Beyond the Abstract - Genetic polymorphisms of CYP17A1, vitamin D receptor and androgen receptor in Italian heredo-familial and sporadic prostate cancers, by Tiziana Venesio, PhD, et al

BERKELEY, CA ( - 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 specificVDR2 C/T +C/CVDR2 T/T
Odds ratio (95% CI) Odds ratio (95% CI)
C/C T/C 1 1
T/T 0.79 (0.33-1.92) 4.83 (1.37-17.02)
<12.51mg 1 1
≥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.


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Written by:
Tiziana Venesio, Elena Kolomoets, Antonella Balsamo, Federica Gallo, Paola Armaroli, Nereo Segnan and Mauro Risio as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.


Genetic polymorphisms of CYP17A1, vitamin D receptor and androgen receptor in Italian heredo-familial and sporadic prostate cancers - Abstract Prostate Cancer Section

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