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Biomedical subjects

O P Kallioniemi

Publications and source records attributed to O P Kallioniemi.

At least 73 records · Page 4Linked to original sources
PubMed1997

AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer.

Members of the recently recognized SRC-1 family of transcriptional coactivators interact with steroid hormone receptors to enhance ligand-dependent transcription. AIB1, a member of the SRC-1 family, was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number were elevated in human breast cancers. AIB1 amplification and overexpression were observed in four of five estrogen receptor-positive breast and ovarian cancer cell lines. Subsequent evaluation of 105 unselected specimens of primary breast cancer found AIB1 amplification in approximately 10 percent and high expression in 64 percent of the primary tumors analyzed. AIB1 protein interacted with estrogen receptors in a ligand-dependent fashion, and transfection of AIB1 resulted in enhancement of estrogen-dependent transcription. These observations identify AIB1 as a nuclear receptor coactivator whose altered expression may contribute to development of steroid-dependent cancers.

Amino Acid Sequence↗
PubMed1997

Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer.

To understand the genetic basis and clonal evolution underlying metastatic progression of human breast cancer in vivo, we analyzed the genetic composition of 29 primary breast carcinomas and their paired asynchronous metastases by comparative genomic hybridization and fluorescence in situ hybridization. The mean number of genetic changes by comparative genomic hybridization was 8.7 +/- 5.3 in primary tumors and 9.0 +/- 5.7 in their metastases. Although most of the genetic changes occurred equally often in the two groups, gains of the Xq12-q22 region were enriched in the metastases. According to a statistical analysis of shared genetic changes and breakpoints in paired specimens, 20 of the metastases (69%) showed a high degree of clonal relationship with the corresponding primary tumor, whereas the genetic composition of 9 metastases (31%) differed almost completely from that of the paired primary tumors. In both groups, however, chromosome X inactivation patterns suggested that the metastatic lesions originated from the same clone as the primary tumor. Fluorescence in situ hybridization analysis with probes specific to metastatic clones usually failed to find such cells in the primary tumor sample. In conclusion, detailed characterization of the in vivo progression pathways of metastatic breast cancer indicates that a linear progression model is unlikely to account for the progression of primary tumors to metastases. An early stem line clone apparently evolves independently in the primary tumor and its metastasis, eventually leading to multiple, genetically almost completely different, clones in the various tumor locations in a given patient. The resulting heterogeneity of metastatic breast cancer may underlie its poor responsiveness to therapy and explain why biomarkers of prognosis or therapy responsiveness measured exclusively from primary tumors give a restricted view of the biological properties of metastatic breast cancer.

Adenocarcinoma↗
PubMed1997

Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations.

BRCA1 and BRCA2 mutations confer increased risk for development of breast cancer, but a number of additional, currently largely unknown, somatic genetic defects must also accumulate in the breast epithelial cells before malignancy develops. To evaluate the nature of these additional somatic genetic defects, we performed a genome-wide survey by comparative genomic hybridization on breast cancers from 21 BRCA1 mutation carriers, 15 BRCA2 mutation carriers, and 55 unselected controls. The total number of genetic changes was almost two times higher in tumors from both BRCA1 and BRCA2 mutation carriers than in the control group. In BRCA1 tumors, losses of 5q (86%), 4q (81%), 4p (64%), 2q (40%), and 12q (40%) were significantly more common than in the control group (7-13%). BRCA2 tumors were characterized by a higher frequency of 13q (73%) and 6q (60%) losses and gains of 17q22-q24 (87%) and 20q13 (60%) as compared to the prevalence of these changes in the control group (12-18%). In conclusion, accumulation of somatic genetic changes during tumor progression may follow a unique pathway in individuals genetically predisposed to cancer, especially by the BRCA1 gene. Activation or loss of genes in the affected chromosomal regions may be selected for during tumor progression in cells lacking functional BRCA1 or BRCA2. Identification of such genes could provide targets for therapeutic intervention and early diagnosis.

Adult↗
PubMed1997

Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer.

Progression of prostate cancer during endocrine therapy is a major clinical problem, the molecular mechanisms of which remain poorly understood. Amplification of the androgen receptor (AR) gene was recently described in recurrent prostate carcinomas from patients who had failed androgen deprivation therapy. To evaluate the hypothesis that amplification of the AR gene is a cause for the failure of androgen deprivation therapy in prostate cancer, we studied whether AR amplification leads to gene overexpression, whether the amplified AR gene is structurally intact, and whether tumors with AR amplification have distinct biological and clinical characteristics. Tumor specimens were collected from 54 prostate cancer patients at the time of a local recurrence following therapy failure. In 26 cases, paired primary tumor specimens from the same patients prior to therapy were also available. Fifteen (28%) of the recurrent therapy-resistant tumors, but none of the untreated primary tumors, contained AR gene amplification as determined by fluorescence in situ hybridization. According to single-stranded conformation polymorphism analysis, the AR gene was wild type in all but one of the 13 AR amplified cases studied. In one tumor, a presumed mutation in the hormone-binding domain at codon 674 leading to a Gly --> Ala substitution was found, but functional studies indicated that this mutation did not change the transactivational properties of the receptor. AR amplification was associated with a substantially increased level of mRNA expression of the gene by in situ hybridization. Clinicopathological correlations indicated that AR amplification was most likely to occur in tumors that had initially responded well to endocrine therapy and whose response duration was more than 12 months. Tumors that recurred earlier or those that showed no initial therapy response did not contain AR amplification. The median survival time after recurrence was two times longer for patients with AR amplification in comparison to those with no amplification (P = 0.03, Willcoxon-Breslow test). In conclusion, failure of conventional androgen deprivation therapy in prostate cancer may be caused by a clonal expansion of tumor cells that are able to continue androgen-dependent growth despite of the low concentrations of serum androgens. Amplification and the increased expression of a wild-type AR gene may play a key role in this process.

Aged↗
PubMed1997

Frequent loss of the 11q14-24 region in chronic lymphocytic leukemia: a study by comparative genomic hybridization. Tampere CLL Group.

The genetic basis and molecular pathogenesis of chronic lymphocytic leukemia (CLL) and the molecular mechanisms responsible for its progression remain poorly understood. Here, karyotyping techniques specifically optimized for CLL, comparative genomic hybridization (CGH), and fluorescence in situ hybridization were used to search for CLL-specific genetic aberrations. CGH and karyotyping both revealed copy number changes in 12 of the 25 CLL cases (48%) analyzed. Loss at 11q emerged as the most common aberration (6 cases), followed by a gain of chromosome 12 (4) and loss at 13q (3). Concordance between CGH and G-banding was found in 23 of the 25 cases (92%), which is more than reported in a recent similar CGH study of CLL. Owing to the basic differences in G-banding and CGH, however, their simultaneous clinical application is recommended. The frequent loss of 11q14-24 suggests that this chromosomal region deserves further attention as a candidate locus involved in the pathogenesis of CLL.

Aged↗
PubMed1997

Comparative genomic hybridization reveals frequent gains of 20q, 8q, 11q, 12p, and 17q, and losses of 18q, 9p, and 15q in pancreatic cancer.

Comparative genomic hybridization (CGH) was used to screen for genomic imbalances in 24 exocrine pancreatic carcinomas, including II low-passage cell lines (4-8 subcultures) and 13 uncultured samples. Aberrations were found in all cell lines and in seven of the 13 biopsies. The most frequent changes in the cell lines were gains of 20q (91%), 11q (64%), 17q (64%), 19q (64%), 8q, 12p, 14q, and 20p (55%), and losses of 18q (100%), 9p (91%), 15q(73%), 21q (64%), 3p (55%), and 13q (55%). High-levels gains (tumor to normal ratio over 1.5) were detected at 3q, 6p, 7q, 8q, 12p, 19q, and 20q. Among the tumor biopsies, overrepresentations of 7p and 8q were most common (31%), followed by 5p, 5q, 11p, 11q, 12p, and 18q (23%), whereas the most frequent losses involved 18p and 18q (31%) and 6q and 17p (23%). The genetic changes in nine samples obtained from metastatic lesions did not differ significantly from those in 15 primary carcinomas. Most of the gains and losses detected in this CGH study correspond well to those identified in previous cytogenetic and molecular genetic investigations of pancreatic carcinomas. However, frequent gain of 12p and loss of 15q have not been previously reported. Molecular genetic analyses of these chromosome arms are warranted, and may lead to the discovery of novel genes important in pancreatic carcinogenesis.

Aged↗
PubMed1997

Genome screening by comparative genomic hybridization.

Comparative genomic hybridization (CGH) provides a molecular cytogenetic approach for genome-wide scanning of differences in DNA sequence copy number. The technique is now attracting wide-spread interest, especially among cancer researchers. The rapidly expanding database of CGH publications already covers about 1500 tumors and is beginning to reveal genetic abnormalities that are characteristic of certain tumor types or stages of tumor progression. Six novel gene amplifications, as well as a locus for a cancer-predisposition syndrome, have been discovered based on CGH data. CGH has now been established as a first-line screening technique for cancer researchers and will serve as a basis for ongoing efforts to develop high-resolution next-generation genome scanning, such as the microarray technology.

Animals↗
PubMed1997

Genetic changes associated with the acquisition of androgen-independent growth, tumorigenicity and metastatic potential in a prostate cancer model.

Genetic changes underlying the progression of human prostate cancer are incompletely understood. Recently, an experimental model system that resembles human prostate cancer progression was developed based on the serial passage of an androgen-responsive, non-tumorigenic LNCaP prostate cancer cell line into athymic castrated mice. Six different sublines, derived after one, two or three rounds of in vivo passage, sequentially acquired androgen independence and tumorigenicity as well as metastatic capacity. Here, we used comparative genomic hybridization (CGH) and locus-specific fluorescence in situ hybridization (FISH) analysis to search for genetic changes that may underlie the phenotypic progression events in this model system. Six genetic aberrations were seen by CGH in the parental LNCaP cell line. The derivative sublines shared virtually all these changes, indicating a common clonal origin, but also contained 3-7 additional genetic changes. Gain of the 13q12-q13 chromosomal region as well as losses of 4, 6q24-qter, 20p and 21q were associated with androgen independence and tumorigenicity with additional changes correlating with metastasis. In conclusion, an accumulation of genetic changes correlates with tumour progression in this experimental in vivo model of prostate cancer progression. It is possible that the specific chromosomal aberrations involved in this model system may provide clues to the location of genes involved in human prostate cancer progression and metastasis.

Androgens↗
PubMed1997

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. In the BRCA1 gene, 10 different protein truncating mutations were found each in one family. Six of these are novel Finnish mutations and four have been previously found in other European populations. Six different BRCA2 mutations were found in 11 families. Altogether only 21% of the breast cancer families were accounted for by mutations in these two genes. Linkage to both chromosome 17q21 (BRCA1) and 13q12 (BRCA2) was also excluded in a subset of seven mutation-negative families with four or more cases of breast or ovarian cancer. These data indicate that additional breast and breast-ovarian cancer susceptibility genes are likely to be important in Finland.

Adult↗
PubMed1997

Androgen receptor gene amplification in a recurrent prostate cancer after monotherapy with the nonsteroidal potent antiandrogen Casodex (bicalutamide) with a subsequent favorable response to maximal androgen blockade.

OBJECTIVE: We recently found amplification of the androgen receptor (AR) gene in approximately 30% of locally recurrent prostate carcinomas from patients treated by conventional androgen deprivation (castration) therapy, whereas none of the untreated primary prostate tumors showed this amplification. This suggests that AR gene amplification was selected during androgen deprivation therapy. The present case study represents our initial approach to evaluate the role that AR amplification may play in therapy resistance after other forms of endocrine therapy. MATERIAL AND METHODS: Specimens from both a primary and a subsequent locally recurrent tumor were studied for amplification of the AR gene by fluorescence in situ hybridization from a prostate cancer patient who experienced tumor progression after monotherapy with the potent antiandrogen bicalutamide (Casodex, a trade mark, the property of Zeneca Ltd). RESULTS AND CONCLUSIONS: High-level amplification of the AR gene was found in the recurrent tumor, whereas no evidence of amplification was found in the primary tumor. After recurrence, the patient first received chemotherapy (ifosfamide) for 15 weeks with no response, followed by maximal androgen blockade (MAB). The latter therapy resulted in a favorable short-term response. This case study has the following implications which warrant further research: (1) AR amplification may be selected not only by castration but also by therapy with a competitive peripheral androgen-receptor-blocking agent, and (2) recurrent tumors with AR amplification may be particularly likely to benefit from MAB as a second-line therapy.

Adenocarcinoma↗
PubMed1997

Genetic changes in intraductal breast cancer detected by comparative genomic hybridization.

Ductal carcinoma in situ (DCIS) is considered a direct precursor of invasive ductal breast cancer (IDC). We combined tissue microdissection and comparative genomic hybridization to identify genetic changes in five DCIS lesions with no invasion and in two that were adjacent to IDC. Extensive genetic changes characterized pure DCIS cases with gains of 1q, 6q, 8q, and Xq as well as losses of 17p and chromosome 22 being most often involved. Except for the Xq gain, these changes are also common to IDC. Separate analysis of DCIS and IDC components in the same tumor revealed an almost identical pattern of genetic changes in one case, whereas substantial differences were found in another. We conclude that many of the common genetic changes in IDC may take place before development of invasive growth. However, a simple linear progression model may not always account for the DCIS-IDC transition.

Breast Neoplasms↗
PubMed1996

Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search.

Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on chromosome 1.

Adult↗
PubMed1996

Gain of 17q24-qter detected by comparative genomic hybridization in malignant tumors from patients with von Recklinghausen's neurofibromatosis.

The genetic changes leading to the development of malignant peripheral nerve sheath tumors (MPNSTs) are largely unknown. The few tumors that have been investigated cytogenetically had highly complex karyotypes and no consistent rearrangements, and the attempts to pinpoint consistent DNA-level changes have met with only limited success. We used comparative genomic hybridization to analyze seven MPNSTs and one dermatofibrosarcoma protuberans from eight patients with von Recklinghausen's disease (neurofibromatosis type 1), as well as three sporadic MPNSTs. Gains and losses of DNA sequences were found in all tumors, with an average of four losses (range, 0-14) and two gains (range, 0-5) per tumor. Two striking observations were made: (a) an increase in copy number of the distal part of the long arm of chromosome 17, with the smallest region of overlap 17q24-qter, was seen in five of seven MPNSTs and in the only dermatofibrosarcoma protuberans, all of which were from patients with neurofibromatosis, whereas none of the three sporadic MPNSTs had this alteration; and (b) loss of 13q, with the smallest region of overlap 13q14-q21, was found in 6 of 10 MPNSTs. The consistent involvement of these two chromosomal regions probably reflects two different pathogenetic mechanisms for MPNSTs.

Chromosome Deletion↗
PubMed1996

Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy.

The differentiation between malignant and benign adrenocortical tumors is often difficult, and better markers are required. Because the genetic background of adrenocortical tumors is poorly characterized, we used comparative genomic hybridization (CGH) to screen for DNA sequence copy number changes in 8 sporadic primary adrenocortical cancers and 14 adenomas. There was a strong relationship between the number of genetic aberrations detected using CGH and both tumor size and malignancy. No alterations were seen in the smaller adenomas (< 5 cm), whereas the two largest adenomas (5 cm each) and seven of the eight cancers (7-20 cm) showed an increased number of genetic alterations. The presence of genetic aberrations detected using CGH was associated with an aneuploid DNA pattern. In the cancers, losses most often involved the chromosomal regions 2, 11q, and 17p (four of eight tumors), whereas gains took place at chromosomes 4 and 5 (four of eight tumors). In conclusion, our data indicate that genetic changes may help to define the malignant potential of adrenocortical tumors. Furthermore, the CGH results implicate several chromosomal regions that may contain genes with an important role in the development of adrenocortical cancers.

Adenoma↗
PubMed1996

Independent amplification and frequent co-amplification of three nonsyntenic regions on the long arm of chromosome 20 in human breast cancer.

DNA amplification at 20q13.2 is common in breast cancer, correlates with poor prognosis, and may reflect location of an important oncogene. Recently, other regions along 20q were also found to undergo amplification. Here, amplification levels and patterns of co-amplification were analyzed by interphase fluorescence in situ hybridization at 14 loci along 20q in 146 uncultured breast carcinomas and 14 cell lines. Three regions were independently amplified in uncultured tumors: RMC20C001 region at 20q13.2 (highly amplified in 9.6% of the cases), PTPN1 region 3 Mb proximal (6.2%), and AIB3 region at 20q11 (6.2%). Co-amplifications involving two or three of these regions were seen in 11 of the 19 highly amplified tumors. The results suggest that three distinct nonsyntenic regions along 20q may be important and that complex chromosomal rearrangements underlie their frequent co-amplification in breast cancer.

Breast Neoplasms↗
PubMed1996

Low biological aggressiveness of screen-detected lung cancers may indicate over-diagnosis.

All cases of lung cancer diagnosed in the Tampere University Hospital catchment area in 1983-1987 were identified, analyzed for DNA flow cytometry and followed up to 1992. The patients were classified into 3 groups: screen-detected, symptom-detected, and detected by chance. The biological aggressiveness as indicated by DNA flow cytometry was not related to the survival of the symptom-detected patients. Also the screen-detected patients with an aggressive tumour (aneuploid or high S-phase fraction, SPF) had the same survival as the symptom-detected patients. The survival of screen-detected patients with a diploid or low SPF tumour was significantly better than that in the other groups. It is concluded that some of the previously known discrepancy of no effect on mortality and effect on survival of lung-cancer screening may be due to over-diagnosis, i.e., detection of morphologically malignant but biologically indolent lesions by screening.

DNA, Neoplasm↗