Multiple Loci With Different Cancer Specificities Within the 8q24 Gene Desert

Cancer Research UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK.
Journal of the National Cancer Institute (Impact Factor: 12.58). 08/2008; 100(13):962-6. DOI: 10.1093/jnci/djn190
Source: PubMed


Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various
genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb
region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers,
we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case–control
sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal
(2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different
haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely
associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was
associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at
least five separate functional variants in this region.

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Available from: Graham G Giles
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    • "The rs188140481 SNP is located in the 8q24 region, which contains a cluster of SNP markers that are associated with cancers at a number of different sites (Ghoussaini et al., 2008). Various other SNPs in the 8q24 region have been reported to be associated with breast, colorectal, and prostate cancers (Easton et al., 2007; Tomlinson et al., 2007; Wokołorczyk et al., 2010). "
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    ABSTRACT: A number of single nucleotide polymorphisms (SNPs) in the human genome have been associated with increased risk of prostate cancer. Recently, a single SNP in the region of chromosome 8q24 (rs188140481) has been associated with a three-fold increased risk of prostate cancer in Europe and North America. To establish whether rs188140481 is associated with the risk of prostate cancer in Poland, we genotyped 3467 men with prostate cancer and 1958 controls. The A allele of rs188140481 was detected in 44 of 3467 (1.3%) men with prostate cancer and in seven of 1958 (0.4%) controls (odds ratio=3.6; 95% confidence interval 1.6-7.9; P=0.0006). The allele was present in eight of 390 (2.1%) men with familial prostate cancer (odds ratio=5.8; 95% confidence interval 2.1-16.2; P=0.001). A positive family history of cancers at sites other than the prostate was observed in 27% of men who carried the rs188140481 risk allele and in 44% of noncarriers (P=0.04). No cancer at a site other than the prostate was more common in first-degree or second-degree relatives of carriers of the rs188140481 risk allele than relatives of noncarriers. The rs188140481 polymorphism in the 8q24 region confers a moderate increase in the risk of prostate cancer in Polish men. The SNP does not appear to be associated with susceptibility to cancers of other types.
    Full-text · Article · Sep 2014 · European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP)
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    • "Recent advances in the theoretical and experimental methods used to study DNA packaging within cells make it possible to elucidate the biological function and pathways to which SNPs located within gene deserts can contribute. This has been shown in a number of gene deserts, most notably: SNPs within a 1.2 Mb region on chromosome 8q24, a known gene desert, have been implicated in cancer-type-specific interactions with Myc, a highly potent cancer gene > 300 kb away (Amundadottir et al., 2006; Ghoussaini et al., 2008; Ahmadiyeh et al., 2010; Wasserman et al., 2010). This same region has also been implicated in pediatric asthma in an Asian population (Noguchi et al., 2011) and non-syndromic cleft lip in pediatric patients (Grant et al., 2009). "
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    ABSTRACT: Genome wide association studies are central to the evolution of personalized medicine. However, the propensity for single nucleotide polymorphisms (SNPs) to fall outside of genes means that understanding how these polymorphisms alter cellular function requires an expanded view of human genetics. Integrating the study of genome structure (chromosome conformation capture) into its function opens up new avenues of exploration. Changes in the epigenome associated with SNPs in gene deserts will allow us to define complex diseases in a much clearer manner, and usher in a new era of disease pathway exploration.
    Full-text · Article · Feb 2014 · Frontiers in Genetics
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    • "GWAS discoveries is still largely unknown. Many of the disease associations identified by GWAS do not involve previously known candidate genes, such as DNA repair pathway genes, and many associated markers are in genomic regions harboring unknown genes [152] . Therefore, the functions of those variants identified in GWAS should be validated via biological assays, pathway analysis or bioinformatics in the post-GWAS era. "
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    ABSTRACT: Although tobacco and alcohol consumption are two common risk factors of head and neck cancer (HNC), other specific etiologic causes, such as viral infection and genetic susceptibility factors, remain to be understood. Human DNA is often damaged by numerous endogenous and exogenous mutagens or carcinogens, and genetic variants in interaction with environmental exposure to these agents may explain interindividual differences in HNC risk. Single nucleotide polymorphisms (SNPs) in genes involved in the DNA damage-repair response are reported to be risk factors for various cancer types, including HNC. Here, we reviewed epidemiological studies that have assessed the associations between HNC risk and SNPs in DNA repair genes involved in base-excision repair, nucleotide-excision repair, mismatch repair, double-strand break repair and direct reversion repair pathways. We found, however, that only a few SNPs in DNA repair genes were found to be associated with significantly increased or decreased risk of HNC, and, in most cases, the effects were moderate, depending upon locus-locus interactions among the risk SNPs in the pathways. We believe that, in the presence of exposure, additional pathway-based analyses of DNA repair genes derived from genome-wide association studies (GWASs) in HNC are needed.
    Full-text · Article · May 2013
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