Journal of the National Cancer Institute Advance Access published online on June 24, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn190
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© The Author 2008. Published by Oxford University Press.
Multiple Loci With Different Cancer Specificities Within the 8q24 Gene Desert
Affiliations of authors: Cancer Research UK Department of Oncology (MG, HS, TK, KED, KAP, PDPP, BAJP, AMD), Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care (AAAO, JM, DFE), University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; The Institute of Cancer Research, Sutton, Surrey, UK (ZKJ, MG, SME, DPD, ALH, LTO’, BNGS, RAW, RAE); Translational Research Laboratories, Institute for Women’s Health, University College London, London, UK (SJR, SAG); Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark (SKK, EH); Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY (RAD); Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA (ASW); Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria, Australia (GGG); Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Carlton, Victoria, Australia (GGG, JLH); Department of Social Medicine, University of Bristol, Bristol, UK (JLD); Academic Urology Unit, University of Sheffield, Sheffield, UK (FCH); The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (DPD, ATAJ, ALH, BNGS, RAE); The Royal Marsden NHS Foundation Trust, London, UK (DPD, ATAJ, ALH, BNGS, RAE); Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke’s Hospital, UK (DEN); Cancer Research UK Cambridge Cancer Research Institute, Cambridge, UK (BAJP)
Correspondence to: Maya Ghoussaini, PhD, CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK (e-mail: maya{at}srl.cam.ac.uk).
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.
| Context and Caveats Prior knowledge Genetic variants in a region of chromosome 8 had been associated with the risk of breast, colorectal, and prostate cancer. Study design Case subjects with each of four cancers (breast, colorectal, prostate, and ovarian) and control subjects were examined for the presence of previously identified risk variants that span the chromosomal region previously associated with cancer risk. Genotype frequencies were compared using unconditional logistic regression. Contribution At least five distinct cancer susceptibility loci were found within the chromosomal region, each separated by recombination hot spots and specific for one or more of the four cancers. Implications Fine mapping of the identified loci may help elucidate molecular mechanisms that contribute to carcinogenesis. Limitations It is unknown whether any of the cancer-associated polymorphisms examined are causal variants or simply markers of unknown causal variants.
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Manuscript received November 27, 2007; revised April 20, 2008; accepted May 14, 2008.
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J Natl Cancer Inst 2008 100: 907.
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