Search PubMed⌕ Search

Biomedical subjects

O P Kallioniemi

Publications and source records attributed to O P Kallioniemi.

At least 55 records · Page 3Linked to original sources
PubMed1999

Reduced Fhit expression in sporadic and BRCA2-linked breast carcinomas.

Evidence for alteration of the FHIT gene in a significant fraction of breast carcinomas has been reported, in apparent concordance with loss of heterozygosity (LOH) at chromosome region 3p14.2 in breast cancer and benign proliferative breast disease. A significantly higher frequency of LOH at the FHIT locus was reported for BRCA2-/- tumors, possibly due to misrepaired double-strand breaks at this common fragile region. To determine whether such genomic alterations lead to Fhit inactivation, we have assessed the level of Fhit expression by immunohistochemical detection in sporadic tumors and cancers occurring in BRCA2 999del5 carriers. To determine whether Fhit inactivation may have prognostic significance, we have also assessed expression of breast cancer markers and clinical features in sporadic tumors relative to Fhit expression. Of 40 consecutive sporadic breast carcinomas studied for tumor markers, 50% showed reduced Fhit expression. In these sporadic cancers, loss of Fhit expression was not correlated significantly with the presence or absence of other tumor markers. In a study of 58 sporadic and 34 BRCA2 999del5 Icelandic invasive cancers, there was a significant association of LOH at 3p14.2 with reduced expression of Fhit (P = 0.001); also the lower expression of Fhit and higher LOH at 3p14.2 in BRCA2 999del5 tumors relative to sporadic cancers was significant (P = 0.002). Thus, genetic alteration at the fragile site within the FHIT gene leads to loss of Fhit protein in a significant fraction of sporadic breast cancers and a much larger fraction of familial breast cancers with an inherited BRCA2 mutation, consistent with the idea that loss of BRCA2 function affects stability of the FHIT/FRA3B locus.

Acid Anhydride Hydrolases↗
PubMed1999

Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays.

Prostate cancer development and progression is driven by the accumulation of genetic changes, the nature of which remains incompletely understood To facilitate high-throughput analysis of molecular events taking place in primary, recurrent, and metastat prostate cancer, we constructed a tissue microarray containing small 0.6-mm cylindrical samples acquired from 371 formalin-fixed blocks, including benign prostatic hyperplasia (n = 32) and primary tumors (n = 223), as well as both locally recurrent tumors (n = 54) and metastases (n = 62) from patients with hormone-refractory disease. Fluorescence in situ hybridization (FISH) was applied to the analysis of consecutive tissue microarray sections with probes for five different genes. High-level (> or =3X) amplifications were very rare (<2%) in primary prostate cancers However, in metastases from patients with hormone-refractory disease, amplification of the androgen receptor gene was seen in 22%, MYC in 11%, and Cyclin-D1 in 5% of the cases. In specimens from locally recurrent tumors, the corresponding percentages were 23, 4, and 8%. ERBB2 and NMYC amplifications were never detected at any stage of prostate cancer progression. In conclusion, FISH to tissue microarray sections enables high-throughput analysis of genetic alterations contributing to cancer development and progression. Our results implicate a role for amplification of androgen receptor in hormonal therapy failure and that of MYC in the metastatic progression of human prostate cancer.

Cyclin D1↗
PubMed1999

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.

BRCA2 Protein↗
PubMed1999

High-throughput tissue microarray analysis to evaluate genes uncovered by cDNA microarray screening in renal cell carcinoma.

Many genes and signaling pathways are involved in renal cell carcinoma (RCC) development. However, genetic tumor markers have not gained use in RCC diagnostics and prognosis prediction. Identification and evaluation of new molecular parameters are of utmost importance in cancer research and cancer treatment. Here we present a novel approach to rapidly identify clinically relevant molecular changes in cancer. To identify genes with relevance to RCC, a cDNA array analysis was first performed on 5184 cDNA clones on a filter to screen for genes with differential expression between the renal cancer cell line CRL-1933 and normal kidney tissue. There were 89 differentially expressed genes in the cancer cell line, one of them coding for vimentin, a cytoplasmic intermediate filament. In a second step, a renal cancer tissue microarray containing 532 RCC specimen was used to determine vimentin expression by immunohistochemistry. Vimentin expression was seen frequently in clear cell (51%) and papillary RCC (61%), but rarely in chromophobe RCC (4%) and oncocytomas (12%). Furthermore, vimentin expression was significantly associated with poor patient prognosis (P < 0.007) independent of grade and stage. These results obtained from minute arrayed tumor samples match well with previous findings on vimentin expression in renal tumors. It is concluded that the combination of tumor arrays and cDNA arrays is a powerful approach to rapidly identify and further evaluate genes that play a role in tumor biology.

Carcinoma, Renal Cell↗
PubMed1999

Molecular cytogenetic analysis of 11 new breast cancer cell lines.

We describe a survey of genetic changes by comparative genomic hybridization (CGH) in 11 human breast cancer cell lines recently established in our laboratory. The most common gains took place at 8q (73%), 1 q (64%), 7q (64%), 3q (45%) and 7p (45%), whereas losses were most frequent at Xp (54%), 8p (45%), 18q (45%) and Xq (45%). Many of the cell lines displayed prominent, localized DNA amplifications by CGH. One-third of these loci affected breast cancer oncogenes, whose amplifications were validated with specific probes: 17q12 (two cell lines with ERBB2 amplifications), 11q13 (two with cyclin-D1), 8p11-p12 (two with FGFR1) and 10q25 (one with FGFR2). Gains and amplifications affecting 8q were the most common genetic alterations in these cell lines with the minimal, common region of involvement at 8q22-q23. No high-level MYC (at 8q24) amplifications were found in any of the cell lines. Two-thirds of the amplification sites took place at loci not associated with established oncogenes, such as 1q41-q43, 7q21-q22, 7q31, 8q23, 9p21-p23, 11p12-p14, 15q12-q14, 16q13-q21, 17q23, 20p11-p12 and 20q13. Several of these locations have not been previously reported and may harbour important genes whose amplification is selected for during cancer development. In summary, this set of breast cancer cell lines displaying prominent DNA amplifications should facilitate discovery and functional analysis of genes and signal transduction pathways contributing to breast cancer development.

Breast Neoplasms↗
PubMed1999

Inferring tree models for oncogenesis from comparative genome hybridization data.

Comparative genome hybridization (CGH) is a laboratory method to measure gains and losses of chromosomal regions in tumor cells. It is believed that DNA gains and losses in tumor cells do not occur entirely at random, but partly through some flow of causality. Models that relate tumor progression to the occurrence of DNA gains and losses could be very useful in hunting cancer genes and in cancer diagnosis. We lay some mathematical foundations for inferring a model of tumor progression from a CGH data set. We consider a class of tree models that are more general than a path model that has been developed for colorectal cancer. We derive a tree model inference algorithm based on the idea of a maximum-weight branching in a graph, and we show that under plausible assumptions our algorithm infers the correct tree. We have implemented our methods in software, and we illustrate with a CGH data set for renal cancer.

Chromosome Aberrations↗
PubMed1999

Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16.

To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, a panel of 60 tumors (39 carcinomas and 21 adenomas) were screened for loss of heterozygosity. Although the vast majority of loss of heterozygosity (LOH) were detected in the carcinomas and involved chromosomes 2, 4, 11, and 18, only few were found in the adenomas. Therefore, 2 loci that harbor the familial cancer syndromes Carney complex in 2p16 and the multiple endocrine neoplasia type 1 gene in 11q13 were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-centimorgan region, which is separate from the Carney complex locus. LOH for a microsatellite marker (PYGM), very close to the MEN1 gene, was detected in all 8 informative carcinomas (100%) and in 2 of 14 adenomas. Of the 27 cases analyzed in detail, 13 cases (11 carcinomas and 2 adenomas) showed LOH on chromosome 11 and was therefore selected for MEN1 gene mutation analysis. In 6 cases a common polymorphism (Asp418Asp) was found, but no mutation was detected. In conclusion, our data indicate the existence of tumor suppressor genes at multiple chromosomal locations, whose inactivations are involved in the development of adrenocortical carcinomas. Loss of genetic material from 2p16 was strongly associated with the malignant phenotype, as it was seen in almost all carcinomas but not in any of the adenomas. LOH in 11q13 also occurred frequently in the carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome.

Adenoma↗
PubMed1999

Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families.

Positive family history is a significant risk factor for prostate cancer. Improved knowledge of the epidemiology and molecular basis of hereditary prostate cancer has led to a need for counseling and clinical follow-up for men with a positive family history of prostate cancer. However, very little information is available on the efficacy of early screening procedures, such as serum prostate-specific antigen (PSA) measurements, in the management of genetically predisposed, high-risk individuals. In a nationwide study, we obtained family histories from 2099 Finnish prostate cancer patients and identified 302 families with two or more affected cases. Here, 209 asymptomatic 45-75-year-old males from these families were included in a study to determine the frequency of serum PSA positivity and the prevalence of subclinical prostate cancers. Serum PSA was elevated in 21 (10.0%) of these high-risk individuals. Seven prostate cancers (3.3%) and two high-grade prostatic intraepithelial neoplasia lesions were diagnosed, with three cancers occurring in men ages < or = 59 years. Men from prostate cancer families with an average age of onset of < 60 years had a significantly higher frequency of PSA positivity (28.6%, P = 0.01) as well as cancers (14.3%, P = 0.02) than those with a later age of onset. The results suggest that prostate cancer development in genetically predisposed individuals is preceded by a subclinical period when PSA detection is possible. Serum PSA screening may be particularly useful in men with a family history of early-onset prostate cancer.

Adenocarcinoma↗
PubMed1999

Tissue microarrays for gene amplification surveys in many different tumor types.

Gene amplifications are common in many different tumor types and may confer diagnostic, prognostic, or therapeutic information for patient management. Tedious experiments are often required to determine which tumor types have amplifications of a specific oncogene. To facilitate rapid screening for molecular alterations in many different malignancies, a tissue microarray consisting of samples from 17 different tumor types was generated. Altogether, 397 individual tumors were arrayed in a single paraffin block. To determine whether results from the literature can be reproduced on minute tissue samples (diameter, 0.6 mm), amplification of three extensively studied oncogenes (CCND1, CMYC, and ERBB2) was analyzed in three fluorescence in situ hybridization experiments from consecutive sections cut from the tissue microarray. Amplification of CCND1 was found in breast, lung, head and neck, and bladder cancer, as well as in melanoma. ERBB2 was amplified in bladder, breast, colon, stomach, testis, and lung cancer. CMYC was amplified in breast, colon, kidney, lung, ovary, bladder, head and neck, and endometrial cancer. These results confirm and even extend existing data in the literature on such amplifications. In summary, we applied three fluorescence in situ hybridization experiments to analyze amplifications of three oncogenes in three x 397 tumors within a week. This demonstrates the power of using minute arrayed tissue specimens for tumor screening.

Cyclin D1↗
PubMed1999

Androgen receptor gene alterations and chromosomal gains and losses in prostate carcinomas appearing during finasteride treatment for benign prostatic hyperplasia.

Finasteride is commonly used for the treatment of benign prostatic hyperplasia and has been suggested to prevent prostate cancer development. To gain insight to the molecular effects of finasteride on prostate cancer development, we studied six prostate cancers diagnosed during finasteride treatment for benign prostatic hyperplasia. Comparative genomic hybridization detected genetic alterations in four tumors (1-5 changes/tumor). Xq gains and 6q losses were the most common alterations. The recurrent Xq gains motivated us to study the involvement of the androgen receptor (AR) gene. One tumor with Xq gain had a 3-fold amplification of the AR gene, suggesting that tumor development in finasteride-treated patients may require increased AR copy number and expression, as has previously been shown for prostate cancers recurring during hormonal therapy. Furthermore, in another tumor, an Arg726Leu mutation of the AR gene was found. This mutation was also present in the germ-line DNA of the patient. Arg726Leu mutation has previously been reported to affect the transactivational properties of the AR. In summary, prostate cancers developing during finasteride therapy may have distinct biological properties, such as a low number of chromosomal alterations and frequent involvement of the AR gene. Further studies are needed to explore the role of germ-line AR mutations in these patients.

Chromosome Aberrations↗
PubMed1999

[Identification of prognostic parameters for renal cell carcinoma by cDNA arrays and cell chips].

We report here an example of how the combined application of cDNA and tumor array can lead to the identification of a novel prognostic marker within a very short time. A cDNA array analysis was performed on 5184 cDNA clones on a filter to screen for genes with differential expression between the renal cancer cell line CRL-1933 and normal kidney tissue to identify genes with relevance in RCC. There were 89 differentially expressed genes in the cancer cell line, one of them coding for vimentin, a cytoplasmic intermediate filament. To determine the in vivo prevalence and prognostic significance of vimentin expression, a renal cancer tissue micro array containing 532 RCC specimen was constructed and vimentin expression was determined by immunohistochemistry. Vimentin expression was frequently seen in clear-cell (51%) and papillary RCC (61%), but rarely in chromophobe RCC (4%) and oncocytomas (12%). These results obtained from minute arrayed tumor samples match with previous findings on vimentin expression in renal tumors. Furthermore, vimentin expression was significantly associated with poor patient prognosis (p < 0.007) independently of grade and stage. These results suggest that tissue microarray analysis provides a rapid and powerful method to determine the prevalence and prognostic significance of novel candidate genes discovered to be involved in cancer development with large-scale cDNA expression arrays. The tissue array can be adapted as a routine tool in research laboratories for analyses of large tumor series at the DNA, RNA or protein level. With such a tool, cancer researchers can study vast numbers of tumor samples in a short time and can generate a wealth of data on the application of tumor markers.

Biomarkers, Tumor↗
PubMed1998

Positional cloning of ZNF217 and NABC1: genes amplified at 20q13.2 and overexpressed in breast carcinoma.

We report here the molecular cloning of an approximately 1-Mb region of recurrent amplification at 20q13.2 in breast cancer and other tumors and the delineation of a 260-kb common region of amplification. Analysis of the 1-Mb region produced evidence for five genes, ZNF217, ZNF218, and NABC1, PIC1L (PIC1-like), CYP24, and a pseudogene CRP (Cyclophillin Related Pseudogene). ZNF217 and NABC1 emerged as strong candidate oncogenes and were characterized in detail. NABC1 is predicted to encode a 585-aa protein of unknown function and is overexpressed in most but not all breast cancer cell lines in which it was amplified. ZNF217 is centrally located in the 260-kb common region of amplification, transcribed in multiple normal tissues, and overexpressed in all cell lines and tumors in which it is amplified and in two in which it is not. ZNF217 is predicted to encode alternately spliced, Kruppel-like transcription factors of 1,062 and 1,108 aa, each having a DNA-binding domain (eight C2H2 zinc fingers) and a proline-rich transcription activation domain.

Amino Acid Sequence↗
PubMed1998

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. 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, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant 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.

Adult↗
PubMed1998

Tissue microarrays for high-throughput molecular profiling of tumor specimens.

Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes. These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray. Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors.

Animals↗
PubMed1998

Molecular cytogenetic mapping of 24 CEPH YACs and 24 gene-specific large insert probes to chromosome 17.

Defining boundaries of chromosomal rearrangements at the molecular level would benefit from landmarks that link the cytogenetic map to physical, genetic, and transcript maps, as well as from large-insert FISH probes for such loci to detect numerical and structural rearrangements in metaphase or interphase cells. Here, we determined the locations of 24 genetically mapped CEPH-Mega YACs along the FLpter scale (fractional length from p-telomere) by quantitative fluorescence in situ hybridization analysis. This generated a set of cytogenetically mapped probes for chromosome 17 with an average spacing of about 5 cM. We then developed large-insert YAC, BAC, PAC, or P1 clones to the following 24 known genes, and determined refined map locations along the same FLpter scale: pter-TP53-TOP3-cen-TNFAIP1-ERBB2-TOP2A- BRCA1-TCF11-NME1-HLF-ZNF147/CL N80-BCL5/MPO/SFRS1-TBX2-PECAM1-DDX5/ PRKCA-ICAM2-GH1/PRKAR1A-GRB2-CDK3 /FKHL13-qter. Taken together, these 48 cytogenetically mapped large-insert probes provide tools for the molecular analysis of chromosome 17 rearrangements, such as mapping amplification, deletion, and translocation breakpoints in this chromosome, in cancer and other diseases.

Chromosome Mapping↗
PubMed1998

Androgen receptor gene and hormonal therapy failure of prostate cancer.

Androgen receptor (AR) is a nuclear transcription factor that binds male sex steroids and mediates the biological effects of these hormones to the target cells, such as the epithelial cells of the prostate gland, by activating transcription of androgen-dependent genes. Withdrawal of androgens or the peripheral blockade of androgen action remain the critical therapeutic options for the treatment of advanced prostate cancer. However, after initial regression, many prostate cancers become hormone refractory and progress further with eventual fatal outcome. Understanding the mechanisms of tumor progression and endocrine therapy failure is an important goal. A large number of different molecular mechanisms may be responsible for development of hormone-refractory recurrent tumors. Many of these involve the AR gene and its complex downstream signaling pathways. The role of AR mutations and altered transactivational properties of the receptor have received the most attention as causative factors for progression. However, other mechanisms, such as AR gene amplification and overexpression or increased local bioconversion of androgens, may contribute to the development of progression by mechanisms that involve androgen-dependent cell growth. Here we review the role of the AR gene and its putative downstream effector pathways during human prostate cancer progression and endocrine therapy failure.

Genetic Therapy↗
PubMed1998

Molecular cytogenetics of primary breast cancer by CGH.

Comparative genomic hybridization (CGH) reveals DNA sequence copy number changes that are shared among the different cell subpopulations present in a tumor and may help to delineate the average progression pathways of breast cancer. Previous CGH studies of breast cancer have concentrated on selected subgroups of breast cancer. Here, 55 unselected primary breast carcinomas were analyzed using optimized quality-controlled CGH procedures. Gains of 1q (67%) and 8q (49%) were the most frequent aberrations. Other recurrent gains were found at 33 chromosomal regions, with 16p, 5p12-14, 19q, 11q13-14, 17q12, 17q22-24, 19p, and 20q13 being most often (> 18%) involved. Losses found in > 18% of the tumors involved 8p, 16q, 13q, 17p, 9p, Xq, 6q, 11q, and 18q. The total number of aberrations per tumor was highest in poorly differentiated (P = 0.01) and in DNA aneuploid (P = 0.05) tumors. The high frequency of 1q gains and presence of +1q as the sole abnormality suggest that it is an early genetic event. In contrast, gains of 8q were most common in genetically and phenotypically advanced breast cancers. The vast majority of breast cancers (80%) have gains of 1q, 8q, or both, and 3 changes (+1q, +8q, or -13q) account for 91% of the tumors. In conclusion, CGH results indicate that certain chromosomal imbalances are very often selected for, sometimes in a preferential order, during the progression of breast cancer. Further studies of such common changes may form the basis for a molecular cytogenetic classification of breast cancer.

Adult↗