A common 8q24 variant in prostate and breast cancer from a large nested case-control study

University of Cambridge, Cambridge, England, United Kingdom
Cancer Research (Impact Factor: 9.28). 05/2007; 67(7):2951-6. DOI: 10.1158/0008-5472.CAN-06-3591
Source: PubMed

ABSTRACT Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rs1447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 x 10(-13)). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 x 10(-13)). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an OR(AC) = 1.34 (99% confidence intervals, 1.19-1.50) and carriers with two copies of the minor allele had an OR(AA) = 1.86 (99% confidence intervals, 1.30-2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result.

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Available from: Gerald L Andriole, May 25, 2015
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    • "Despite this, it is clear that silent polymorphisms can affect risk, prognosis or treatment response, and are therefore fundamental in the pathological process (Salzman and Weidhaas 2013). This was demonstrated for rs6983267, a polymorphism that increases the risk of multiple cancer types (Amundadottir et al. 2006; Schumacher et al. 2007; Zanke et al. 2007; Kiemeney et al. 2008) thought to be due to its location in the MYC enhancer. Removal of a portion of chromosome 8q24, containing the cancer-associated silent polymorphism rs6983267, in mice reduced MYC transcript levels and resulted in a profound reduction of the formation of intestinal tumours upon APC loss (Sur et al. 2012). "
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    • "Some SNP alleles are not associated with identifiable genes, as is the case for the 8q24 region. Studies indicate that there are up to seven distinct loci within 8q24 in which SNP alleles are correlated with up to a 50% increased risk of PCa [101] [106] [107] [108] [109] [110] [111] [112]. 8q24 was first identified as an important region in familial PCa in 2006, and since then it has been linked with increased risk for other cancers such as colorectal, breast, bladder and ovarian cancer [113] [114] [115]. "
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    • "Two advantages of characterizing all common genetic variants prior to undergoing large-scale Wne-mapping studies are (1) that all common genetic variants may be represented using a tag SNP approach, and (2) the correlations among all genetic variants will be known, which will allow for rapid nomination of variants for functional studies for those that are most highly correlated with the markers that are most highly associated with disease. At least four regions of human chromosome 8q24 have recently been implicated in the risk of prostate, breast, and colorectal cancer (Amundadottir et al. 2006; Freedman et al. 2006; Gruber et al. 2007; Gudmundsson et al. 2007; Haiman et al. 2007a, b; Schumacher et al. 2007; Yeager et al. 2007; Zanke et al. 2007) and colorectal adenoma Fig. 6 Best SNP from centromeric region (rs6983267), conservation , regulatory potential, and enhancer element probabilities . Vista enhancer tracks are shown on the UCSC browser. "
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