Article

Association between Genetic Variants in the 8q24 Cancer Risk Regions and Circulating Levels of Androgens and Sex Hormone-Binding Globulin

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 07/2010; 19(7):1848-54. DOI: 10.1158/1055-9965.EPI-10-0101
Source: PubMed

ABSTRACT Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder.
To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphisms (SNPs) in the 8q24 risk regions spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, 3alphadiol G, and bioavailable testosterone), and sex hormone-binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log-transformed biomarker levels.
Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P < 1.1 x 10(-3)) and bioavailable testosterone (P < 6.3 x 10(-4)). Suggestive associations were seen for a cluster of nine SNPs in prostate cancer risk region 1 and androstenedione (P < 0.05).
These preliminary findings require confirmation in larger studies but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions might correlate with androgen levels. Impact: These results might provide some clues for the strong link between 8q24 and prostate cancer risk.

Download full-text

Full-text

Available from: Jocelyn M Weiss, Apr 25, 2014
0 Followers
 · 
117 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (PC) is the most common malignancy observed in men. It is evident that genetic factors play some important roles in PC etiology. Recently, genome-wide association studies in diverse ethnic groups have identified more than 40 germline variants of various genes or chromosomal loci that are significantly associated with PC susceptibility, including multiple 8q24 loci, prostate-specific genes, metabolic and hormone-related genes, and many regions where no coding gene is annotated. However, there are only a few variants or genes for which biological significance or functions have been elucidated so far. The greatest challenge related to genome-wide association studies loci in prostate genomics is to understand the functional consequences of these PC-associated loci and their involvement in PC biology and carcinogenesis. There have been attempts to determine PC risk estimations by combining multiple PC-associated variants for clinical tests, and these can identify a very minor population with high risk of PC. However, they cannot distinguish risk of aggressive PC from that of non-aggressive PC. Further identification of PC-susceptibility loci in larger genome-wide association studies cohorts and biological insights gained from such functional analyses have the potential to translate into clinical benefits, including the development of reliable biomarkers, risk estimation, and effective strategies for screening and prevention of PC.
    Cancer Science 12/2011; 103(4):607-13. DOI:10.1111/j.1349-7006.2011.02193.x · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is the second leading cancer in Korean women. To assess potential genetic associations between the prostate stem cell antigen (PSCA) gene in the chromosome 8q24 locus and breast cancer risk in Korean women, 13 SNPs were selected and associations with breast cancer risk were analyzed with reference to hormone receptor (HR) and menopausal status. We analyzed DNA extracted from buffy coat from 456 patients and 461 control samples, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) based upon region-specific PCR followed by allele- specific single base primer extension reactions. Risks associated with PSCA genotypes and haplotypes were estimated with chi-square test (χ2 -test), and polytomous logistic regression models using odds ratios (OR) and 95% confidence intervals (CIs), by HR and menopausal status. In case-control analysis, odds ratios (OR) of rs2294009, rs2294008, rs2978981, rs2920298, rs2976395, and rs2976396 were statistically significant only among women with estrogen receptor (ER) negative cancers, and those of rs2294008, rs2978981, rs2294010, rs2920298, rs2976394, rs10216533, and rs2976396 were statistically significant only in pre-menopausal women, and not in postmenopausal women. Risk with the TTGGCAA haplotype was significantly elevated in ER (-) status (OR= 1.48, 95% CI= 1.03~2.12, p<0.05). Especially risk of allele T of rs2294008 is significantly low in pre-menopausal breast cancer patients and AA genotype of rs2976395 in ER (-) status represents the increase of OR value. This report indicated for the first time that associations exist between PSCA SNPs and breast cancer susceptibility in Korean women, particularly those who are pre-menopausal with an estrogen receptor negative tumor status.
    Asian Pacific journal of cancer prevention: APJCP 01/2012; 13(1):41-8. DOI:10.7314/APJCP.2012.13.1.041 · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. There is limited information on the mechanistic basis of these associations, particularly about whether they interact with circulating concentrations of growth factors and sex hormones, which may be important in prostate cancer etiology. Using conditional logistic regression, the authors compared per-allele odds ratios for prostate cancer for 39 GWAS-identified SNPs across thirds (tertile groups) of circulating concentrations of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), testosterone, androstenedione, androstanediol glucuronide, estradiol, and sex hormone-binding globulin (SHBG) for 3,043 cases and 3,478 controls in the Breast and Prostate Cancer Cohort Consortium. After allowing for multiple testing, none of the SNPs examined were significantly associated with growth factor or hormone concentrations, and the SNP-prostate cancer associations did not differ by these concentrations, although 4 interactions were marginally significant (MSMB-rs10993994 with androstenedione (uncorrected P = 0.008); CTBP2-rs4962416 with IGFBP-3 (uncorrected P = 0.003); 11q13.2-rs12418451 with IGF-1 (uncorrected P = 0.006); and 11q13.2-rs10896449 with SHBG (uncorrected P = 0.005)). The authors found no strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of IGF-1, sex hormones, or their major binding proteins.
    American journal of epidemiology 03/2012; 175(9):926-35. DOI:10.1093/aje/kwr423 · 4.98 Impact Factor