dallas R.; Dearnaley, David P.; Ardern‐Jones, Audrey; Hall, Amanda L.; O'Brien, Lynne T.; Wilkinson, Rosemary; Sawyer, Emma; Lophatananon, Artitaya; cancer, UK Prostate testing for; Horwich, A.; Huddart, Robert; Khoo, Vincent; Parker, Christopher; Woodhouse, Christopher; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Christopher S.; Donovan, Jenny; Hamdy, Freddie C.; Neal, David E.; Eeles, Rosalind; Easton, Douglas F.

doi:10.1038/ng.452

Cited by 274 publications

(249 citation statements)

References 15 publications

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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

135

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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Section: Introductionmentioning

confidence: 99%

The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

135

105

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“…A comprehensive epigenetic mapping analysis has identified several enhancer elements within the risk loci that show tissue-specific activity both in vitro and in vivo (22,23). Apart from the rs6983267, another regulatory SNP has been identified in the enhancers, namely rs11986220, which is strongly correlated with prostate cancer predisposition SNP rs10090154 (2). It affects a FoxA1 binding site within an androgen-responsive enhancer at PrCa-1 region (22).…”

Section: Normal Functions Of the Regulatory Elements At 8q24mentioning

confidence: 99%

“…1). For example, multiple independent risk loci for prostate cancer are located at 8q24 (2)(3)(4)(5)(6), and predisposition alleles to several other epithelial cancers are also found in distinct linkage disequilibrium blocks within this region. An intriguing aspect of the risk alleles is that they are located in a 1.2-Mb "gene desert" region.…”

Section: Introductionmentioning

confidence: 99%

Lessons from Functional Analysis of Genome-Wide Association Studies

Sur

Tuupanen²,

Whitington

et al. 2013

Cancer Research

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Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a cancer-specific enhancer element at the 8q24 gene desert that controls the expression of the MYC oncogene. We further discuss implications of the observed difference between normal growth control and cancer for drug development, and the inherent features of genome-wide association studies that may specifically lead to identification of disease-specific regulatory elements.

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“…[49][50][51] This 7.5-Mb locus overlaps with the 8q24 region, which has been reported in linkage and GWASs of PrCa 17,23,24,29,32 and has been replicated in many studied populations. 22,25,26,[52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] The prostate stem cell antigen maps to this region 69 as does the oncogene MYC. The region has been extensively studied and is relatively gene-poor.…”

Section: Discussionmentioning

confidence: 99%

“…17,[22][23][24][25][26][27][28][29][30][31][32] However, more work remains to be done to fully elucidate the role of heredity in the complex disease of PrCa. The causative genes responsible for these associations are still unknown.…”

Section: Introductionmentioning

confidence: 99%

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

et al. 2012

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Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (DLOD ¼ 3.193, empirical P ¼ 0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD ¼ 2.541, DLOD ¼ 1.651, P ¼ 0.03) and 22q11.1-q11.21 (OSA LOD ¼ 2.395, DLOD ¼ 2.36, P ¼ 0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families.

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Multiple loci on 8q24 associated with prostate cancer susceptibility

Cited by 274 publications

References 15 publications

The role of BRCA1 and BRCA2 in prostate cancer

The role of BRCA1 and BRCA2 in prostate cancer

Lessons from Functional Analysis of Genome-Wide Association Studies

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

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