Biomedical subjects

O P Kallioniemi

Publications and source records attributed to O P Kallioniemi.

At least 19 recordsLinked to original sources

PubMed2001

Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas-a possible mechanism for altering the nm23-H1 activity.

PRUNE, the human homologue of the Drosophila gene, is located in 1q21.3, a region highly amplified in human sarcomas, malignant tumours of mesenchymal origin. Prune protein interacts with the metastasis suppressor nm23-H1, but shows impaired affinity towards the nm23-H1 S120G mutant associated with advanced neuroblastoma. Based on these observations, we previously suggested that prune may act as a negative regulator of nm23-H1 activity. We found amplification of PRUNE in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant fibrous histiocytomas (MFH) as well as in the less malignant liposarcomas. PRUNE amplification was generally accompanied by high mRNA and moderate to high protein levels. The sarcoma samples expressed nm23-H1 mostly at low or moderate levels, whereas mRNA and protein levels were moderate to high in breast carcinomas. For the more aggressive sarcoma subtypes, 9/13 patients with PRUNE amplification developed metastases. A similar situation was observed in all breast carcinomas with amplification of PRUNE. Infection of NIH3T3 cells with a PRUNE recombinant retrovirus increased cell proliferation. Possibly, amplification and overexpression of PRUNE has the same effect in the tumours. We suggest that amplification and overexpression of PRUNE could be a mechanism for inhibition of nm23-H1 activity that affect the development or progression of these tumours.

3T3 Cells↗

PubMed2001

Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling.

Androgen deprivation therapy for advanced prostate cancer is often effective, but not curative. Molecular pathways mediating the therapeutic response and those contributing to the subsequent hormone-refractory cell growth remain poorly understood. Here, cDNA microarray analysis of human CWR22 prostate cancer xenografts during the course of androgen deprivation therapy revealed distinct global gene expression profiles in primary, regressing and recurrent tumors. Elucidation of the genes involved in the transition between these states implicated specific molecular mechanisms in therapy failure and tumor progression. First, we identified a set of androgen-responsive genes whose expression decreased during the therapy response, but was then systematically restored in the recurrent tumors. In addition, altered expression of genes that encode known targets of rapamycin or that converge on the PI3K/AKT/FRAP pathway was observed in the recurrent tumors. Further suggestion for the involvement of these genes in hormone-refractory prostate cancer came from the observation that cells established from the recurrent xenografts were strongly inhibited in vitro by rapamycin. The results of this functional genomic analysis suggest that the combined effect of re-expression of androgen-responsive genes as well as the activation of rapamycin-sensitive signaling may drive prostate cancer progression, and contribute to the failure of androgen-deprivation therapy.

Algorithms↗

PubMed2001

Tissue microarrays (TMAs) for high-throughput molecular pathology research.

A rapidly increasing number of genes are being suspected to play a role in cancer biology. To evaluate the clinical significance of newly detected potential cancer genes, it is usually required to examine a high number of well-characterized primary tumors. Using traditional methods of molecular pathology, this is a time consuming endeavor rapidly exhausting precious tissue resources. To allow for a high throughput tissue analysis we have developed a "tissue chip" approach (Kononen et al., Nat. Med. 1998;4:844-7). Using this tissue microarray (TMA) technology, samples from up to 1,000 different tumors are arrayed in one recipient paraffin block, sections of which can be used for all kind of in situ analyses. Section from TMA blocks can then be utilized for the simultaneous analysis of up to 1,000 different tumors on the DNA, RNA or protein level. TMAs allow a high throughput molecular analysis of thousands of tumors within a few hours. All currently available data have suggested that minute arrayed tissue specimens are highly representative of their donor tissues. There are multiple different types of TMAs that can be utilized in cancer research including multi tumor arrays (containing different tumor types), tumor progression arrays (tumors of different stages) and prognostic arrays (tumors with clinical endpoints). The combination of multiple different TMAs allows a very quick but comprehensive characterization of biomarkers of interest. We anticipate that the use of TMAs will greatly accelerate the transition of basic research findings to clinical applications.

Humans↗

PubMed2001

ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer.

The ELAC2/HPC2 gene at 17p11 is the first candidate gene identified for human prostate cancer (PRCA) based on linkage analysis and positional cloning (S. V. Tavtigian et al. Nat. Genet., 27:172-180, 2001). A truncating mutation was found in one hereditary prostate cancer (HPC) family, whereas two missense variants, Ser217Leu and Ala541Thr, were reported to be associated with increased PRCA risk in the general population. Here, we screened for mutations of the ELAC2/HPC2 gene in 66 Finnish HPC families. Several sequence variants, including a new exonic variant (Glu622Val) were found, but none of the mutations were truncating. We then analyzed the frequency of the three found missense variants in 1365 individuals, including hereditary (n = 107) and unselected (n = 467) PRCA, benign prostatic hyperplasia (n = 223), and population controls (568 healthy male blood donors). Ser217Leu and Ala541Thr variants carried no significantly elevated risk for HPC or PRCA, although the latter variant was associated with benign prostatic hyperplasia. The previously undescribed Glu622Val variant had a 1.0% population prevalence, but a significantly higher frequency in PRCA cases (3.0% odds ratio, 2.94; 95% confidence interval, 1.05-8.23). We conclude that ELAC2/HPC2 truncating mutations are rare in HPC, but that rare variants of the ELAC2/HPC2 require additional study as risk factors for PRCA in the general population.

Aged↗

PubMed2001

A missense substitution A49T in the steroid 5-alpha-reductase gene (SRD5A2) is not associated with prostate cancer in Finland.

Prostatic steroid 5-alpha-reductase gene (SRD5A2) encodes a critical enzyme involved in the conversion of testosterone to dihydrotestosterone. A germline mis-sense substitution (A49T) leads to a variant SRD5A2 protein, which has a 5-fold higher in vitro V(max)than the wild-type protein (Ross et al, 1998; Makridakis et al, 1999). The A49T variant was recently associated with 2.5 to 3.28-fold increased risk of prostate cancer (PC) in African-American and Hispanic men (Makridakis et al, 1999). Also, Jaffe et al (2000) reported an association between A49T and more aggressive disease among Caucasian patients. Here, we report that the prevalence of the A49T variant in 449 Finnish PC patients was 6.0%, not significantly different from 6.3% observed in 223 patients with benign prostatic hyperplasia or 5.8% in 588 population-based controls (odds ratio for PC 1.04, 95% C.I. 0.62-1.76, P = 0.89). There was no association between A49T and the family history of the patients nor with tumour stage or grade. Our results argue against a prominent role of the A49T variant as a genetic risk factor for prostate cancer development and progression in the Finnish population.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2001

ANX7, a candidate tumor suppressor gene for prostate cancer.

The ANX7 gene is located on human chromosome 10q21, a site long hypothesized to harbor a tumor suppressor gene(s) (TSG) associated with prostate and other cancers. To test whether ANX7 might be a candidate TSG, we examined the ANX7-dependent suppression of human tumor cell growth, stage-specific ANX7 expression in 301 prostate specimens on a prostate tissue microarray, and loss of heterozygosity (LOH) of microsatellite markers at or near the ANX7 locus. Here we report that human tumor cell proliferation and colony formation are markedly reduced when the wild-type ANX7 gene is transfected into two prostate tumor cell lines, LNCaP and DU145. Consistently, analysis of ANX7 protein expression in human prostate tumor microarrays reveals a significantly higher rate of loss of ANX7 expression in metastatic and local recurrences of hormone refractory prostate cancer as compared with primary tumors (P = 0.0001). Using four microsatellite markers at or near the ANX7 locus, and laser capture microdissected tumor cells, 35% of the 20 primary prostate tumors show LOH. The microsatellite marker closest to the ANX7 locus showed the highest rate of LOH, including one homozygous deletion. We conclude that the ANX7 gene exhibits many biological and genetic properties expected of a TSG and may play a role in prostate cancer progression.

Annexin A7↗

PubMed2001

Gene-expression profiles in hereditary breast cancer.

BACKGROUND: Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles. METHODS: RNA from samples of primary tumor from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype. RESULTS: Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations. CONCLUSIONS: Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cancer.

Algorithms↗

PubMed2001

Genetic changes in familial prostate cancer by comparative genomic hybridization.

BACKGROUND: Germline mutations in recessive cancer predisposition genes are uncovered by somatic genetic deletions during tumor development. Analysis of genetic changes in tumor tissues from patients with an inherited predisposition may therefore highlight regions of the genome containing susceptibility or modifier genes. Our aim was to characterize genetic changes in familial prostate cancer METHODS: Twenty-one primary prostate cancers from 19 Finnish prostate cancer families were analyzed for somatic genetic changes by comparative genomic hybridization (CGH). RESULTS: The average number of genetic alterations per tumor was 4.0 +/- 1.9, distributed equally among losses and gains. The most common losses were found at chromosomal regions 13q14-q22 (29%), 8p12-pter (24%), and 6q13-q16 (14%), and the most common gains at 19p (25%), 19q (14%) and 7q (14%). CONCLUSIONS: These results suggest that prostate cancers in genetically predisposed individuals arise for the most part through similar somatic genetic progression pathways as sporadic prostate cancers. This also implies that the biological properties of tumors from the two groups may not be different from one another.

Aged↗

PubMed2001

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.

Breast Neoplasms↗

PubMed2001

From chromosomal alterations to target genes for therapy: integrating cytogenetic and functional genomic views of the breast cancer genome.

A vast number of recurrent chromosomal alterations have been implicated in cancer development and progression. However, most of the genes involved in recurrent chromosomal alterations in solid tumors remain unknown, despite the recent substantial progress in genomic research and availability of high-throughput technologies. For example, it is now possible to quickly identify large numbers of differentially expressed genes in cancer specimens using cDNA microarrays. Integration of this "functional genomic view" of the cancer genome with the "cytogenetic view" could lead to the identification of genes playing a critical role in cancer development and progression. In this review, we illustrate how the combination of three different microarray technologies, cDNA, CGH, and tissue microarrays, makes it possible to directly identify genes involved in chromosomal rearrangements in cell line model systems and then rapidly explore their significance as potential diagnostic and therapeutic targets in human primary breast cancer progression.

Breast Neoplasms↗

PubMed2001

Tissue microarrays for rapid linking of molecular changes to clinical endpoints.

Advances in genomics and proteomics are dramatically increasing the need to evaluate large numbers of molecular targets for their diagnostic, predictive or prognostic value in clinical oncology. Conventional molecular pathology techniques are often tedious, time-consuming, and require a lot of tissue, thereby limiting both the number of tissues and the number of targets that can be evaluated. Here, we demonstrate the power of our recently described tissue microarray (TMA) technology in analyzing prognostic markers in a series of 553 breast carcinomas. Four independent TMAs were constructed by acquiring 0.6 mm biopsies from one central and from three peripheral regions of each of the formalin-fixed paraffin embedded tumors. Immunostaining of TMA sections and conventional "large" sections were performed for two well- established prognostic markers, estrogen receptor (ER) and progesterone receptor (PR), as well as for p53, another frequently examined protein for which the data on prognostic utility in breast cancer are less unequivocal. Compared with conventional large section analysis, a single sample from each tumor identified about 95% of the information for ER, 75 to 81% for PR, and 70 to 74% for p53. However, all 12 TMA analyses (three antibodies on four different arrays) yielded as significant or more significant associations with tumor-specific survival than large section analyses (p < 0.0015 for each of the 12 comparisons). A single sample from each tumor was sufficient to identify associations between molecular alterations and clinical outcome. It is concluded that, contrary to expectations, tissue heterogeneity did not negatively influence the predictive power of the TMA results. TMA technology will be of substantial value in rapidly translating genomic and proteomics information to clinical applications.

Adult↗

PubMed2001

Relatives of prostate cancer patients have an increased risk of prostate and stomach cancers: a population-based, cancer registry study in Finland.

OBJECTIVE: Five to ten percent of prostate cancers may be caused by inherited genetic defects. In order to explore the nature of inherited cancer risks in the genetically homogeneous Finnish population, we investigated the incidence of prostate cancer and other cancers in first-degree relatives of prostate cancer patients by linking the population-based parish records on relatives with the Finnish Cancer Registry (FCR) data. METHODS: The study population was composed of first-degree relatives of two groups of prostate cancer patients diagnosed in Finland during 1988-1993: (1) all early-onset (<60 years) patients (n = 557) from the entire country, (2) a sample (n = 989) of prostate cancer patients diagnosed at an age of > 60 years. A total of 11,427 first-degree relatives were identified through parish records, and their cancer incidence was determined based on a total of 299,970 person-years. Standardized incidence ratios (SIR) were calculated based on expected cancer rates in the general population. RESULTS: The SIR of prostate cancer was increased in both Cohort 1 (2.5, 95% CI 1.9-3.2) and Cohort 2 (1.7, 95% CI 1.4 2.1). The risk of prostate cancer was high for relatives of patients diagnosed at an early age, and then leveled off for patients in the median age of prostate cancer diagnosis (70-79 years). However, the prostate cancer risk for relatives of patients diagnosed > or = 80 years was again statistically significantly elevated (SIR 1.8, 95% CI 1.3-2.6), suggesting a contribution of genetic factors to prostate cancer also at a late age of onset. Gastric cancer was the only other cancer type with a significantly elevated risk among the relatives. Increased risk of gastric cancer was seen only in male relatives of prostate cancer patients diagnosed at an early age, with the highest risk detected for the male relatives of prostate cancer patients diagnosed at an age of 55 years or less (SIR 5.0, 95% CI 2.8-8.2). CONCLUSIONS: Our population-based study indicates that hereditary factors may play an important role in the development of prostate cancer among the relatives of men diagnosed both at younger and older ages. This finding is relevant in the context of our observations that HPCX (hereditary prostate cancer susceptibility locus on Xq27-28) linkage in Finland is found exclusively among families with late age of onset. The association of gastric cancer with prostate cancer has not been reported previously, and may reflect the effects of a novel predisposition locus, which increases the risk to both of these common tumor types.

Adult↗

PubMed2001

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 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.

Breast Neoplasms↗

PubMed2001

Tissue microarray technology for high-throughput molecular profiling of cancer.

Tissue microarray (TMA) technology allows rapid visualization of molecular targets in thousands of tissue specimens at a time, either at the DNA, RNA or protein level. The technique facilitates rapid translation of molecular discoveries to clinical applications. By revealing the cellular localization, prevalence and clinical significance of candidate genes, TMAs are ideally suitable for genomics-based diagnostic and drug target discovery. TMAs have a number of advantages compared with conventional techniques. The speed of molecular analyses is increased by more than 100-fold, precious tissues are not destroyed and a very large number of molecular targets can be analyzed from consecutive TMA sections. The ability to study archival tissue specimens is an important advantage as such specimens are usually not applicable in other high-throughput genomic and proteomic surveys. Construction and analysis of TMAs can be automated, increasing the throughput even further. Most of the applications of the TMA technology have come from the field of cancer research. Examples include analysis of the frequency of molecular alterations in large tumor materials, exploration of tumor progression, identification of predictive or prognostic factors and validation of newly discovered genes as diagnostic and therapeutic targets.

Animals↗

PubMed2001

Tissue microarrays: what will they bring to molecular and anatomic pathology?

The analysis of a large number of tumor tissues with conventional techniques of molecular pathology is tedious and slow. The authors recently developed the tissue microarray technology that makes it possible to sample up to 1,000 tumors on one glass slide, which then can be analyzed by fluorescence in situ hybridization, RNA in situ hybridization, or immunohistochemistry. The tissue microarray technology has the potential to significantly accelerate molecular studies that seek associations between molecular changes and clinicopathologic features of the cancer. Examples of potential applications for tissue microarrays include testing and optimization of probes and antibodies, the organization of large tissue repositories, and the facilitation of multicenter studies. Further, tissue microarrays can be used for educational purposes as well as to improve quality control and standardization of staining methods and interpretation. Tissue microarrays have become one of the most promising tools for the molecular and anatomic pathologist and will have many applications in cancer research, as well as in other fields of pathology. This review article gives an overview of current applications of tissue microarrays as well as possible future development of the technology.

Female↗

PubMed2001

ANX7 as a bio-marker in prostate and breast cancer progression.

The ANX7 gene codes for a Ca2+-activated GTPase, which has been implicated in both exocytotic secretion in cells and control of growth. In this review, we summarize information regarding increased tumor frequency in the Anx7 knockout mice, ANX7 growth suppression of human cancer cell lines, and ANX7 expression in human tumor tissue micro-arrays. The loss of ANX7 is significant in metastatic and hormone refractory prostate cancer compared to benign prostatic hyperplasia. In addition, ANX7 expression has prognostic value for predicting survival of breast cancer patients.

Animals↗

PubMed2001

Biochip technologies in cancer research.

Development of high-throughput 'biochip' technologies has dramatically enhanced our ability to study biology and explore the molecular basis of disease. Biochips enable massively parallel molecular analyses to be carried out in a miniaturized format with a very high throughput. This review will highlight applications of the various biochip technologies in cancer research, including analysis of 1) disease predisposition by using single-nucleotide polymorphism (SNP) microarrays, 2) global gene expression patterns by cDNA microarrays, 3) concentrations, functional activities or interactions of proteins with proteomic biochips, and 4) cell types or tissues as well as clinical endpoints associated with molecular targets by using tissue microarrays. One can predict that individual cancer risks can, in the future, be estimated accurately by a microarray profile of multiple SNPs in critical genes. Diagnostics of cancer will be facilitated by biochip readout of activity levels of thousands of genes and proteins. Biochip diagnostics coupled with informatics solutions will form the basis of individualized treatment decisions for cancer patients.

Computational Biology↗

PubMed2001

Association of E-cadherin germ-line alterations with prostate cancer.

In our recent cancer registry-based study, the incidence of gastric carcinoma was increased up to 5-fold in male relatives of early-onset prostate cancer (PCA) patients. This association may reflect the influence of genetic factors predisposing individuals to both tumor types. Germ-line mutations of the CDH1 gene at 16q have recently been associated with familial gastric cancer. Furthermore, two genome-wide linkage studies of PCA recently reported positivity at 16q. We therefore identified families and individual patients with both gastric and PCA and investigated whether the CDH1 gene mutations were involved in cancer predisposition in these cases. Fifteen of the 180 Finnish hereditary PCA families (8.3%) had one or more gastric cancer cases. No truncating or splice site CDH1 mutations were identified by PCR single-strand conformational polymorphism in these families or in eight individual patients who had both prostate and gastric cancer. However, a novel S270A missense mutation in exon 6 of the CDH1 gene was seen in a single family with four prostate and two gastric cancers. A large-scale population-based survey indicated a higher prevalence of S270A among both familial PCA cases (3.3%; n = 120; P = 0.01) and unselected PCA patients (1.5%; n = 472; P = 0.12) as compared with blood donors serving as population controls (0.5%; n = 923). We conclude that individual rare mutations and polymorphisms in the CDH1 gene, such as S270A, may contribute to the onset of PCA and warrant further investigations in other populations. However, the CDH1 gene does not appear to explain the link between prostate and gastric cancer.

Adaptor Proteins, Signal Transducing↗