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S Knuutila

Publications and source records attributed to S Knuutila.

At least 127 records · Page 7Linked to original sources
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

17q12-21 amplicon, a novel recurrent genetic change in intestinal type of gastric carcinoma: a comparative genomic hybridization study.

We studied DNA copy number changes in gastric cancer (GC) using comparative genomic hybridization (CGH) analysis on 35 resected gastric carcinomas (22 of the intestinal type and 13 of the diffuse type). Eighty-three percent of the cases showed DNA copy number changes. Gains were more common than losses (median of 3 and 1 in primary tumors of the intestinal and diffuse type, respectively). The most common gains were detected on 20q [46%; 12 intestinal type (55%) and four diffuse type (31%)], 8q [37%; 10 intestinal type (45%) and three diffuse type (23%)], and 17q12-21 [29%; all but one intestinal type (41%)]. The most frequent losses were detected on 18q [26%; all intestinal type (41%)] and on 4q [23%; all intestinal type (32%)]. High-level amplifications were observed in the intestinal type of tumors at 17q12-21 (three tumors), 20q (three tumors). 2q (one tumor), and 18q (one tumor). In the diffuse type, high-level amplification was detected once at 13q.

Adult↗
PubMed1997

Clonal CD5-positive B lymphocytes in myelodysplastic syndrome with systemic vasculitis and trisomy 8.

Bone marrow and peripheral blood from a myelodysplastic syndrome (MDS) patient with trisomy 8 and associated systemic vasculitis was investigated for clonal lymphoid lineage involvement using simultaneous metaphase and interphase fluorescence in situ hybridization (FISH) and immunocytochemistry with antibodies against CD13 (granulocytic), glycophorin A (GPA, erythroid), and the lymphocytic antigens CD3. CD5, CD20, and CD22. Trisomy 8 was detected in 55% of CD13+, 40% of GPA+, 6% of CD5+, and 5% of CD20/22+, but not in CD3+ cells. In a complementary experiment using interphase FISH on bone marrow cells sorted by flow cytometry, 13% of CD5/CD19 double-positive cells (76% purity) were found to be trisomic. The results indicate the existence of a small CD5-positive B-lymphoid clone as part of the MDS process in this patient. Since CD5/19-positive cells have been proposed to be autoantibody producing, this finding might be a clue to the pathogenesis underlying the propensity for MDS patients to develop immune-mediated complications.

B-Lymphocytes↗
PubMed1997

CB1093, a novel vitamin D analog; effects on differentiation and clonal growth on HL-60 and de novo leukemia cells.

We studied the effects of a novel vitamin D analog CB1093, EB1089 (one of the most antileukemic analogs yet) and 1 alpha,25(OH)2D3 both on HL-60 cells and cells from 13 AML patients. Differentiation was measured both by induction of superoxide production and non-specific esterase. Cell proliferation was assessed by colony assay and 3H-thymidine incorporation. The effect on serum calcium was measured in rats. The CB1093 proved to be the most efficient of the analogs tested so far, both in inducing differentiation and in inhibiting proliferation. This, combined with its low hypercalcemic effect shown here, makes it a promising candidate for preclinical animal studies.

Animals↗
PubMed1997

Microsatellite markers as tools for characterization of DNA amplifications evaluated by comparative genomic hybridization.

To test the applicability of microsatellite markers in the study of DNA amplifications evaluated by comparative genomic hybridization, we analyzed 55 highly polymorphic microsatellite marker loci from six liposarcoma tumors (seven specimens) and from one atypical lipoma with a gain or high-level amplification at 12q13-22. Twelve-trisomic neoplastic cells from a patient with B-cell chronic lymphocytic leukemia were used as a positive control, in which 74% of informative loci showed allelic imbalance. In every tumor specimen microsatellite marker loci analysis showed allelic imbalance. The amplicons were discontinuous, indicating the presence of separate amplicons in the 12q13-22 region. Not only gains but also losses as well as concomitant gains and losses of alleles were observed. The use of microsatellite markers has several advantages: gene loci as well as flanking DNA loci can be analyzed, it is fast and lends itself to automation, and allows a large number of marker loci to be analyzed simultaneously.

Chromosome Mapping↗
PubMed1997

Overrepresentation of 1q21-23 and 12q13-21 in lipoma-like liposarcomas but not in benign lipomas: a comparative genomic hybridization study.

Twenty lipomatous tumors, including eight lipoma-like liposarcomas and 12 benign lipomas, were analyzed using comparative genomic hybridization (CGH). DNA sequence copy number changes detected in five lipoma-like liposarcomas (mean, 1.1 aberrations/tumor; range, 0-2) consisted of gains of 12q13-21 (five tumors) and 1q21-23 (four tumors). Two of the tumors showed high-level amplification at 12q14-21 and one tumor at 1q21-22. No copy number changes were found in lipomas. Overrepresentation of 1q and 12q sequences was a recurrent finding in lipoma-like liposarcomas but not in lipomas. Thus, CGH may help in the differential diagnosis of low-grade or borderline adipose neoplasms.

Adult↗
PubMed1997

Recurrent gains of 1q, 8 and 12 in the Ewing family of tumours by comparative genomic hybridization.

Comparative genomic hybridization (CGH) was used to detect copy number changes of DNA sequences in the Ewing family of tumours (ET). We analysed 20 samples from 17 patients. Fifteen tumours (75%) showed copy number changes. Gains of DNA sequences were much more frequent than losses, the majority of the gains affecting whole chromosomes or whole chromosome arms. Recurrent findings included copy number increases for chromosomes 8 (seven out of 20 samples; 35%), 1q (five samples; 25%) and 12 (five samples; 25%). The minimal common regions of these gains were the whole chromosomes 8 and 12, and 1q21-22. High-level amplifications affected 8q13-24, 1q and 1q21-22, each once. Southern blot analysis of the specimen with high-level amplification at 1q21-22 showed an amplification of FLG and SPRR3, both mapped to this region. All cases with a gain of chromosome 12 simultaneously showed a gain of chromosome 8. Comparison of CGH findings with cytogenetic analysis of the same tumours and previous cytogenetic reports of ET showed, in general, concordant results. In conclusion, our findings confirm that secondary changes, which may have prognostic significance in ET, are trisomy 8, trisomy 12 and a gain of DNA sequences in 1q.

Adolescent↗
PubMed1997

Evidence for divergence of DNA copy number changes in serous, mucinous and endometrioid ovarian carcinomas.

Comparative genomic hybridization was applied to detect and map changes in DNA copy number in 24 well or moderately differentiated epithelial ovarian carcinomas (eight serous, eight mucinous and eight endometrioid carcinomas). Twenty-three of the 24 tumours showed changes in DNA copy number in one or several regions (median 4, range 1-17). Gains were more frequent than losses (ratio 1.6:1.0). The most frequent gains occurred in chromosomes 1q (38%), 2p (29%), 7q (25%), 8q(38%) and 17q (38%), and the most common losses were located in chromosomes 8p (21%), 9p (25%) and 13q (21%). High-level amplifications were detected in seven tumours at 1q22-32, 2p15-22, 3qcen-23, 6p21-22 and 8q. In the three histological subtypes the copy number karyotypes showed substantial differences. Gains at 1q were observed in endometrioid (five cases) and serous tumours (four cases). Increased copy number at 10q was seen in endometrioid tumours only (four cases), whereas gains at 11q occurred mostly in serous tumours (four cases). In mucinous tumours, the most common copy number change was a gain at 17q (six cases). The results show that, in epithelial ovarian carcinoma, changes in DNA copy number are a rule rather than an exception, chromosomes 1, 2, 7, 8, 9, 13 and 17 being the most frequently affected. The diverging pattern of genetic changes seen in epithelial ovarian carcinomas with different histological phenotypes suggests that various pathways may lead to tumorigenesis and/or progression in these subgroups.

Adenocarcinoma, Mucinous↗
PubMed1997

Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma.

Comparative genomic hybridization (CGH) analyses were performed on 27 human pleural mesothelioma tumour specimens, consisting of 18 frozen tumours and nine paraffin-embedded tumours, to screen for gains and losses of DNA sequences. Copy number changes were detected in 15 of the 27 specimens with a range from one to eight per specimen. On average, more losses than gains of genetic material were observed. The loss of DNA sequences occurred most commonly in the short arm of chromosome 9 (p21-pter), in 60% of the abnormal specimens. Other losses among the abnormal specimens were frequently detected in the long arms of chromosomes 4 (q31.1-qter, 20%), 6 (q22-q24, 33%), 13 (33%),14 (q24-qter, 33%) and 22 (q13, 20%). A gain in DNA sequences was found in the long arm of chromosome 1 (cen-qter) in 33% of the abnormal specimens. Our analysis is the first genome-wide screening for gains and losses of DNA sequences using comparative genomic hybridization in malignant pleural mesothelioma tumours. The recurrent DNA sequence changes detected in this study suggest that the corresponding chromosomal areas most probably contain genes important for the initiation and progression of mesothelioma.

Adult↗
PubMed1997

Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis.

Many human cancer susceptibility genes have been successfully mapped by genetic linkage studies. One that has so far eluded researchers is that for Peutz-Jeghers (P-J) syndrome, a condition characterized by intestinal hamartomatous polyposis and melanin spots of the lips, buccal mucosa and digits. A dramatically elevated risk of malignancy has also been documented. Gastrointestinal tumours as well as cancers of the breast, ovary, testis and uterine cervix appear to be overrepresented in families with this syndrome. The nature of hamartomatous polyps is equivicol. Hamartomas are usually considered histologically benign, but in the case of Peutz-Jeghers patients, there are reports of adenomatous and malignant changes in the polyps, and the possibility of a hamartoma-carcinoma sequence has been discussed. A search for a putative tumour suppressor locus was made using comparative genomic hybridization (CGH) of Peutz-Jeghers polyps, combined with loss of heterozygosity (LOH) study. Genetic linkage analysis in 12 families using markers from a deletion site demonstrated the presence of a high-penetrance locus in distal 19p with a multipoint lod score of 7.00 at marker D19S886 without evidence of genetic heterogeneity. The study demonstrates the power of CGH combined with LOH analysis in identifying putative tumour suppressor loci, and provides molecular evidence of malignant potential in hamartomas.

Adenocarcinoma↗
PubMed1997

Follow-up of residual disease using metaphase-FISH in patients with acute lymphoblastic leukemia in remission.

Metaphase-FISH (fluorescence in situ hybridization) was used to detect cells with a chromosomal trisomy and/or translocation in 25 patients with acute lymphoblastic leukemia (ALL) in remission. Twelve patients were treated with chemotherapy alone and 13 patients received bone marrow transplantation after initial chemotherapy. Patients were followed up for 8-56 months (median 18 months). In this study, a total of 82 bone marrow samples were analyzed. Metaphase-FISH identified chromosome morphology, even banding, in cells from which FISH signals were studied. Thus, it is as reliable as standard karyotype analysis and does not cause false positive results. Furthermore, more than 1000 cells can be analyzed in 3-6 h which equals the time it takes to analyze 20 metaphases by standard karyotype. The time span before the first positive sample seems to be insignificant with regard to the outcome of relapse. All six patients, who had more than 1% of abnormal cells detected at any sampling or whose consecutive follow-up samples showed an increasing frequency (up to 1%) of abnormal cells, relapsed. Absence or occurrence of low numbers of abnormal cells at a frequency of 0.05-0.8% followed by their disappearance was in agreement with continuing complete clinical and hematologic remission (CR) in 16 (84%) of 19 patients. Our results indicate that metaphase-FISH is a reliable technique for quantifying residual leukemic cells. The technique is available in standard cytogenetic laboratories and can be applied to routine follow-up of ALL patients who have a suitable chromosomal aberration.

Adolescent↗
PubMed1997

Chromosomal breakpoints and changes in DNA copy number in refractory acute myeloid leukemia.

Comparative genomic hybridization (CGH) was used to detect changes in DNA copy number in 25 cases of refractory acute myeloid leukemia (AML). CGH detected changes in DNA copy number in nine AML (36%). Losses (82%) were more frequent than gains (18%). No high-level amplifications were detected in any of the cases. Losses involved minimal overlapping regions at 5q14q32, 7q31.2q32 and 12p12. The most frequent gain was detected at 8q. CGH gave normal results in all cases with a normal karyotype or a translocation as the sole aberration. The absence of high-level DNA copy gains suggests that, in contrast to other malignancies, gene amplification is not an important mechanism for drug resistance in AML. In addition to 5q and 7q, known to be associated with disease refractoriness, 12p may be another region related to poor prognosis.

Adult↗
PubMed1997

Evidence for two molecular steps in the pathogenesis of myeloid disorders associated with deletion of chromosome 7 long arm.

Partial deletion of the long arm of chromosome 7 (7q-) is a frequent chromosomal aberration in many neoplasias, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Recurrent deletions, leading to loss of heterozygosity (LOH), may be indicative of a tumor suppressor gene nearby. We studied eight AML or MDS patients with 7q-, in order to define the commonly deleted area in more detail. Separated blood lymphocytes and granulocytes were typed with 48 polymorphic microsatellite markers, and the heterozygosity between the two cell lineages was compared. The minimum commonly deleted region spanned from D7S658 to D7S655. Unexpectedly, four of the patients showed remarkable homozygosity in both lymphocytes and granulocytes around the commonly deleted area, and thus no deletions could be demonstrated by comparing the two cell lineages. Comparison to leukemic patients without 7q- and to normal individuals revealed that the homozygosity was restricted to patients with 7q-. We suggest that a specific mechanism, such as mitotic recombination in bone marrow stem cells, leading to homozygosity in both granulocytes and lymphocytes, represents a leukemogenetic step in these patients.

Chromosome Deletion↗
PubMed1997

Treatment of adrenoleukodystrophy with bone marrow transplantation.

Three children with adrenoleukodystrophy (ALD) underwent allogeneic bone marrow transplantation (BMT) between 1992 and 1993. The first boy had attention deficits, marked neuropsychological deficits and widespread demyelination in the frontal lobes on MRI before transplantation. Four years later he has mentally deteriorated and the demyelination on MRI has progressed. The second boy had no symptoms but had white matter lesions on MRI when diagnosed. He was regularly followed with MRI and neuropsychological investigations until BMT 18 months later. A progress of the lesions was noted on the initial MRI investigations, and 4 months before BMT a worsening of deficits in attention and kinaesthetic praxis could be observed. He rapidly deteriorated after the transplantation and died 18 months later. Both PCR and in situ hybridization confirmed the presence of donor cells in the brain. The third boy had no symptoms but white matter lesions on MRI when diagnosed. The neuropsychological tests remained normal but a slight progress was observed on MRI just before transplantation. This boy is still healthy 3.5 years after BMT. BMT as treatment for ALD has to be considered very early, even if a child without symptoms but signs of demyelination on MRI, if a suitable donor is available.

Bone Marrow Transplantation↗
PubMed1997

Gains, losses, and amplifications of DNA sequences evaluated by comparative genomic hybridization in chondrosarcomas.

Comparative genomic hybridization was used to search for previously unknown gains and losses of DNA sequences along all chromosome arms in 29 chondrosarcoma specimens obtained from 23 patients. Extensive genetic aberrations, with a mean of 6 changes per tumor (range, 1 to 24), were detected in 21 of the 29 samples analyzed (72%). The majority of these changes were gains of whole chromosomes or whole chromosome arms. Gains of DNA sequence copy number were most frequent at 20q (38%), 17p (38%), 20p (31%), 1cen-q24 (28%), and 14q23-qter (28%). High-level amplifications of small chromosome regions were sporadic, detected in only 17% of the samples. The only recurrent high-level amplification, seen in two tumors (7%), affected the minimal common region 12cen-q15. Other amplifications, each encountered only once, involved 1p33-p35, 2p23-pter, 4p, 6p22-pter, 18q12-q22, 19p13.2, 19q13.2, and 20q13.1. Losses of DNA sequences were rare and were most commonly observed at 6cen-q22 (17%) and 9p (17%).

Adult↗
PubMed1997

Comparative genomic hybridization analysis of chromosomal changes occurring during development of acquired resistance to cisplatin in human ovarian carcinoma cells.

The genetic changes underlying the development of resistance to the platinum-containing drugs are poorly defined. We analyzed six resistant cell lines using comparative genomic hybridization (CGH) in order to screen and identify possible genetic changes in common. We compared parental 2008 and A2780 human ovarian cancer cells to sublines selected for resistance to cisplatin (DDP) (2008/C8, 2008/C13*5.25, 2008/A, A2780/CP); we also compared 2008 cells to sublines selected for resistance to antimonite (2008/H) and arsenite (2008/I) which demonstrated cross-resistance to DDP. DNA samples from the resistant cell lines were hybridized against DNA from the parental cells rather than from normal human cells to permit detection of only those changes associated with the development of resistance. The DNA sequence copy number changes were surprisingly numerous in the DDP, antimony, and arsenite-resistant variants of the 2008 cell line and most of the chromosomes were affected. On the other hand, in the A2780/CP subline only a few changes were found and these were limited to just four chromosomes. The most common findings among the DDP-resistant cell lines were gains of material from chromosomes or chromosome arms 2q (5 out of 6 lines), 4 (4/6), 6q (5/6), and 8q (4/6). Deletions were observed on chromosomes or chromosome arms 2p (4/6), X (4/6), 7p (5/6), 11p (4/6), and 13 (4/6). The most frequently involved chromosomal regions, affected in the majority of cell lines, were: gain of 2q14.1-q33, 4p15.2-p13, 4q22-q25, 4q31.1-q34, 6q13-q16, 8q12-q21.2, and loss of Xp22.2-q21, 7p21-p14, 11cen-p14 in sublines of 2008, and loss of 2pter-p22 and 13q21 in sublines of 2008 and A2780. The results suggest that the acquired resistance and cross-resistance to DDP in these cell lines was associated with substantial genomic instability, quite unlike the changes observed in association with the development of resistance to drugs participating in the multidrug resistance phenotype.

Chromosome Aberrations↗