Michelle Guy

Multiple newly identified loci associated with prostate cancer susceptibility

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at ≤60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 × 10−8 to P = 8.7 × 10−29). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.

Multiple Loci With Different Cancer Specificities Within the 8q24 Gene Desert

Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.

Multiple loci on 8q24 associated with prostate cancer susceptibility

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 × 10−8; rs620861: OR = 0.90, P = 4.8 × 10−8). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.

Germline BRCA Mutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer

PURPOSE To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes. PATIENTS AND METHODS This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1). RESULTS PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup. CONCLUSION Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.

Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue

Purpose: Vitamin D seems to exert a protective effect against common cancers, although this does not correlate with circulating levels of active 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], indicating a more localized activation of vitamin D. The aim of this study was to investigate the significance of this in breast cancer. Experimental Design: Quantitative reverse transcription-PCR analysis of mRNA expression was carried out for the vitamin D–activating enzyme 1α-hydroxylase, the catabolic enzyme 24-hydroxylase, and the vitamin D receptor in 41 tumors and paired nonneoplastic tissue as well as breast cancer cell lines. Immunohistochemistry was used to assess 1α-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism. Results: Expression of mRNA for 1α-hydroxylase (27-fold; P < 5 × 10−11), vitamin D receptor (7-fold; P < 1.5 × 10−8), and 24-hydroxylase (4-fold; P < 0.02) was higher in breast tumors. 1α-Hydroxylase enzyme activity was also higher in tumors (44.3 ± 11.4 versus 12.4 ± 4.8 fmol/h/mg protein in nonneoplastic tissue; P < 0.05). However, production of inactive 1,24,25-trihydroxyvitamin D3 was also significantly higher in tumors (84.8 ± 11.7 versus 33.6 ± 8.5 fmol/h/mg protein; P < 0.01). Antisense inhibition of 24-hydroxylase in vitro increased antiproliferative responses to 1,25(OH)2D3. Conclusion: These data indicate that the vitamin D–activating enzyme 1α-hydroxylase is up-regulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH)2D3 production in tumors by catalyzing catabolism to less active vitamin D metabolites. The enzymes involved in autocrine metabolism of vitamin D in breast tissue may therefore provide important targets for both the prevention and treatment of breast cancer.

BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients

Background:A family history of prostate cancer (PrCa) is a strong risk factor for the disease, indicating that inherited factors are important in this disease. We previously estimated that about 2% of PrCa cases diagnosed ⩽55 years harbour a BRCA2 mutation and PrCa among BRCA2 carriers has been shown to be more aggressive, with poorer survival.Methods:To further evaluate the role of BRCA2 in PrCa predisposition, we screened 1864 men with PrCa aged between 36 and 88 years. We analysed the BRCA2 gene using a novel high-throughput multiplex fluorescence heteroduplex detection system developed for the ABI3130xl genetic analyzer.Results:We identified 19 protein-truncating mutations, 3 in-frame deletions and 69 missense variants of uncertain significance (UV) in our sample set. All the carriers of truncating mutations developed PrCa at ⩽65 years, with a prevalence of BRCA2 mutation of 1.20% for cases in this age group.Conclusion:Based on the estimated frequency of BRCA2 mutations in the United Kingdom we estimate that germline mutations in the BRCA2 gene confer an ∼8.6-fold increased risk of PrCa by age 65, corresponding to an absolute risk of ∼15% by age 65. These results suggest that routine testing of early onset PrCa cases for germline BRCA2 mutations will further help to refine the prevalence and risk associated with BRCA2 mutations and may be useful for guiding management options.

Genome-wide association study identifies new prostate cancer susceptibility loci

Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.

Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2052–61)

Vitamin D Receptor Gene Polymorphisms and Breast Cancer Risk

Purpose: The steroid hormone 1,25-dihydroxyvitamin D3 is thought to protect against breast cancer. The actions of 1,25-dihydroxyvitamin D3 are mediated via the vitamin D receptor (VDR), and a number of polymorphisms in the VDR gene have been identified. These result in distinct genotypes, some of which may alter susceptibility to breast cancer. We have investigated whether specific VDR gene polymorphisms are associated with breast cancer risk in a United Kingdom Caucasian population. Experimental Design: In a retrospective case-control study, female breast cancer patients (n = 398) and control women (n = 427) were recruited, and three VDR polymorphisms were determined. Results: The 3′ VDR polymorphisms BsmI and variable-length poly(adenylate) sequence were both significantly associated with breast cancer risk; odds ratios (adjusted for age menopausal status and hormone replacement therapy usage) for bb genotype versus BB genotype = 1.92 (95% confidence interval, 1.20–3.10; P < 0.01) and for LL versus SS = 1.94 (95% confidence interval, 1.20–3.14; P < 0.01). A 5′ VDR gene variant, FokI, was not associated with breast cancer risk when analyzed in isolation (P > 0.05). However, FokI did modulate the increased risk associated with the bb/LL genotype such that possession of one or more F alleles together with the bb/LL genotype augmented breast cancer risk. Furthermore, the highest proportion of bb and FFLL/FfLL genotypes occurred in women with metastatic breast cancer. Conclusions: VDR polymorphisms are associated with breast cancer risk and may be associated with disease progression. Additional investigations into how different genotypes may affect the functional mechanisms of the VDR will provide a better strategy for identifying women at risk of breast cancer and for developing improved treatments.

The genetic epidemiology of prostate cancer and its clinical implications

Worldwide, familial and epidemiological studies have generated considerable evidence of an inherited component to prostate cancer. Indeed, rare highly penetrant genetic mutations have been implicated. Genome-wide association studies (GWAS) have also identified 76 susceptibility loci associated with prostate cancer risk, which occur commonly but are of low penetrance. However, these mutations interact multiplicatively, which can result in substantially increased risk. Currently, approximately 30% of the familial risk is due to such variants. Evaluating the functional aspects of these variants would contribute to our understanding of prostate cancer aetiology and would enable population risk stratification for screening. Furthermore, understanding the genetic risks of prostate cancer might inform predictions of treatment responses and toxicities, with the goal of personalized therapy. However, risk modelling and clinical translational research are needed before we can translate risk profiles generated from these variants into use in the clinical setting for targeted screening and treatment.