A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region.

Background: Prostate cancer (PRCA) is the most common cancer in males in the western world. In Finland PRCA has an age-adjusted incidence of 81.5 per 100,000.

BRCA2 mutations in 154 finnish male breast cancer patients.

The etiology and pathogenesis of male breast cancer (MBC) are poorly known. This is due to the fact that the disease is rare, and large-scale genetic epidemiologic studies have been difficult to carry out. Here, we studied the frequency of eight recurrent Finnish BRCA2 founder mutations in a large cohort of 154 MBC patients (65% diagnosed in Finland from 1967 to 1996).

Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation.

Background: A distinct clinical syndrome characterized by megalencephaly, mild to moderate cognitive decline, slowly progressive spasticity, ataxia, occasional seizures, and extensive white matter changes with temporal cysts by imaging studies has been described in a particular ethnic group (Agarwals) in India. This disorder is very similar to megalencephalic leukoencephalopathy with subcortical cysts (MLC), a newly characterized leukodystrophy whose molecular basis was recently shown to be mutations in a gene (KIAA0027) that has been renamed MLC1.

Objective: To determine if this disorder among the Agarwals is due to mutations in MLC1 by a mutation screening study conducted on affected Agarwal patients.

Genome-wide scan for linkage in finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25-26.

Background: In order to identify predisposition loci to hereditary prostate cancer (HPC), we performed a genome-wide linkage analysis using samples from a genetically homogeneous population, with 13 Finnish multiplex prostate cancer families.

Methods: Altogether 87 DNA samples were genotyped from 13 families. Logarithm-of-odds (LOD) scores were calculated for all autosomes using FASTLINK and GENEHUNTER designating all unaffected men and all women as unknown.

Genome-wide scanning for linkage in Finnish breast cancer families.

Only a proportion of breast cancer families has germline mutations in the BRCA1 or BRCA2 genes, suggesting the presence of additional susceptibility genes. Finding such genes by linkage analysis has turned out to be difficult due to the genetic heterogeneity of the disease, phenocopies and incomplete penetrance of the mutations. Isolated populations may be helpful in reducing the level of genetic heterogeneity and in providing useful starting points for further genetic analyses.

Androgen receptor gene alterations in Finnish male breast cancer.

Mutations in the androgen receptor (AR) gene have been suggested to predispose to male breast cancer (MBC). Studies on MBC patients have not been based on the mutation screening of the entire coding region of the AR and the number of subjects has been small. Therefore, some AR gene alterations may have remained undetected.

A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes.

Chromosomal region 13q21-q22 harbors a putative breast cancer susceptibility gene and has been implicated as a common site for somatic deletions in a variety of malignant tumors. We have built a complete physical clone contig for a region between D13S1308 and AFM220YE9 based on 18 yeast artificial chromosome and 81 bacterial artificial chromosome (BAC) clones linked together by 22 genetic markers and 61 other sequence tagged sites. Combining data from 47 sequenced BACs (as of June 2001), we have assembled in silico an integrated 5.

Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.

The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.

A genetic epidemiological study of hereditary prostate cancer (HPC) in Finland: frequent HPCX linkage in families with late-onset disease.

Several predisposition loci for hereditary prostate cancer (HPC) have been suggested, including HPC1 at 1q24-q25 (OMIM #601518) and HPCX at Xq27-q28 (OMIM #300147). Genetically homogeneous populations, such as that of Finland, and distinct subsets of families may help to minimize the genetic heterogeneity that complicates the genetic dissection of complex traits. Here, the role of the HPC1, and HPCX loci in a series of Finnish prostate cancer families was studied, especially in subgroups of families defined by age, number of affected cases, and the mode of disease transmission.

Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites.

We have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases.

Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland.

In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors.

Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus.

A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations.

Somatic genetic alterations in BRCA2-associated and sporadic male breast cancer.

The genetic changes underlying the development and progression of male breast cancer are poorly understood. Germline BRCA2 mutations account for a significant part of male breast cancer, but the majority of patients lack a known inherited predisposition. We recently demonstrated that the progression of breast cancer in female carriers of a germline BRCA1 or BRCA2 mutation follows specific genetic pathways, distinct from each other and from sporadic breast cancer.

Evidence for a prostate cancer susceptibility locus on the X chromosome.

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref.

Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes.

One hundred breast and breast-ovarian cancer families identified at the Helsinki University Central Hospital in southern Finland and previously screened for mutations in the BRCA2 gene were now analyzed for mutations in the BRCA1 gene. The coding region and splice boundaries of BRCA1 were analyzed by protein truncation test (PTT) and heteroduplex analysis (HA)/SSCP in all 100 families, and 70 were also screened by direct sequencing. Contrary to expectations based on Finnish population history and strong founder effects in several monogenic diseases in Finland, a wide spectrum of BRCA1 and BRCA2 mutations was found.

Localization of the Rev-ErbA orphan receptors in the brain.

In the present study, we report the localization of the Rev-ErbA alpha and beta nuclear orphan receptors, two closely related members of the nuclear hormone receptor superfamily, in the brain. Both Rev-ErbA variant mRNAs were highly expressed in the olfactory bulb, the hippocampus, and in the granular cells of the cerebellum, areas enriched also in other nuclear orphan receptors. Furthermore, the alpha-isoform was found in high amounts in the frontal cortex, the superficial gray layer of the superior colliculus, and the stria terminalis.

Cytochrome P4502D4 in the brain: specific neuronal regulation by clozapine and toluene.

Twenty-four hr after a single dose of the neuroleptic drug clozapine, cytochrome P4502D4 (P4502D4) immunoreactivity, which was barely detectable in the brains of untreated rats, was clearly evident in neurons of the substantia nigra pars compacta, ventral tegmental area, granular neurons of the olfactory bulb, and Purkinje and granular neurons of the cerebellum. Induction was maintained with daily administration for 3 weeks. The mRNA for P4502D4 was detected by Northern blotting and localized by in situ hybridization in neurons throughout the brain and in the Bergman glia in the cerebellum.

Detection of germline BRCA1 mutations in breast cancer patients by quantitative messenger RNA in situ hybridization.

Mutations in the breast cancer susceptibility gene 1 (BRCA1) may account for one half of all familial breast cancers. Because of the wide spectrum of different germline mutations, identification of BRCA1 mutation carriers using current techniques is laborious and difficult. The majority of the identified mutations, however, lead to aberrant expression of the gene product in tumor tissue, potentially allowing the detection of BRCA1-linked breast cancers using simple histochemical techniques.

Localization and ontogeny of the orphan receptor OR-1 in the rat brain.

This study describes the expression of the OR-1 orphan receptor in embryonic, postnatal, and adult brain tissue studied by in situ hybridization. This newly characterized member of the nuclear receptor superfamily functions as a modulator of retinoic acid and thyroid hormone signalling by influencing gene activation by these hormones from a distinct promoter region. In the fetal brain OR-1 mRNA was observed from E13-E16 in the developing pons, tegmentum, pontine flexure, medulla, inferior and superior colliculi, cerebellum, hippocampus, thalamus, striatum, and cortical plate.

The dioxin receptor and its nuclear translocator (Arnt) in the rat brain.

Dioxins are environmental pollutants, whose detrimental effects on health are the cause of wide public concern due to their accumulation in the food chain and resistance to metabolism. The most well known dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dioxins exert their effects through a ligand activated transcription factor termed the dioxin or aryl hydrocarbon receptor (Ahr), which acts in concert with another structurally related protein: the aryl hydrocarbon nuclear translocator (Arnt).

Localization of the peroxisome proliferator-activated receptor in the brain.

This paper describes the localization of the alpha-type peroxisome proliferator-activated receptor (PPAR alpha) in the rat brain using immunocytochemistry and in situ hybridization. Expression of PPAR alpha mRNA was highest in the granular cells of the cerebellar cortex and in the dentate gyrus, with a somewhat lower expression in areas CA1-CA4 of the hippocampus. PPAR alpha mRNA was also found in some neurones of the cerebral cortex (layers II-IV) and the molecular layer of the cerebellar cortex, and in the olfactory tubercle.

Identification of a novel member of the nuclear receptor superfamily which is closely related to Rev-ErbA.

Degenerate PCR primers were designed based upon conserved regions within the DNA and ligand binding domains of several nuclear receptors. PCR was performed using these primers starting with total brain cDNA. Several members of the nuclear receptor superfamily were identified, one of which was novel, but showing a high degree of homology to the previously known orphan receptor Rev-ErbA.

Induction of multiple immediate early genes in rat hypothalamic paraventricular nucleus after stress.

We have previously demonstrated that stress causes a rapid and transient elevation in the expression of the immediate early genes (IEGs) c-fos and the members of the jun gene family in the brain. Here we demonstrate the effect of stress on the expression of fra-1, fra-2 and recently characterized IEGs encoding zinc finger containing proteins. Capsaicin-induced stress caused a rapid and transient induction of NGFI-A, NGFI-B, fra-2 and TIS11 in the hypothalamic paraventricular nucleus.