Telomere length as a risk factor for hereditary prostate cancer.

Background: Telomeres are repetitive nucleotide sequences that stabilize the ends of chromosomes. Critically short telomeres are thought to contribute to cancer development by increasing chromosomal instability. We hypothesized that shorter leukocyte telomere length, a surrogate for inherited prostate cell telomere length, would be associated with increased risk of prostate cancer in hereditary prostate cancer (HPC) families.

Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.

NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.

Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease.

Background: One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer.

Evidence for a general cancer susceptibility locus at 3p24 in families with hereditary prostate cancer.

To identify genes that generally increase the risk of cancer, we performed a systematic search throughout the genome in 188 families primarily ascertained for prostate cancer but which also included individuals with other cancers. We observed significant evidence for linkage between susceptibility to all cancers and markers at 3p24, with a peak HLOD of 3.08 (P=0.

Interaction effect of PTEN and CDKN1B chromosomal regions on prostate cancer linkage.

The tumor suppressor functions of PTEN and CDKN1B have been extensively characterized. Recent data from mouse models suggest that, for some organs, the combined action of both PTEN and CDKN1B has a stronger tumor suppressor function than each alone; for the prostate, heterozygous knockout of both genes leads to 100% penetrance for prostate cancer. To assess whether such an interaction contributes to an increased risk of prostate cancer in humans, we performed a series of epistatic PTEN and CDKN1B interaction analyses in a collection of 188 high-risk hereditary prostate cancer families.

A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer.

The loss of cell cycle control is believed to be an important mechanism in the promotion of carcinogenesis. CDKN1B (p27) belongs to the Cip/Kip family and functions as an important cell cycle gatekeeper. Several lines of evidence from clinical studies and laboratory experiments demonstrate that CDKN1B is an important tumor suppressor gene in prostate cancer etiology.

Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families.

Background: Although the subject of intensive study, the genetic influences responsible for familial clustering of prostate cancer remain largely unidentified. Genome-wide scans for linkage in prostate cancer families can be used to systematically search for genes capable of affecting risk for the disease.

Methods: All available family members from 188 families, each having at least three first-degree relatives affected with prostate cancer, were genotyped at 406 markers distributed across the genome at average intervals of less than 10 cM.

Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study.

A gene or genes on chromosome 8p22-23 have been implicated in prostate carcinogenesis by the observation of frequent deletions of this region in prostate cancer cells. More recently, two genetic linkage studies in hereditary prostate cancer (HPC) families suggest that germline variation in a gene in this region may influence prostate cancer susceptibility as well. DLC1 (deleted in liver cancer), a gene in this interval, has been proposed as a candidate tumor suppressor gene because of its homology (86% similarity) with rat p122 RhoGAP, which catalyzes the conversion of active GTP-bound rho complex to the inactive GDP-bound form, and thus suppresses Ras-mediated oncogenic transformation.

Polymorphisms in the CYP1A1 gene are associated with prostate cancer risk.

CYP1A1 is likely to play an important role in the etiology of CaP through its function in activating environmental procarcinogens and catalyzing the oxidative metabolites of estrogens. To test the hypothesis that genetic polymorphisms in the CYP1A1 gene may be associated with the risk for CaP, we compared the allele, genotype and haplotype frequencies of 3 SNPs (3801T>C, 2455A>G and 2453C>A) of CYP1A1 among 159 HPC probands, 245 sporadic CaP cases and 222 unaffected men. Two SNPs (3801T>C and 2455A>G) were each individually associated with CaP risk when the allele and genotype frequencies were compared between CaP patients and unaffected controls.

Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate cancer risk.

The enzyme alpha-methylacyl-CoA racemase (AMACR) plays an important role in peroxisomal beta-oxidation of branched-chain fatty acid and therefore is relevant to carcinogenesis. The involvement of AMACR in prostate cancer (CaP) is implicated by the recent observation that expression of AMACR is consistently and extensively up-regulated in CaP. This observation is of particular interest, given previous findings from epidemiological studies that red meat and dairy products, major sources of branched-chain fatty acid, are associated with CaP risk and from linkage studies that the AMACR gene region at 5p13 is linked to a CaP susceptibility gene.

Sequence variants in the human 25-hydroxyvitamin D3 1-alpha-hydroxylase (CYP27B1) gene are not associated with prostate cancer risk.

Background: 1,25-dihydroxyvitamin D(3) has been shown to have antiproliferative properties on normal and neoplastic prostatic cells. 25-hydroxyvitamin D(3) 1-alpha-hydroxylase, the enzyme that catalyzes the final step of vitamin D synthesis, converting 25-hydroxyvitamin D(3) to 1,25-dihydroxyvitamin D(3), is expressed in the prostate.

Methods: The human 25-hydroxyvitamin D(3) 1-alpha-hydroxylase gene (CYP27B1) was resequenced in a case/control panel consisting of 64 individuals (48 Caucasians and 16 African Americans), with equal numbers of hereditary prostate cancer cases, sporadic cases, and unaffected controls.

Associations between hOGG1 sequence variants and prostate cancer susceptibility.

8-Hydroxyguanine is a mutagenic base lesion produced by reactive oxygen species. The hOGG1 gene encodes a DNA glycosylase/AP lyase that can suppress the mutagenic effects of 8-hydroxyguanine by catalyzing its removal from oxidized DNA. A population-based (245 cases and 222 controls) and family-based (159 hereditary prostate cancer families) association study was performed to test the hypothesis that sequence variants of hOGG1 increase susceptibility to prostate cancer.

Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk.

Androgen receptor (AR) has long been hypothesized to play an important role in prostate cancer etiology. Two trinucleotide repeat polymorphisms (CAG and GGC repeats in exon 1 of the AR gene) have been investigated as risk factors for prostate cancer in several studies. However, the results are inconclusive, probably because of the variations of study designs, characteristics of study samples, and choices of analytical methods.

Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility.

3beta-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3'-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing.