-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions. METHODS: The Physicians' Health Study (PHS) is a prospective cohort of 22,071 US physicians; we utilized a nested case-control study of 1,352 PCa cases and 1,382 controls. We assessed four SNPs capturing common variation within the SEPP1 locus. In a subset of men (n = 80), we evaluated SEPP1 mRNA expression in tumors. RESULTS: Two SNPs were significantly associated with PCa risk. For rs11959466, each T allele increased risk (odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.02,1.69; P(trend) = 0.03). For rs13168440, the rare homozygote genotype decreased risk compared to the common homozygote (OR = 0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with plasma selenium; increasing selenium levels were associated with decreased PCa risk only among men with the minor allele (P(interaction) = 0.01). SEPP1 expression was significantly lower in men with lethal PCa than long-term survivors. CONCLUSIONS: SEPP1 genetic variation was associated with PCa incidence; replication of these results in an independent dataset is necessary. These findings further support a causal link between selenium and PCa, and suggest that the effect of selenium may differ by genetics. Prostate © 2012 Wiley Periodicals, Inc.
The Prostate 11/2012; · 3.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether 1) common genetic variation in CaSR was associated with PCa risk and 2) these associations varied by calcium intake or plasma 25-hydroxyvitamin D (25(OH)D) levels. METHODS: We included 1193 PCa cases and 1244 controls nested in the prospective Health Professionals Follow-up Study (1993-2004). We genotyped 18 CaSR SNPs to capture common variation. The main outcome was risk of lethal PCa (n=113); secondary outcomes were overall (n=1193) and high-grade PCa (n=225). We used the kernel machine approach to conduct a gene-level multi-marker analysis and unconditional logistic regression to compute per-allele odds ratios (OR) and 95% confidence intervals (CI) for individual SNPs. RESULTS: The joint association of SNPs in CaSR was significant for lethal PCa (p=0.04); this association was stronger in those with low 25(OH)D (p=0.009). No individual SNPs were associated after considering multiple testing; 3 SNPs were nominally associated (p<0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42-0.99): rs6438705; 0.65(0.47-0.89)): rs13083990; and 1.55(1.09-2.20): rs2270916. The 3 non-synonymous SNPs (rs1801725, rs1042636, rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D (OR(95%CI): 0.54(0.31-0.95)). There were no significant associations with overall or high-grade PCa. CONCLUSIONS: Our findings indicate that CaSR may be involved in PCa progression. Impact: Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted.
Cancer Epidemiology Biomarkers & Prevention 11/2012; · 4.12 Impact Factor
-
Andreas Pettersson,
Rebecca E Graff,
Scott R Bauer,
Michael J Pitt,
Rosina T Lis,
Edward C Stack,
Neil E Martin,
Lauren Kunz, Kathryn L Penney,
Azra H Ligon, [......],
Jennifer R Rider,
Christopher Sweeney,
Meir J Stampfer,
Michelangelo Fiorentino,
Philip W Kantoff,
Martin G Sanda,
Edward L Giovannucci,
Eric L Ding,
Massimo Loda,
Lorelei A Mucci
[show abstract]
[hide abstract]
ABSTRACT: Whether the genomic rearrangement transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear.
Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random-effects models to estimate associations between rearrangement status and outcomes.
The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.78-1.26] or lethal disease (HR, 0.93; 95% CI, 0.61-1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis [risk ratio (RR)(≥T3 vs. T2), 1.23; 95% CI, 1.16-1.30) but not with biochemical recurrence (RR, 1.00; 95% CI, 0.86-1.17) or lethal disease (RR, 0.99; 95% CI, 0.47-2.09).
These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy. Impact: This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy. Cancer Epidemiol Biomarkers Prev; 21(9); 1497-509. ©2012 AACR.
Cancer Epidemiology Biomarkers & Prevention 06/2012; 21(9):1497-509. · 4.12 Impact Factor
-
Mara M Epstein,
Ove Andrén,
Julie L Kasperzyk,
Irene M Shui, Kathryn L Penney,
Katja Fall,
Jennifer R Rider,
Meir J Stampfer,
Swen-Olof Andersson,
Edward Giovannucci,
Lorelei A Mucci
[show abstract]
[hide abstract]
ABSTRACT: Recent studies suggest variation in genes along the vitamin D pathway, as well as vitamin D receptor (VDR) protein levels, may be associated with prostate cancer. As serum vitamin D levels vary by season, we sought to determine whether the expression of genes on the vitamin D pathway, assessed in prostate tumor tissue, do the same.
Our study incorporates mRNA expression data from 362 men in the Swedish Watchful Waiting cohort, diagnosed between 1977 and 1999, and 106 men enrolled in the US Physicians' Health Study (PHS) diagnosed between 1983 and 2004. We also assayed for VDR protein expression among 832 men in the PHS and Health Professionals Follow-up Study cohorts. Season was characterized by date of initial tissue specimen collection categorically and by average monthly ultraviolet radiation levels. One-way analysis of variance was used to examine variation in the expression levels of six genes on the vitamin D pathway-VDR, GC, CYP27A1, CYP27B1, RXRα, CYP24A1-and VDR protein by season, adjusted for age at diagnosis and Gleason grade. Variation was also examined separately among lethal and nonlethal cases.
Tumor expression levels of the six genes did not vary significantly by season of tissue collection. No consistent patterns emerged from subgroup analyses by lethal versus nonlethal cases.
Unlike circulating levels of 25(OH) vitamin D, expression levels of genes on the vitamin D pathway and VDR protein did not vary overall by season of tissue collection. Epidemiological analyses of vitamin D gene expression may not be biased by seasonality.
Cancer Causes and Control 06/2012; 23(8):1359-66. · 2.88 Impact Factor
-
Irene M Shui,
Lorelei A Mucci,
Peter Kraft,
Rulla M Tamimi,
Sara Lindstrom, Kathryn L Penney,
Katharina Nimptsch,
Bruce W Hollis,
Natalie Dupre,
Elizabeth A Platz,
Meir J Stampfer,
Edward Giovannucci
[show abstract]
[hide abstract]
ABSTRACT: The association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease.
We assessed prediagnostic 25-hydroxyvitamin D [25(OH)D] levels in plasma, variation in vitamin D-related genes, and risk of lethal prostate cancer using a prospective case-control study nested within the Health Professionals Follow-up Study. We included 1260 men who were diagnosed with prostate cancer after providing a blood sample in 1993-1995 and 1331 control subjects. Men with prostate cancer were followed through March 2011 for lethal outcomes (n = 114). We selected 97 single-nucleotide polymorphisms (SNPs) in genomic regions with high linkage disequilibrium (tagSNPs) to represent common genetic variation among seven vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR). We used a logistic kernel machine test to assess whether multimarker SNP sets in seven vitamin D pathway-related genes were collectively associated with prostate cancer. Tests for statistical significance were two-sided.
Higher 25(OH)D levels were associated with a 57% reduction in the risk of lethal prostate cancer (highest vs lowest quartile: odds ratio = 0.43, 95% confidence interval = 0.24 to 0.76). This finding did not vary by time from blood collection to diagnosis. We found no statistically significant association of plasma 25(OH)D levels with overall prostate cancer. Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer.
In this prospective study, plasma 25(OH)D levels and common variation among several vitamin D-related genes were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer.
CancerSpectrum Knowledge Environment 04/2012; 104(9):690-9. · 14.07 Impact Factor
-
Preet K Dhillon, Kathryn L Penney,
Fredrick Schumacher,
Jennifer R Rider,
Howard D Sesso,
Michael Pollak,
Michelangelo Fiorentino,
Stephen Finn,
Massimo Loda,
Nader Rifai,
Lorelei A Mucci,
Edward Giovannucci,
Meir J Stampfer,
Jing Ma
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin, an insulin-sensitizing adipokine, is inversely associated with adiposity and prostate cancer risk and progression. However, the role of genetic variation in the adiponectin (ADIPOQ) and receptor genes (ADIPOR1/R2) in prostate cancer is largely unknown.
In a nested case-control study of 1,286 cases and 1,267 controls within the Physicians' Health Study, we evaluated 29 common single-nucleotide polymorphisms (SNP) in ADIPOQ (n = 13), ADIPOR1 (n = 5), and ADIPOR2 (n = 11) in relation to the risk of prostate cancer. In subgroups, we also evaluated the association of genotype and circulating adiponectin levels (n = 951) and prostate tumor expression of insulin receptor (IR) and insulin-like growth factor 1 (IGF-IR) receptor (n = 181).
Among the 12 tagging polymorphisms in ADIPOQ, four (rs266729, rs182052, rs822391, and rs2082940) were significantly associated (P < 0.05) with overall prostate cancer risk, with no significant difference by tumor grade or clinical stage. Two of the risk SNPs (rs266729 and rs182052) plus four other SNPs (rs16861209, rs17366568, rs3774261, and rs7639352) were also associated with plasma adiponectin levels, and three of these (rs1686109, rs17366568, and rs3774261) were also significantly associated with IR expression in prostate tumor tissue. One additional SNP was associated with IGFI-R tumor tissue expression (rs16861205). None of the 16 variants in ADIPOR1/R2 were related to cancer risk or circulating adiponectin levels.
Common variants in the adiponectin gene were associated with prostate cancer risk, plasma adiponectin levels, and IR or IGF-IR expression in the prostate tumor. Impact: These genotype-phenotype associations support the biological relevance of adiponectin for prostate carcinogenesis, particularly in earlier stages of development.
Cancer Epidemiology Biomarkers & Prevention 09/2011; 20(12):2618-27. · 4.12 Impact Factor
-
Whitney K Hendrickson,
Richard Flavin,
Julie L Kasperzyk,
Michelangelo Fiorentino,
Fang Fang,
Rosina Lis,
Christopher Fiore, Kathryn L Penney,
Jing Ma,
Philip W Kantoff,
Meir J Stampfer,
Massimo Loda,
Lorelei A Mucci,
Edward Giovannucci
[show abstract]
[hide abstract]
ABSTRACT: Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies.
We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI.
Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression.
High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression.
Journal of Clinical Oncology 06/2011; 29(17):2378-85. · 18.37 Impact Factor
-
Kathryn L Penney,
Jennifer A Sinnott,
Katja Fall,
Yudi Pawitan,
Yujin Hoshida,
Peter Kraft,
Jennifer R Stark,
Michelangelo Fiorentino,
Sven Perner,
Stephen Finn, [......],
Neil Martin,
Philip W Kantoff,
Jan-Erik Johansson,
Hans-Olov Adami,
Mark A Rubin,
Massimo Loda,
Todd R Golub,
Ove Andrén,
Meir J Stampfer,
Lorelei A Mucci
[show abstract]
[hide abstract]
ABSTRACT: Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis.
Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases.
We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006).
Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.
Journal of Clinical Oncology 06/2011; 29(17):2391-6. · 18.37 Impact Factor
-
Irene M Shui,
Jennifer R Stark, Kathryn L Penney,
Fredrick R Schumacher,
Mara M Epstein,
Michael J Pitt,
Meir J Stampfer,
Rulla M Tamimi,
Sara Lindstrom,
Howard D Sesso,
Katja Fall,
Jing Ma,
Peter Kraft,
Edward Giovannucci,
Lorelei A Mucci
[show abstract]
[hide abstract]
ABSTRACT: Common genetic variants in the Toll-like receptor 4 (TLR4), which is involved in inflammation and immune response pathways, may be important for prostate cancer.
In a large nested case-control study of prostate cancer in the Physicians' Health Study (1982-2004), 10 single nucleotide polymorphisms (SNPs) were selected and genotyped to capture common variation within the TLR4 gene as well as 5 kb up and downstream. Unconditional logistic regression was used to assess associations of these SNPs with total prostate cancer incidence, and with prostate cancers defined as advanced stage/lethal (T3/T4, M1/N1(T1-T4), lethal) or high Gleason grade (7 (4 + 3) or greater). Cox-proportional hazards regression was used to assess progression to metastases and death among prostate cancer cases.
The study included 1,267 controls and 1,286 incident prostate cancer cases, including 248 advanced stage/lethal and 306 high grade cases. During a median follow-up of 10.6 years, 183 men died of prostate cancer or developed distant metastases. No statistically significant associations between the TLR4 SNPs were found for total prostate cancer incidence, including SNPs for which an association was reported in other published studies. Additionally, there were no significant associations with TLR4 SNPS and the incidence of advanced stage/lethal, or high grade cancers; nor was there evidence among prostate cancer cases for associations of TLR4 SNPs with progression to prostate cancer specific mortality or bony metastases.
Results from this prospective nested case-control study suggest that genetic variation across TLR4 alone is not strongly associated with prostate cancer risk or mortality.
The Prostate 05/2011; 72(2):209-16. · 3.48 Impact Factor
-
Kathryn L Penney,
Fredrick R Schumacher,
Peter Kraft,
Lorelei A Mucci,
Howard D Sesso,
Jing Ma,
Yuxin Niu,
Jit Kong Cheong,
David J Hunter,
Meir J Stampfer,
Stephen I Hsu
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies have identified genetic markers in kallikrein-related peptidase 3 (KLK3) associated with prostate cancer. However, some of these markers are also associated with prostate-specific antigen (PSA) levels, so it is unclear whether the polymorphisms are causal or if the association with risk is solely due to detection bias through PSA screening. PSA is a biologically active serine protease, cleaving insulin-like growth factor-binding protein. We examined the association of single-nucleotide polymorphisms (SNPs) in KLK3 with prostate cancer risk, disease-specific survival and pre-diagnostic PSA levels in a case-control study nested within the Physicians' Health Study, which began in 1982, with over 27 years of follow-up. We genotyped SNPs spanning the entire KLK3 locus to capture common variation at high resolution. Six polymorphisms were significantly associated with prostate cancer incidence (P < 0.05); the odds ratios per minor allele ranged from 0.88 to 0.73. For four of these, the odds ratios were lower when restricting to cases diagnosed in the pre-PSA screening era (before 1989). The four alleles significantly associated with lower PSA levels were also associated with lower prostate cancer risk. KLK3 variants were not significantly associated with stage at diagnosis, risk of lethal cancer or survival. Our results suggest that detection bias due to the association of KLK3 variants with PSA levels cannot completely explain the association with prostate cancer risk. Understanding the mechanism by which genetic variation in KLK3 affects prostate cancer risk has important implications for study of the biological role of PSA in prostate tumorigenesis.
Carcinogenesis 03/2011; 32(6):853-9. · 5.70 Impact Factor
-
Kathryn L Penney,
Saumyadipta Pyne,
Fredrick R Schumacher,
Jennifer A Sinnott,
Lorelei A Mucci,
Peter L Kraft,
Jing Ma,
William K Oh,
Tobias Kurth,
Philip W Kantoff,
Edward L Giovannucci,
Meir J Stampfer,
David J Hunter,
Matthew L Freedman
[show abstract]
[hide abstract]
ABSTRACT: A pressing clinical issue in prostate cancer is to distinguish which men will have an indolent or aggressive course of disease. Clinical variables such as Gleason grade and stage are useful predictors of lethal cancer; however, the low predictive values of the common Gleason scores, changes in grading over time, and earlier diagnosis of patients due to screening limits their clinical utility. Identifying genetic variants associated with lethal prostate cancer could inform clinical decision making.
We conducted a genome-wide association study, comparing lethal prostate cancer cases to cases surviving at least 10 years beyond their initial diagnosis. Genotyping was done with the Affymetrix 5.0 chip [∼500,000 single nucleotide polymorphisms (SNP) and 1,483 copy number variants (CNV)] on DNA from participants in the Physicians' Health Study and Health Professionals Follow-up Study (196 lethal cases, 368 long-term survivors). After excluding SNPs and individuals based on quality control criteria, logistic regression assuming an additive model was done using the PLINK software.
No SNP reached genome-wide significance (P ≤ 1 × 10(-7)); however, three independent SNPs had P < 1 × 10(-5). One top-ranked SNP replicated (P = 0.05) in an independent follow-up study. Although no CNV had genome-wide significance, 14 CNVs showed nominal association with prostate cancer mortality (P < 0.05).
No variants were significantly associated at a genome-wide level with prostate cancer mortality. Common genetic determinants of lethal prostate cancer are likely to have odds ratios <2.0.
Genetic markers identified could provide biological insight to improve therapy for men with potentially fatal cancer. Larger studies are necessary to detect the genetic causes of prostate cancer mortality.
Cancer Epidemiology Biomarkers & Prevention 10/2010; 19(11):2869-76. · 4.12 Impact Factor
-
Paul L Nguyen,
Jing Ma,
Jorge E Chavarro,
Matthew L Freedman,
Rosina Lis,
Giuseppe Fedele,
Christopher Fiore,
Weiliang Qiu,
Michelangelo Fiorentino,
Stephen Finn, Kathryn L Penney,
Anna Eisenstein,
Fredrick R Schumacher,
Lorelei A Mucci,
Meir J Stampfer,
Edward Giovannucci,
Massimo Loda
[show abstract]
[hide abstract]
ABSTRACT: Fatty acid synthase (FASN) regulates de novo lipogenesis, body weight, and tumor growth. We examined whether common germline single nucleotide polymorphisms (SNPs) in the FASN gene affect prostate cancer (PCa) risk or PCa-specific mortality and whether these effects vary by body mass index (BMI).
In a prospective nested case-control study of 1,331 white patients with PCa and 1,267 age-matched controls, we examined associations of five common SNPs within FASN (and 5 kb upstream/downstream, R(2) > 0.8) with PCa incidence and, among patients, PCa-specific death and tested for an interaction with BMI. Survival analyses were repeated for tumor FASN expression (n = 909).
Four of the five SNPs were associated with lethal PCa. SNP rs1127678 was significantly related to higher BMI and interacted with BMI for both PCa risk (P(interaction) = .004) and PCa mortality (P(interaction) = .056). Among overweight men (BMI > or = 25 kg/m(2)), but not leaner men, the homozygous variant allele carried a relative risk of advanced PCa of 2.49 (95% CI, 1.00 to 6.23) compared with lean men with the wild type. Overweight patients carrying the variant allele had a 2.04 (95% CI, 1.31 to 3.17) times higher risk of PCa mortality. Similarly, overweight patients with elevated tumor FASN expression had a 2.73 (95% CI, 1.05 to 7.08) times higher risk of lethal PCa (P(interaction) = .02).
FASN germline polymorphisms were significantly associated with risk of lethal PCa. Significant interactions of BMI with FASN polymorphisms and FASN tumor expression suggest FASN as a potential link between obesity and poor PCa outcome and raise the possibility that FASN inhibition could reduce PCa-specific mortality, particularly in overweight men.
Journal of Clinical Oncology 09/2010; 28(25):3958-64. · 18.37 Impact Factor
-
Mara S Meyer, Kathryn L Penney,
Jennifer R Stark,
Fredrick R Schumacher,
Howard D Sesso,
Massimo Loda,
Michelangelo Fiorentino,
Stephen Finn,
Richard J Flavin,
Tobias Kurth,
Alkes L Price,
Edward L Giovannucci,
Katja Fall,
Meir J Stampfer,
Jing Ma,
Lorelei A Mucci
[show abstract]
[hide abstract]
ABSTRACT: Variation in genes contributing to the host immune response may mediate the relationship between inflammation and prostate carcinogenesis. RNASEL at chromosome 1q25 encodes ribonuclease L, part of the interferon-mediated immune response to viral infection. We therefore investigated the association between variation in RNASEL and prostate cancer risk and progression in a study of 1286 cases and 1264 controls nested within the prospective Physicians' Health Study. Eleven single-nucleotide polymorphisms (SNPs) were selected using the web-based 'Tagger' in the HapMap CEPH panel (Utah residents of Northern and Western European Ancestry). Unconditional logistic regression models assessed the relationship between each SNP and incident advanced stage (T(3)/T(4), T(0)-T(4)/M(1) and lethal disease) and high Gleason grade (>/=7) prostate cancer. Further analyses were stratified by calendar year of diagnosis. Cox proportional hazards models examined the relationship between genotype and prostate cancer-specific survival. We also explored associations between genotype and serum inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha receptor 2 using linear regression. Individuals homozygous for the variant allele of rs12757998 had an increased risk of prostate cancer [AA versus GG; odds ratio (OR): 1.63, 95% confidence interval (CI): 1.18-2.25), and more specifically, high-grade tumors (OR: 1.90, 95% CI: 1.25-2.89). The same genotype was associated with increased CRP (P = 0.02) and IL-6 (P = 0.05) levels. Missense mutations R462Q and D541E were associated with an increased risk of advanced stage disease only in the pre-prostate-specific antigen era. There were no significant associations with survival. The results of this study support a link between RNASEL and prostate cancer and suggest that the association may be mediated through inflammation. These novel findings warrant replication in future studies.
Carcinogenesis 09/2010; 31(9):1597-603. · 5.70 Impact Factor
-
Mara S. Meyer, Kathryn L. Penney,
Jennifer R. Stark,
Frederick R. Schumacher,
Howard Sesso,
Massimo Loda,
Michelangelo Fiorentino,
Stephen Finn,
Richard J. Flavin,
Tobias Kurth,
Alkes L. Price,
Edward L. Giovannucci,
Katja Fall,
Meir J. Stampfer,
Jing Ma,
Lorelei A. Mucci
Carcinogenesis; a comprehensive survey 09/2010; 31(9):1597-1603.
-
Kathryn L Penney,
Fredrick R Schumacher,
Haojie Li,
Peter Kraft,
J Steven Morris,
Tobias Kurth,
Lorelei A Mucci,
David J Hunter,
Philip W Kantoff,
Meir J Stampfer,
Jing Ma
[show abstract]
[hide abstract]
ABSTRACT: The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency >5%; R(2) > 0.8) within SEP15, as well as rs5859 in the 3' untranslated region, previously reported to reduce the efficiency of selenium incorporation into SEP15. We examined the association of these single-nucleotide polymorphisms with PCa risk and PCa-specific mortality, as well as their interactions with plasma selenium levels, in the Physicians' Health Study. In this nested case-control study (1,286 cases and 1,267 controls), SEP15 polymorphisms were not significantly associated with PCa risk. However, among the cases, three variants were significantly associated with PCa-specific mortality [rs479341 hazard ratio (HR), 1.94; 95% confidence interval (95% CI), 1.15-3.25; rs1407131 HR, 2.85; 95% CI, 1.45-5.59; rs561104 HR, 1.54; 95% CI, 1.12-2.11] with a recessive model. Additionally, rs561104 significantly modified the association of plasma selenium with PCa survival (P(interaction) = 0.02); an inverse relationship of high levels of selenium with PCa mortality was apparent only among those without the increased risk genotype. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype.
Cancer Prevention Research 05/2010; 3(5):604-10. · 4.91 Impact Factor
-
Mark M Pomerantz,
Yashaswi Shrestha,
Richard J Flavin,
Meredith M Regan, Kathryn L Penney,
Lorelei A Mucci,
Meir J Stampfer,
David J Hunter,
Stephen J Chanock,
Eric J Schafer,
Jennifer A Chan,
Josep Tabernero,
José Baselga,
Andrea L Richardson,
Massimo Loda,
William K Oh,
Philip W Kantoff,
William C Hahn,
Matthew L Freedman
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.
PLoS Genetics 01/2010; 6(11):e1001204. · 8.69 Impact Factor
-
Hiroki Yamada, Kathryn L Penney,
Hiroyuki Takahashi,
Takahiko Katoh,
Yuko Yamano,
Minoru Yamakado,
Takahiro Kimura,
Hidetoshi Kuruma,
Yuko Kamata,
Shin Egawa,
Matthew L Freedman
[show abstract]
[hide abstract]
ABSTRACT: Two prostate cancer genome-wide scans in populations of European ancestry identified several genetic variants that are strongly associated with prostate cancer risk. The effect of these risk variants and their cumulative effect in other populations are unknown.
We evaluated the association of 23 risk single-nucleotide polymorphisms (SNPs) with prostate cancer risk and clinical covariates (Gleason score, tumor aggressiveness, and age at diagnosis) in men of Japanese ancestry (311 case subjects and 1035 control subjects) using unconditional logistic regression. We also used logistic regression to test the association between increasing numbers of independently associated risk alleles and the risk of prostate cancer, prostate cancer aggressiveness, and age at diagnosis. All statistical tests were two-sided.
Seven of the 23 SNPs (five independent loci) were associated with prostate cancer risk (P values ranged from .0084 to 2.3 x 10(-8) and effect sizes [estimated as odds ratios, ORs] ranged from 1.35 to 1.82). None of the seven SNPs was associated with Gleason score or aggressive disease. rs6983561 and rs4430796 were associated with age at diagnosis (Ps = .0188 and .0339, respectively). Men with six or more risk alleles (27% of case patients and 11% of control subjects) had a higher risk of prostate cancer than men with two or fewer risk alleles (7% of case patients and 20% of control subjects) (OR = 6.22, P = 1.5 x 10(-12)).
These results highlight the critical importance of considering ancestry in understanding how risk alleles influence disease and suggest that risk estimates and variants differ across populations. It is important to perform studies in multiple ancestral populations so that the composite genetic architecture of prostate cancer can be rigorously addressed.
CancerSpectrum Knowledge Environment 10/2009; 101(19):1330-6. · 14.07 Impact Factor
-
Mark M Pomerantz,
Christine A Beckwith,
Meredith M Regan,
Stacia K Wyman,
Gyorgy Petrovics,
Yongmei Chen,
Dorota J Hawksworth,
Fredrick R Schumacher,
Lorelei Mucci, Kathryn L Penney, [......],
Daniel W Lin,
Michelle Dyke,
Paula Herman,
Steve Lee,
William K Oh,
Philip W Kantoff,
Muneesh Tewari,
David G McLeod,
Shiv Srivastava,
Matthew L Freedman
[show abstract]
[hide abstract]
ABSTRACT: Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in nonprotein coding regions and their mechanism has not been fully elucidated. To further dissect the function of this locus, we tested two hypotheses: (a) unannotated microRNAs (miRNA) are transcribed in the region, and (b) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel miRNAs in histologically normal radical prostatectomy tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 prostatectomy specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk single nucleotide polymorphisms. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus.
Cancer Research 07/2009; 69(13):5568-74. · 7.86 Impact Factor
-
Kathryn L Penney,
Claudia A Salinas,
Mark Pomerantz,
Fredrick R Schumacher,
Christine A Beckwith,
Gwo-Shu Lee,
William K Oh,
Oliver Sartor,
Elaine A Ostrander,
Tobias Kurth,
Jing Ma,
Lorelei Mucci,
Janet L Stanford,
Philip W Kantoff,
David J Hunter,
Meir J Stampfer,
Matthew L Freedman
[show abstract]
[hide abstract]
ABSTRACT: Variants at chromosomal loci 8q24 and 17q are established risk factors for prostate cancer. Many studies have confirmed the findings for risk, but few have examined aggressiveness and other clinical variables in detail. Additionally, Gleason score is typically used as a surrogate for the primary end point of prostate cancer mortality. We investigated whether the 8q24 and 17q risk variants are associated with clinical variables as well as prostate cancer mortality.
In the Physicians' Health Study (1,347 cases and 1,462 controls), the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center; 3,714 cases), and the Fred Hutchinson Cancer Research Center King County Case-Control Studies (1,308 cases and 1,266 controls), we examined eight previously identified 8q24 and 17q risk variants for association with prostate cancer mortality in men of European ancestry. We considered associations with other surrogate markers of prostate cancer aggressiveness, such as Gleason score, pathologic stage, prostate-specific antigen at diagnosis, and age at diagnosis.
Six of the eight variants were confirmed as prostate cancer risk factors. Several variants were nominally associated with age at diagnosis; when totaling all alleles for single nucleotide polymorphisms significantly associated with risk, each additional allele decreased age at diagnosis by an average of 6 months in the Physicians' Health Study (P = 0.0005) and 4 months in the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center) cohort (P = 0.0016). However, there were no statistically significant associations with prostate cancer mortality.
Our results suggest that the 8q24 and 17q prostate cancer risk variants may influence age at diagnosis but not disease aggressiveness.
Clinical Cancer Research 05/2009; 15(9):3223-30. · 7.74 Impact Factor
-
Paul I W de Bakker,
Noël P Burtt,
Robert R Graham,
Candace Guiducci,
Roman Yelensky,
Jared A Drake,
Todd Bersaglieri, Kathryn L Penney,
Johannah Butler,
Stanton Young, [......],
Christopher A Haiman,
Matthew L Freedman,
Xiaofeng Zhu,
Richard Cooper,
Leif Groop,
Laurence N Kolonel,
Brian E Henderson,
Mark J Daly,
Joel N Hirschhorn,
David Altshuler
[show abstract]
[hide abstract]
ABSTRACT: A general question for linkage disequilibrium-based association studies is how power to detect an association is compromised when tag SNPs are chosen from data in one population sample and then deployed in another sample. Specifically, it is important to know how well tags picked from the HapMap DNA samples capture the variation in other samples. To address this, we collected dense data uniformly across the four HapMap population samples and eleven other population samples. We picked tag SNPs using genotype data we collected in the HapMap samples and then evaluated the effective coverage of these tags in comparison to the entire set of common variants observed in the other samples. We simulated case-control association studies in the non-HapMap samples under a disease model of modest risk, and we observed little loss in power. These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world.
Nature Genetics 12/2006; 38(11):1298-303. · 35.53 Impact Factor
