Tommi Kainu

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 annually1. 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. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, θ=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.

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. Immunocytochemistry revealed nuclear PPAR alpha-immunoreactivity (-IR) in the same areas as seen with the in situ hybridization. Furthermore, PPAR alpha-IR was also localized in oligodendrocytes, whereas the other glial cell types appeared to lack PPAR alpha. These results suggest that peroxisome proliferators and chemicals acting similarly have effects on discrete populations of neurones. The presence of PPAR alpha in oligodendrocytes lends further support to the suggestion that peroxisomes are important in the assembly and degradation of myelin.

Fos and jun in rat central amygdaloid nucleus and paraventricular nucleus after stress

The present paper describes the effect of capsaicin-induced stressful stimulus on the expression of immediate early genes (IEGs) c-fos, c-jun, junB and junD in the hypothalamic paraventricular nucleus (PVN) and the central amygdaloid nucleus (ACe) using in situ hybridization. Stress caused an intense expression of c-fos, c-jun and junB especially in the PVN and ACe and also a clear induction of junD was observed in the PVN. This suggests that the PVN and the ACe are two major targets of stress in the brain. The intense expression of the IEGs in the ACe and PVN suggests that stress may affect neurotransmitter gene expression through Fos and Jun proteins in both these nuclei.

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. The NGFI-A mRNA levels were also slightly increased in the cerebral cortex and striatum. The expression of fra-1, NGFI-C, egr-3 and Nurr1 did not show any change. The time course of the induction of NGFI-A, NGFI-B, fra-2 and TIS11 was similar to that previously observed with c-fos and the members of the jun family. The present results suggest that NGFI-A, NGFI-B, fra-2 and TIS11 mediate some of the stress-induced changes of the PVN at the level of gene expression. Although the genes of the NGFI/egr family encode structurally similar proteins, they seem to be regulated differentially and thus have diverse roles in regulating gene expression in the brain.

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. In the present study, we performed a genome‐wide survey by comparative genomic hybridization (CGH) of somatic genetic aberrations in 26 male breast cancers, including five tumors from BRCA2 mutation carriers. BRCA2 tumors exhibited a significantly higher number of chromosomal aberrations than sporadic tumors. The most common alterations in sporadic male breast cancer were +1q (38%), +8q (33%), +17q (33%), –13q (29%), and –8p (24%). In tumors from BRCA2 mutation carriers, the five most common genetic changes were +8q (100%), +20q (100%), +17q (80%), –13q (80%), and –6q (60%). The CGH results in these two groups of male breast cancers are almost identical to those identified in the corresponding sporadic and BRCA2‐associated female breast cancers. The results suggest that despite substantial hormonal differences between females and males, similar genetic changes are selected for during tumor progression. Furthermore, the presence of a highly penetrant germline BRCA2 mutation apparently leads to a characteristic somatic tumor progression pathway, again shared between affected male and female mutation carriers. Genes Chromosomes Cancer 24:56–61, 1999.

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.

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). In the present study, we have employed in situ hybridization to study the localization of the mRNAs for these two proteins in the rat brain. We found mRNAs for both Ahr and Arnt predominantly in the same neuronal populations: in the olfactory bulb, the hippocampus, and the cerebral and cerebellar cortices. Arnt, however, had a more widespread expression than Ahr in the brain. The present results demonstrate that dioxins may act directly in the brain and that the effects of dioxin may occur in discrete neuronal populations. However, in some parts of the brain, e.g. the hypothalamus, that are thought to be targets of the toxic effects of dioxins, we did not observe detectable levels of Ahr mRNA. Furthermore, it appears that Arnt may have additional functions in the brain, apart from being the heterodimerization partner of Ahr, possibly through heterodimerizing with other transcription factors.

Evidence for a Prostate Cancer Susceptibility Locus on the X Chromosome

Jianfeng Xu1*, Deborah Meyers1, Diha Freije2, Sarah Isaacs2, Kathy Wiley2, Deborah Nusskern2, Charles Ewing2, Eric Wilkens2, Piroska Bujnovszky2, G. Steven Bova2,3, Patrick Walsh2 & William Isaacs2,4 (Group 1) Johanna Schleutker5*, Mika Matikainen5*, Teuvo Tammela5, Tapio Visakorpi5 & Olli-P. Kallioniemi12 (Group 2) Rebecca Berry6*, Daniel Schaid7*, Amy French6, Shannon McDonnell7, Jennifer Schroeder6, Michael Blute8 & Stephen Thibodeau6 (Group 3) Henrik Gronberg9*, Monika Emanuelsson9, Jan-Erik Damber10, Anders Bergh11 & Bjorn-Anders Jonsson11 (Group 4) Jeffrey Smith12*, Joan Bailey-Wilson12, John Carpten12, Dietrich Stephan12, Elizabeth Gillanders12, Isaac Amundson12, Tommi Kainu12, Diana Freas-Lutz12, Agnes Baffoe-Bonnie13, Anne Van Aucken12, Raman Sood12, Francis Collins12, Michael Brownstein12 & Jeffrey Trent12 (Group 5) *These authors contributed equally to this work.

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. In the present study, we have comprehensively screened the entire coding region of the AR gene for mutations and also studied the role of AR CAG and GGC repeat lengths as risk factors for MBC in a cohort of 32 Finnish MBC patients. To estimate the possible involvement of the prostate cancer predisposing AR Arg726Leu germ-line mutation in MBC, this mutation was tested in 117 MBC patients. No germ-line mutations were found and the CAG and GGC repeat lengths were similar among MBC cases as among Scandinavian population. Our data indicate that the AR gene does not substantially contribute to MBC predisposition.

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 byin 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. At E18, OR-1 was expressed in the hippocampus, cerebellum, ventricular layer of the developing cortex and cortical plate, striatum, and olfactory bulb. In the E21 to early postnatal brain the highest expression of OR-1 mRNA was seen in the hippocampus, cerebellum, striatum, and olfactory bulb. The expression of OR-1 in the cerebellum increased during postnatal development and by d P21 OR-1 mRNA had reached the levels present in the adult in the cerebellar cortex. In the adult brain the highest expression of OR-1 mRNA was observed in the Ca1 area of the hippocampus and the cerebellar cortex. We conclude that OR-1 is widely expressed in the fetal brain, whereas in the postnatal and adult brains OR-1 mRNA is more discretely localized, and that the amount of OR-1 mRNA increases in the cerebellum during postnatal development. The results of this study suggest that, in the fetal brain, OR-1 has a spatially widespread role in modulating gene activation by retinoids and thyroid hormone, whereas in the adult brain this modulation occurs only in distinct neuronal populations.