Risk Of Prostate Cancer Aggressiveness Research Articles

Exploring Prostate Cancer Patients' Interest and Preferences for Receiving Genetic Risk Information About Cancer Aggressiveness.

The number of cases of aggressive prostate cancer is increasing. Differentiating between aggressive and indolent cases has resulted in increased difficulty for the physician and patient to decide on the best treatment option. Due to this challenge, efforts are underway to profile genetic risk for prostate cancer aggressiveness, which may help physicians and patients at risk for developing aggressive prostate cancer to select an appropriate treatment option. This study explores patients’ interest in receiving genetic results, preference for how genetic risk information should be communicated, and willingness to share results with adult male first-degree relatives (FDRs). A nine-item survey was adapted to assess their beliefs and attitudes about genetic testing for prostate cancer aggressiveness. In addition, participants (n = 50) responded to hypothetical scenarios and questions associated with perceived importance of risk disclosure, preferences for receiving genetic risk information, and sharing of results with FDRs. As the hypothetical risk estimate for aggressive prostate cancer increased, patients’ willingness to receive genetic risk information increased. This study found that most patients preferred receiving genetic risk education in the form of a DVD (76%), one-page informational sheet (75%), or educational booklet (70%). Almost all patients (98%) reported that they would be willing to share their test results with FDRs. The results of this study highlight prostate cancer patients’ desire to receive and share genetic risk information. Future research should focus on assessing the long-term benefits of receiving genetic information for prostate cancer patients and implications of sharing this information with FDRs.

Abstract B16: Association of calcium and vitamin D intake and vitamin D receptor genotypes with prostate cancer in multiethnic samples

Abstract Background: Prostate cancer (PCa) is the most common cancer among men in the U.S., and African American (AA) men have higher incidence and mortality rate compared to European American (EA) men. Social and behavioral factors affect stage and tumor grade at diagnosis, treatment choice, and mortality. However, the cause for PCa disparities is still unclear. Several roles have been proposed for calcium, vitamin D, and the vitamin D receptor (VDR) in PCa pathogenesis and progression, but epidemiologic studies, mainly conducted in European descent populations, often show inconsistent evidence of associations. Here, we investigated the association of calcium and vitamin D intake and VDR genotypes with prostate cancer incidence and aggressiveness in multiethnic samples. Methods: The total of 1,403 individuals was included in this study (751 AAs, 481 EAs, 126 Hispanic Americans, and 45 others). Study participants were recruited from six hospitals in Chicago, IL and Washington, D.C. Calcium and vitamin D intake was evaluated using the Block calcium and vitamin D screener. Seven single-nucleotide polymorphisms (SNPs) in and around the VDR gene and 105 ancestry informative markers were genotyped. STRUCTURE was used to estimate genetic ancestry. We performed logistic regression analyses adjusting for relevant variables using SPSS. Results: In the pooled data set, calcium and vitamin D intake was not associated with PCa risk (P>0.05), but high total calcium intake (≥800 mg/day) was significantly associated with aggressive PCa (Gleason Score ≥4+3, P=0.002, OR=2.05, 95% C.I.: 1.29-3.26). In the race/ethnicity stratified analyses, we confirmed the statistically significant associations of calcium intake with aggressive PCa in AAs. High total vitamin D intake (≥600IU/day), on the other hand, revealed a protective effect against aggressive PCa (OR=0.47, 95% C.I.: 0.24-0.92, P=0.026). In EAs, total calcium intake was significantly associated with PCa aggressiveness, only when we compared PCa cases with Gleason Score ≥4+3 to cases with Gleason Score <4+3 (P=0.047, OR=2.52, 95% C.I.: 1.01-6.27). In AAs, the G allele of rs11568820 (Cdx2) had a protective effect, and AG/GG genotype was strongly associated with high risk PCa (P=0.014, OR=0.35, 95% C.I.: 0.15-0.81). In EAs, rs73136 (TaqI) C allele and rs1544410 (BsmI) G allele showed a protective effect against aggressive PCa. TaqI CT/CC genotypes had odds ratio of 0.40 (95% C.I.: 0.18-0.91, P=0.03), and the odds ratio for BsmI AG/GG genotypes was 0.33 (95% C.I.: 0.14-0.76, P=0.009) in EAs. We also observed evidence of interactions between Cdx2 genotypes and total calcium intake and between rs11574143 genotype and total calcium intake in AAs. Significant interactions were also observed between TaqI genotype and total calcium intake in EAs. Conclusion: In this study, we showed that high calcium intake increases the risk of prostate cancer aggressiveness, while high vitamin D intake has protective effects. Although a larger sample size is necessary to confirm the observation, we demonstrated that VDR genotypes may modify the effect of calcium intake. The findings from this study may help develop better PCa management plans. Citation Format: Ken Batai, Adam B. Murphy, Ebony Shah, Maria Ruden, Jennifer Newsome, Michael A. Dixon, Ahaghotu Chiledum, Rick A. Kittles. Association of calcium and vitamin D intake and vitamin D receptor genotypes with prostate cancer in multiethnic samples. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B16.

Abstract 5569: p73 dinucleotide polymorphism genotyping of human cancer cell lines

Abstract The p73 gene is a member of the p53 tumor suppressor family. The p73 dinucleotide polymorphism (DNP) (rs1801173) is a G4C14-to-A4T14 linked pair of transitions located in exon 2 between the P1 and P2 gene promoters. The P1 and P2 p73 gene promoters are the transcription initiation sites for mRNAs encoding TAp73 and ΔNp73 isoforms, respectively. Recently, we reported the p73 DNP allele was associated with (1) decreased risk [OR = 0.55, 95%CI = 0.31-0.99] for aggressive prostate cancer (PCa) and (2) increased TAp73/ΔNp73 protein isoform ratios in ten human cancer cell lines. We hypothesize the presence of the p73 DNP allele causes altered p73 promoter usage resulting in increased TAp73/ΔNp73 protein isoform ratios, which could explain the observed decreased risk for PCa aggressiveness. Our ultimate goal is to assess the potential of p73 DNP as a biomarker for lower aggressive PCa risk. Therefore, our initial aim in this study was to determine the p73 DNP genotype in ten additional human cancer cell lines (DU 145, JEG-3, K-562, LNCaP, MDA-MB-231, MDA-MB-468, MRC-5, PC-3, SW48 and U-2OS) not yet characterized for p73 DNP status. We previously reported the p73 DNP genotype of three human cancer cell lines that we used as genotyping controls: Caco-2 (homozygous polymorphic), NCI-H1299 (homozygous wild type), and HepG2 (heterozygous). Cell lines were cultured and genomic DNA was isolated and quantitated. Cell line genomic DNA samples were used in TaqMan Real Time-PCR allelic discrimination assays to determine the p73 DNP genotypes. Our data conclusively determined that DU 145, JEG-3, K-562, LNCaP, MDA-MB-468, MRC-5, SW48 and U-2OS were p73 DNP homozygous wild type, while PC-3 and MDA-MB-231 werw p73 DNP heterozygous. Cell Line p73 DNP GenotypesCELL LINE NAMEP73 DNP GENOTYPEDU145CCJEG-3CCK-562CCLNCaPCCMDA-MB-231CTMDA-MB-468CCMRC-5CCPC-3CTSW48CCU-2OSCC Citation Format: L. Michael Carastro, Kaia K. Hampton, Ricardo A. Cordova Estupinan, Hyun Y. Park, Dongwha Kim, Jong Y. Park. p73 dinucleotide polymorphism genotyping of human cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5569. doi:10.1158/1538-7445.AM2015-5569

Abstract 5070: Role of p73 di-nucleotide polymorphism in prostate cancer and p73 protein isoform balance

Abstract The p73 gene is a member of the p53 tumor suppressor family. Compared to p53, the molecular consequences of and risk factors associated with variants of the p73 gene are not well understood. Prostate cancer (PCa) is the most frequently occurring cancer in men, and the second leading cause of cancer mortality among US men. Available molecular markers for PCa risk of incidence or aggressiveness are currently lacking. Though the mechanism of PCa progression is not well understood, several lines of evidence support a role for a di-nucleotide polymorphism (DNP) in the p73 gene as a risk factor for several cancer types. However, results are inconsistent. We investigated a DNP linked pair of transition changes, G4C14-to-A4T14 (rs1801173), located in the 5′-UTR portion of exon 2 of the p73 gene. The goals of this study were to address the potential associations between p73 DNP (rs1801173) and PCa risk and/or progression, and to discern any detectable disruption of p73 protein isoforms in cells harboring the p73 DNP allele. We have analyzed 1,292 PCa patients and 682 healthy control men. Although we detected no association between p73 DNP and PCa risk (OR =1.02, 95%CI=0.86-1.21), a significant inverse relationship between p73 DNP and PCa aggressiveness (OR = 0.55, 95%CI=0.31-0.99) was detected. Several p73 protein isoforms have been identified and can be grouped into two major categories, TAp73 and ΔNp73, which differ in their N-termini and are transcribed from different promoters. The transcriptionally active TAp73 isoforms are transcribed from the P1 promoter and include the full-length N-terminal sequence encompassing exons 1 through 3. However, the ΔNp73 isoforms are transcribed from promoter P2 and do not contain the N-terminal trans-activation (TA) domain. Therefore, the ΔNp73 protein isoform is dominate negative toward TAp73 because ΔNp73 isoforms are able to form tetramers with TAp73, as well as p53, but do not activate transcription of p73- or p53-target genes. The balance between TAp73 and ΔNp73 is disrupted in many cancer types. In this study, Western Blot analyses of eleven cancer cell lines for p73 protein isoforms indicate that the two cell lines with heterozygous genotype for p73 DNP have higher TAp73/ΔNp73 ratios (TAp73/ΔNp73 = 1.39 and 1.4) than the other wild-type cell lines not harboring the p73 DNP allele (TAp73/ΔNp73 = 0.68 to 0.97). Our combined findings are consistent with an association between the p73 DNP allele and lower risk for PCa aggressiveness by increasing the expressed TAp73/ΔNp73 protein isoform ratio. Citation Format: L. Michael Carastro, Hui-Yi Lin, Hyun Y. Park, Donghwa Kim, Selina Radlein, Kaia K. Hampton, Ardeshir Hakam, Babu Zachariah, Julio M. Pow-Sang, Jong Y. Park. Role of p73 di-nucleotide polymorphism in prostate cancer and p73 protein isoform balance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5070. doi:10.1158/1538-7445.AM2014-5070

Does benign prostatic hyperplasia treatment with alpha-blockers affect prostate cancer risk?

To determine whether alpha-blockers, commonly used for the treatment of benign prostatic hyperplasia, are associated with prostate cancer risk. Alpha-blockers have been associated with a reduced risk of prostate cancer aggressiveness in some observational studies and an increased risk in other studies. However, this relationship is complex as different alpha-blockers have divergent effects in laboratory studies and there are many confounders in daily practice such as differential screening practices. Both benign prostatic hyperplasia and prostate cancer are common conditions in the aging male population, such that an interaction between alpha-blockers and prostate cancer risk is clinically relevant. Prospective evidence is necessary to establish a definitive link.

Obesity, metabolic syndrome, and prostate cancer

Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-α, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.