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: 9.33). 05/2007; 67(7):2951-6. DOI: 10.1158/0008-5472.CAN-06-3591
Source: PubMed


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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    ABSTRACT: Understanding the role of single nucleotide polymorphisms (SNPs) in the pathological process represents a unique experimental challenge especially when the variants occur outside of coding regions. The non-coding, single-nucleotide polymorphism (SNP) rs61764370 located in the 3' untranslated region (UTR) of Kirsten rat sarcoma viral oncogene homolog (KRAS) has been implicated as a risk factor for the development of cancer and the response to targeted therapies. This cancer-associated variant is thought to affect binding of the microRNA let-7, which allegedly modulates KRAS expression. Using site-specific homologous recombination we inserted the rs61764370:T>G KRAS gene variant in the colorectal cancer cell line SW48 (SW48 +SNP) and assessed the cellular and biochemical phenotype. We observed a significant increase in cellular proliferation, as well as a reduction in the levels of the microRNA let-7a, let-7b and let-7c. Transcriptional and biochemical analysis showed no concomitant change in the KRAS protein expression or modulation of the downstream MAPK or PI3K/AKT signaling. These results suggest that the cancer-associated rs61764370 variant exerts a biological effect not through transcriptional modulation of KRAS but rather by tuning the expression of the microRNA let-7. This article is protected by copyright. All rights reserved.
    Human Mutation 02/2014; 35(2). DOI:10.1002/humu.22487 · 5.14 Impact Factor
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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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    ABSTRACT: Recent technological advancements in gene expression analysis have led to the discovery of a promising new group of prostate cancer (PCa) biomarkers that have the potential to influence diagnosis and the prediction of disease severity. The accumulation of deleterious changes in gene expression is a fundamental mechanism of prostate carcinogenesis. Aberrant gene expression can arise from changes in epigenetic regulation or mutation in the genome affecting either key regulatory elements or gene sequences themselves. At the epigenetic level, a myriad of abnormal histone modifications and changes in DNA methylation are found in PCa patients. In addition, many mutations in the genome have been associated with higher PCa risk. Finally, over- or underexpression of key genes involved in cell cycle regulation, apoptosis, cell adhesion and regulation of transcription has been observed. An interesting group of biomarkers are emerging from these studies which may prove more predictive than the standard prostate specific antigen (PSA) serum test. In this review, we discuss recent results in the field of gene expression analysis in PCa including the most promising biomarkers in the areas of epigenetics, genomics and the transcriptome, some of which are currently under investigation as clinical tests for early detection and better prognostic prediction of PCa.
    American Journal of Cancer Research 12/2012; 2(6):620-57. · 4.17 Impact Factor
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    • "Variants in the 8q24 region have been associated with numerous cancers in addition to colorectal cancer. The region was identified as a top hit in genome-wide association studies of prostate [5-10,12-14], breast [15], urinary bladder [16] and colorectal cancers [8,29,32]. Follow-up in studies of multiple cancers have confirmed these findings [20] and have found additional associations for kidney, thyroid, and larynx cancer [31], as well as cancers of the upper aerodigestive tract [54]. "
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    ABSTRACT: Genome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with colorectal cancer susceptibility. We examined 11 SNP markers in the 8q24 region between 128.47 and 128.54 Mb, using a total of 1,987 colon cases and 2,339 controls who self-reported as white from two independent, well-characterized study populations. Analysis was performed separately within each study, and combined using random effects meta-analysis. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) and to test for effect modification by known colon cancer risk factors. We also performed a meta-analysis combining our results with previous studies. We observed evidence of association for four SNPs in low to high linkage disequilibrium (r2 ranging from 0.18 to 0.93) localized in a 16.2 kb region defined by rs10505477 and rs1056368. The combined results for our two studies of colon cancer showed an OR of 1.10 (95% CI: 1.01-1.20, Ptrend = 0.023), and a meta-analysis of our results with previously reported studies of colon and colorectal cancer strongly support the association for this SNP (combined OR for rs6983267 = 1.21, 95% CI: 1.18-1.24, p = 5.5 × 10-44). We did not observe any notable evidence of effect modification by known colon cancer risk factors, and risk did not differ significantly by tumor site or stage. Our study confirms the association between polymorphisms on chromosome 8q24 and colon cancer risk and suggests that the susceptibility locus in region 8q24 is not strongly modified by various lifestyle, environmental, and demographic risk factors for colon cancer.
    BMC Cancer 12/2010; 10(1):670. DOI:10.1186/1471-2407-10-670 · 3.36 Impact Factor
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