BERKELEY, CA (UroToday.com) - Family history as a risk factor for prostate cancer was confirmed by numerous epidemiological studies.(1-3)
In an effort to discriminate between genetic and sporadic prostate cancer, investigators have applied Carter’s criteria.(4) According to these, 9% of the total number of cases and about 43% of those diagnosed before 55 years of age may be directly attributable to inheritance.(5) However, presently, neither clinical nor pathologic characteristics are useful to distinguish between these two forms of disease, the only difference being an earlier age at diagnosis for heredo-familial prostate cancer (HFPC).(6)
The current study intended to investigate the role of genetic and environmental factors in predisposing to prostate cancer. To this aim, common single nucleotide polymorphisms (SNPs) in genes belonging to pathways whose genetic variations have been associated with an increased risk of cancer, such as CYP17A1, VDRI and the CAG repeat number from AR , were profiled in HFPC patients, controlled for dietary intake and lifestyle habits, from a region wide Northern-Italian population.
We carried out a multicentric recruitment based on 717 Italian men of Caucasian origin. All patients underwent a face-to-face interview to obtain information on clinico-pathological data, including medical history, prostate cancer screening history and life-style habits, assessed by the two self-administered questionnaires adopted by the European Prospective Investigation into cancer and Nutrition study (EPIC).(7) In this study habitual dietary intake was assessed by using a 248-item semi-quantitative food-frequency questionnaire (FFQ). Food and nutrients were grouped into two classes on the basis of the intake of the whole study population. Based on family cancer history, subjects were classified as cases and controls. Cases were considered as HFPC according to Carter et al.’s definition,(4) whereas those without a family history of prostate cancer were considered as the control group. Overall, we identified 95 patients with HFPC and 378 men with sporadic prostate cancer, randomly selected as controls.
Genomic DNA was isolated from whole blood of each patient. The genotyping of polymorphisms was carried out by using pyrosequencing whereas the CAG repeat length was measured by direct sequencing of amplified fragments according to Andersson et al.(8) The study design was based on comparing solely cancer cases with different baseline characteristics in genotyping, as it has been previously used in colorectal cancer research.(9)
As far as the demographic and clinical results, our data are consistent with those previously reported, showing that the only parameter associated with HFPC was early age at diagnosis, while Gleason score, pathological stage, and PSA level did not display any significant difference compared with sporadic cancers. In spite of the similar clinico-pathological features, sporadic and heredo-familial cases were characterized by statistical differences in the SNPs profiles, supporting the effective role of genetic variance in triggering or sustaining the development of HFPC. In particular, we found a significant evidence for interaction between VDR1 and VDR2 polymorphisms (interaction term OR = 5.15; 95% CI: 1.24-21.35). As a matter of fact, the effect of VDR1 genotypes was different among subjects belonging to VDR2 C/T+C/C groups (OR = 0.79; 95% CI: 0.33-1.92) in respect to the patients with VDR2 T/T genotype (Table). In these latter subjects the probability of being a HFPC case vs. a sporadic one was significantly about five times higher (OR = 4.83; 95% CI: 1.37-17.02).
|VDR2 genotype stratum specific||VDR2 C/T +C/C||VDR2 T/T|
|Odds ratio (95% CI)||Odds ratio (95% CI)|
|T/T||0.79 (0.33-1.92)||4.83 (1.37-17.02)|
|≥12.51mg||0.79 (0.44-1.42)||3.14 (1.12-8.81)|
Table: VDR2 stratum specific estimates of the effects of studied genotypes and zinc intake
To the best of our knowledge, this is the first report concerning such an association. VDR is a crucial mediator for the cellular effects of vitamin D and exerts various VDR-independent effects of vitamin D, including regulation of calcium and inhibition of cell proliferation .(10) The association between some VDR genetic polymorphisms and prostate cancer risk has been extensively studied, although with conflicting results. Recent reviews and meta-analysis concerning this association have pointed out that combined analysis of multiple polymorphisms may be more informative than a single-locus analysis to identify individuals at high risk of prostate cancer.(11) Besides inheritance of susceptibility genes or polymorphisms in genes, familial clustering of prostate cancer may be caused by exposure to common environmental factors.(12) The Western lifestyle, particularly the high intake of fat, meat and dairy products were hypothesized to be responsible for conveying a higher prostate cancer risk.(13) In the present study, no differences in diet-associated risk were found between cases and controls, except for zinc. In that case we observed a statistically significant increased risk of HFPC among patients with high dietary zinc intake (≥12.51mg) and VDR2 T/T genotype (OR = 3.14; 95%CI: 1.12-8.81). Gallus and colleagues also reported a statistically significant increased risk of prostate cancer with zinc intake. High intraprostatic zinc concentrations may affect this risk by enhancing the activity of telomerase, an enzyme thought to be responsible for unlimited proliferation of tumour cells, and by increasing circulating levels of insulin-like growth factor I and testosterone.(14, 15) In addition, gene transcription and binding function of VDR are mediated by zinc through specific zinc finger motifs for the interaction with DNA or other proteins.
In conclusion, we have provided new evidence that the two common gene variants, VDR1 T/T combined with VDR2 T/T genotype, are associated with a significant increase of HFPC. Among non-genetic risk factors, only dietary zinc intake turned out to modify cancer risk, indicating the interplay between inherited and environmental factors in the development of HFPC.
- Bock CH, Peyser PA, Gruber SB, Bonnell SE, Tedesco KL, Cooney KA. Prostate cancer early detection practices among men with a family history of disease. Urology 2003; 62: 470-5
- Valeri A, Cormier L, Moineau MP, Cancel-Tassin G, Azzouzi R, Doucet L et al. Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives. J Urol 2002 ; 168: 483-7
- Conlon EM, Goode EL, Gibbs M, Stanford JL, Badzioch M, Janer M et al. Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset. Int J Cancer 2003; 105: 630-5
- Carter BS, Bova GS, Beaty TH, Steinberg GD, Childs B, Isaacs WB et al. Hereditary prostate cancer: epidemiologic and clinical features. J Urol 1993; 150: 797-802
- Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 1992; 89: 3367-71
- Coughlin SS, Hall IJ. A review of genetic polymorphisms and prostate cancer risk. Ann Epidemiol 2002; 12: 182-96
- Margetts BM, Pietinen P. European Prospective Investigation into Cancer and Nutrition: validity studies on dietary assessment methods. Int J Epidemiol 1997; 26 Suppl 1: S1-5
- Andersson P, Varenhorst E, Soderkvist P. Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk. Eur J Cancer 2006; 42: 2833-7
- Tomlinson IP, Dunlop M, Campbell H, Zanke B, Gallinger S, Hudson T et al. COGENT (Colorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer. Br J Cancer 2010;102: 447-454
- Panda DK, Miao D, Bolivar I, Li J, Huo R, Hendy GN et al. Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem 2004; 279: 16754-66
- Raimondi S, Johansson H, Maisonneuve P, Gandini S. Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis 2009; 30: 1170-80.
- Gronberg H. Prostate cancer epidemiology. Lancet 2003; 361: 859-64
- Allen NE, Key TJ, Appleby PN, Travis RC, Roddam AW, Tjonneland A et al. Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 2008; 98: 1574-81
- Nemoto K, Kondo Y, Himeno S, Suzuki Y, Hara S, Akimoto M et al. Modulation of telomerase activity by zinc in human prostatic and renal cancer cells. Biochem Pharmacol 2000; 59: 401-5.
- Holmes MD, Pollak MN, Willett WC, Hankinson SE. Dietary correlates of plasma insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations. Cancer Epidemiol Biomarkers Prev 2002; 11: 852-61
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