Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24.

BACKGROUND: Family-based linkage studies, association studies, and studies of tumors have highlighted human chromosome 8q as a genomic region of interest for prostate cancer susceptibility loci. Recently, a locus at 8q24, characterized by both a single nucleotide polymorphism (SNP) and a microsatellite marker, was shown to be associated with prostate cancer risk in Icelandic, Swedish, and U.S. samples. Although the data were provocative, the U.S. samples were not population based, which precludes assessment of the potential contribution of this locus to prostate cancer incidence in the United States. METHODS: We analyzed both markers in a population-based, case-control study of middle-aged men from King County, Washington. RESULTS: Overall, there was a significant positive association between the A allele of the SNP rs1447295 and prostate cancer risk [odds ratio, 1.4; 95% confidence interval (95% CI), 1.1-2.0] but no significant association with the microsatellite DG8S737. However, significant associations were observed for both markers in men with high Gleason scores. Adjusting for age, first-degree family history of prostate cancer, and prostate cancer screening history, the adjusted odds ratios were 1.4 (95% CI, 1.1-1.8) for the A allele of the SNP and 1.9 (95% CI, 1.2-2.8) for the -10 allele of the microsatellite. CONCLUSIONS: These data suggest that the locus on chromosome 8q24 harbors a genetic variant associated with prostate cancer and that the microsatellite marker is a stronger risk factor for aggressive prostate cancers defined by poorly differentiated tumor morphology.

Serologic evidence of human papillomavirus 16 and 18 infections and risk of prostate cancer.

Human papillomavirus (HPV) subtypes 16 and 18 are sexually transmitted and have been associated with an increased incidence of several anogenital tumors. Although previous epidemiological studies have suggested that sexual behaviors such as an early age at first intercourse and larger numbers of sexual partners are also related to an increased risk of prostate cancer, seroepidemiological studies of these infectious agents in relation to prostate cancer have produced differing results. To further evaluate this potential relationship, we completed a population-based control study in King County, Washington. Middle-aged (40-64 years) men diagnosed with prostate cancer (n = 642) were ascertained through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry between January 1993 and December 1996. Controls (n = 570) of similar age were selected from the same population as the cases by random digit dialing. Overall, there was no association between serological evidence of prior HPV-16 (adjusted odds ratio, 1.06; 95% confidence interval, 0.71-1.57) or HPV-18 (adjusted odds ratio, 1.36; 95% confidence interval, 0.69-2.69) infection and the risk of prostate cancer. Analyses of clinical features demonstrated no relationship between HPV infection status and Gleason score, stage of disease, or a combined measure of disease aggressiveness. Our findings indicate that HPV-16 and HPV-18 are not associated with prostate cancer risk.

Association of HPC2/ELAC2 polymorphisms with risk of prostate cancer in a population-based study.

Genetic polymorphism in HPC2/ELAC2 was recently associated with risk of sporadic prostate cancer. To determine the contribution of two HPC2/ELAC2 missense variants (Ser217Leu and Ala541Thr) to the risk of developing prostate cancer, we conducted a population-based case-control study of middle-aged men (40-64 years). Cases (n=591) were ascertained from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results Cancer Registry and Controls (n=538) from the same general population were identified through random-digit dialing. Subjects were residents of King County, Washington, and were frequency matched on age. Cases (32%) had a slightly higher frequency of the Leu217 variant compared with controls (29%), but there were no differences in the frequency of the Thr541 allele (4%). When considering joint genotypes, white men homozygous for the Leu217 variant on an Ala541/Ala541 background had an increased risk of prostate cancer [odds ratio (OR)=1.84; 95% confidence interval (CI), 1.11-3.06]. Different risk profiles were also observed when cases were stratified by disease aggressiveness. Men with at least one Leu217 allele had an elevated risk (OR=1.34; 95% CI, 1.02-1.76) of less aggressive prostate cancer (localized stage and Gleason score < or = 7), with a stronger association among men with two Leu217 alleles (OR=1.73; 95% CI, 1.08-2.77). The Ala541Thr polymorphism was not associated with risk, and neither variant was associated with more aggressive prostate cancer phenotypes. We estimate that the Ser217Leu genotype may account for approximately 14% of less aggressive prostate cancer cases and 9% of all sporadic cases in the general United States population of white men

A polymorphism in the CYP17 gene and risk of prostate cancer.

Steroid hormones are important in the etiology and progression of prostate cancer, and expression of genes involved in hormone production may alter susceptibility. One such gene is CYP17, which encodes the cytochrome P450c17a enzyme responsible for the biosynthesis of testosterone. A T to C transition (A2 allele) in the 5' promoter region of the gene is hypothesized to increase the rate of gene transcription, increase androgen production, and thereby increase risk of prostate cancer. To test this hypothesis, germ-line DNA samples from a large population-based study of incident prostate cancer cases (n = 590) and controls (n = 538) of similar age without the disease were genotyped. The frequency of the A2 allele was similar in cases and controls. Compared with men with the A1/A1 genotype, the adjusted odds ratio was 0.81 for the A1/A2 and 0.87 for the A2/A2 genotype. Risk estimates did not vary substantially by age or race. However, stratification by family history of prostate cancer revealed that among white men with an affected first-degree relative, homozygotes for the A2 allele had a significant elevation in risk (odds ratio = 19.2; 95% confidence interval, 2.2-157.4) compared with men who were homozygous for the A1 allele (interaction P = 0.0005). These results suggest that the CYP17 A2/A2 genotype predicts susceptibility to prostate cancer in white men with a family history of the disease. It is also possible that CYP17 interacts with other genes that influence risk of familial prostate cancer.

BRCA1 and BRCA2 mutations in women from Shanghai China.

Little is known about the frequency of germ-line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 among Asian populations. We investigated the distribution of BRCA1 and BRCA2 germ-line mutations and polymorphisms in a cohort of women from Shanghai, China. Study subjects totaled 1306, and included 645 women with breast cancer, 342 women with benign breast disease, and 319 unaffected controls, born between 1924 and 1958, selected from women enrolled in a randomized trial of Breast Self-Examination in Shanghai, China. Women were selected without regard to family history of breast or ovarian cancer. All of the coding regions and exon-intron boundaries were screened. Data were analyzed with respect to age at diagnosis, and family history of breast and ovarian cancer. The prevalence of known disease-associated mutations in women with breast cancer was 1.1% each, for BRCA1 and BRCA2. Among breast cancer cases with a family history of breast or ovarian cancer, 8.1% and 2.7% carried likely BRCA1 and BRCA2 disease-associated mutations, respectively. Overall, these results suggest that inherited susceptibility to breast cancer due to germ-line BRCA1/2 mutations among women with a family history of breast cancer is comparable between women from Shanghai and Caucasian women of Western European descent. Most alterations observed appear unique to the Chinese population, suggesting a resource that will be useful for assessing risk among both Chinese women and United States women of Chinese descent.

Suggestive genetic linkage to chromosome 11p11.2-q12.2 in hereditary prostate cancer families with primary kidney cancer.

BACKGROUND: The Seattle-based PROGRESS study was started in 1995 to ascertain hereditary prostate cancer (HPC) families for studies of genetic susceptibility. Subsequent studies by several research groups, including our own, suggest that HPC is a genetically heterogeneous disease. To be successful in mapping loci for such a complex disease, one must consider ways of grouping families into subsets that likely share the same genetic origin. Towards that end, we analyzed a genome-wide scan of HPC families with primary kidney cancer. METHODS: An 8.1 cM genome-wide scan including 441 microsatellite markers was analyzed by both parametric and non-parametric linkage approaches in fifteen HPC families with the co-occurrence of kidney cancer. RESULTS: There was no evidence for significant linkage in the initial findings. However, two regions of suggestive linkage were observed at 11q12 and 4q21, with HLOD scores of 2.59 and 2.10, respectively. The primary result on chromosome 11 was strengthened after excluding two families with members who had rare transitional cell carcinoma (TCC). Specifically, we observed a non-parametric Kong and Cox P-value of 0.004 for marker D11S1290 at 11p11.2. The 8 cM region between 11p11.2 and 11q12.2 was refined by the addition of 16 new markers. The subset of HPC families with a median age of diagnosis >65 years demonstrated the strongest evidence for linkage, with an HLOD = 2.50. The P-values associated with non-parametric analysis ranged from 0.004 to 0.05 across five contiguous markers. CONCLUSIONS: Analysis of HPC families with members diagnosed with primary renal cell carcinoma demonstrates suggestive linkage to chromosome 11p11.2-q12.2.

IGF-I and IGFBP-3 polymorphisms and risk of prostate cancer.

BACKGROUND: Insulin-like growth factor-I (IGF-I) is a potent mitogen for both normal and malignant prostate epithelial cells. The majority of circulating IGF-I is bound in a complex with IGF binding protein-3 (IGFBP-3), which in turn limits IGF-I bioavailability. Multiple studies suggest that higher IGF-I and/or lower IGFBP-3 serum levels are positively associated with prostate cancer risk. Several polymorphisms within the IGF-I and IGFBP-3 coding regions have been associated with increased serum protein levels. METHODS: To ascertain the potential relationship between serum levels and polymorphism, and prostate cancer risk, we investigated the role of two polymorphisms the IGF-I cytosine-adenosine (CA)-repeat and the IGFBP-3 Ala32Gly, and prostate cancer in a population-based, case-control, study of middle-aged men. RESULTS: We found no significant association between the IGFBP-3 Ala32Gly polymorphism and prostate cancer risk, even though the presence of at least one Gly allele did correlate with increased serum levels of IGFBP-3. For IGF-I, more controls (42%) than cases (38%) were homozygous for 19-CA-repeats (odds ratio, OR = 0.85; 95% confidence interval (CI) = 0.66-1.09). After stratifying by disease characteristics, 19-CA-repeat homozygous men displayed a decreased risk of low-grade disease (OR = 0.50; 95% CI = 0.27-0.93), but no associations were observed with more aggressive features of disease. Additionally, there was no correlation between mean serum IGF-I protein levels and IGF-I genotype in controls. CONCLUSIONS: Further evaluation of the IGF-I CA-repeat polymorphism and prostate cancer is necessary to determine if the modest risk reduction associated with the 19-CA-repeat homozygous state is observed in other study populations.

Vitamin D receptor gene polymorphisms and prostate cancer risk.

BACKGROUND: Vitamin D is a steroid hormone that is thought to play a role in the etiology and progression of prostate cancer. Hormone activity requires binding to the vitamin D receptor (VDR), which contains several genetic polymorphisms that have been associated with risk of prostate cancer. To further evaluate this relationship, we conducted a population-based case-control study of the VDR BsmI, FokI, and Poly-A polymorphisms, and prostate cancer. METHODS: Germline DNA samples and survey data from incident prostate cancer cases (n = 559) and controls (n = 523) of similar age (40-64 years) without a history of the disease who resided in King County, Washington were analyzed. RESULTS: The frequency of the BsmI, FokI, and Poly-A genotypes were similar in cases and controls, and no overall association between any variants and prostate cancer risk were noted. Stratification by clinical features of disease revealed that among men with localized stage disease, the BsmI bb genotype was associated with a modest increase in risk (OR, 1.49; 95% CI, 1.02-2.17; P = 0.04) compared to the BB genotype. CONCLUSIONS: These results suggest that polymorphisms in the VDR gene are not strong predictors of prostate cancer risk among Caucasian men in the U.S.

Genomic scan of 254 hereditary prostate cancer families.

Hereditary prostate cancer (HPC) is a genetically heterogeneous disease, complicating efforts to map and clone susceptibility loci. We have used stratification of a large dataset of 254 HPC families in an effort to improve power to detect HPC loci and to understand what types of family features may improve locus identification. The strongest result is that of a dominant locus at 6p22.3 (heterogeneity LOD (HLOD) = 2.51), the evidence for which is increased by consideration of the age of PC onset (HLOD = 3.43 in 214 families with median age-of-onset 56-72 years) and co-occurrence of primary brain cancer (HLOD = 2.34 in 21 families) in the families. Additional regions for which we observe modest evidence for linkage include chromosome 7q and 17p. Only weak evidence of several previously implicated HPC regions is detected. These analyses support the existence of multiple HPC loci, whose presence may be best identified by analyses of large, including pooled, datasets which consider locus heterogeneity.