Biomedical subjects

S Knuutila

Publications and source records attributed to S Knuutila.

At least 91 records · Page 5Linked to original sources

PubMed1999

BCL2 overexpression in diffuse large B-cell lymphoma.

Translocation (14;18)(q32;q21), which is detected in 20-30% of diffuse large B-cell lymphomas (DLBCL), is regarded as a major mechanism for BCL2 protein overexpression. Nevertheless, BCL2 overexpression is not always caused by t(14;18), because it is often detected in lymphomas without BCL2 rearrangement. Recent studies have shown that increased expression of BCL2 may also result from BCL2 gene amplification in DLBCL. Similarly, it has been speculated that the mutations of the open reading frame might cause increased expression of BCL2 by affecting the interactions of BCL2 with other proteins. The results obtained from studies on the association of BCL2 protein overexpression with survival of DLBCL are controversial, although a correlation with decreased overall survival seems to exist. However, BCL2 rearrangement does not seem to have any major association with poor prognosis, but it is difficult to assess its true impact on prognosis due to differences in treatment and follow-up, and methodologies applied to study the BCL2 rearrangement. This review summarizes the BCL2 expression studies in DLBCL and discusses the prognostic relevance of BCL2 overexpression and its mechanisms.

Animals↗

PubMed1999

Comparative genomic hybridization and conventional cytogenetic analyses in childhood acute myeloid leukemia.

Comparative genomic hybridization (CGH) analysis was performed on bone marrow specimens from 19 children with acute myeloid leukemia (AML) at diagnosis. The results of CGH were compared to those of conventional cytogenetic analysis. The most common CGH aberrations were gains of whole chromosomes 6 and 8, both of which appeared three times. Two losses were seen twice; losses of whole chromosomes 7 and X. The CGH findings were concordant with the results of conventional karyotyping. CGH did not add new information to the karyotypes. Since no high-level amplification was found among the samples and standard karyotyping was highly successful, we do not advocate routine use of CGH in the diagnostic evaluation of childhood AML.

Acute Disease↗

PubMed1999

Among numerous DNA copy number changes, losses of chromosome 13 are highly recurrent in plasmacytoma.

Chromosomal imbalances were studied by comparative genomic hybridization (CGH) on 27 specimens from 24 patients with plasmacytoma. All the specimens exhibited DNA copy number changes (mean, 7.7 aberrations/tumor; range, 2-15). The most recurrent change involved losses at 13q, found in 19 out of 24 patients. Other frequent losses were at 1p (42%), 14q (33%), X (33%), 8p (25%), and 6q (25%). Gains were frequent at 19p (58%), 9q (58%), 1q (58%), 7p (42%), 11q (38%), 15 (33%), 6p (25%), 8q (25%), and 5p (21%). High-level copy number increases were found at 1q, 5, 7, 8q, 9q, 11q, 15, and 19. The findings of highly recurrent chromosomal imbalances in plasmacytomas confirm the analytical power of CGH to detect chromosomal abnormalities in malignancies characterized by low mitotic activity. Our most striking finding, the losses in chromosome 13, provides a basis to investigate the role of the 13q loss in the tumorigenesis and progression of plasmacytoma and to evaluate the prognostic significance of this loss.

Adult↗

PubMed1999

Comparison of genetic changes in primary sarcomas and their pulmonary metastases.

The aims of the present study were to compare genetic aberrations in primary sarcomas and their pulmonary metastases and to explore the pathways associated with disease spreading. The primary tumor and its subsequent pulmonary metastasis of 22 patients were analyzed by comparative genomic hybridization. All samples were obtained before the initiation of chemo- or radiotherapy. The mean total number of aberrations per tumor was 7.6 (range, 0-17) in primary tumors and 7. 5 (range, 0-19) in metastases. The mean numbers of high-level amplifications per tumor were similar (0.32 in primary tumors and 0. 36 in metastases). The frequencies of the most common aberrations were relatively similar in primary tumors and metastases: the most frequent gain affected 1q (minimal common regions 1q21-q23 in 36% of primary tumors and 1q21 in 45% of metastases). The most frequent losses were detected at 9p (9p22-pter in 32% of primary tumors and 9p21-pter in 32% of metastases), 10p (10p11.2-p12 in 41% of primary tumors and 10p11.2-pter in 32% of metastases), 11q (11q23-qter in 36% of primary tumors and 32% of metastases), and 13q (13q14-q21 in 45% of primary tumors and 50% of metastases). No aberrations specific to metastases were detected. An increase in the total number of changes during progression was a predominant feature in a majority of these paired samples. Also, the number of differences in the genetic profile outnumbered common changes in a majority of the samples. However, despite the heterogeneous and numerous changes, all pairs with aberrations in both specimens had some shared alterations in both samples. Genes Chromosomes Cancer 25:323-331, 1999.

Adolescent↗

PubMed1998

Comparative genomic hybridization reveals differences in DNA copy number changes between sporadic gastric carcinomas and gastric carcinomas from patients with hereditary nonpolyposis colorectal cancer.

Comparative genomic hybridization was used to search for DNA copy number changes in samples of gastric cancer from 12 hereditary nonpolyposis colon cancer (HNPCC) patients and in samples of sporadic gastric carcinoma from 13 patients. The gastric cancer samples from HNPCC patients showed gains affecting 19q, Xp, and whole chromosome 22, each in a single patient. Neither high-level amplifications nor losses of DNA copy number were detected. On the other hand, 10 of the 13 (77%) sporadic gastric carcinoma samples had multiple DNA copy number changes. The most frequent gains occurred with minimal common overlapping regions at 1q22-q31, 8q23-qter, 17p11.2-q22, and 20q, all at a frequency of 31%. High-level amplifications were also seen at 17q21 in three cases (23%). Losses were rare, and the most frequent loss was with a minimal common overlapping region at 4q32 (23%). This suggests that multiple DNA copy number changes are needed for the development of sporadic gastric carcinoma but not for gastric carcinoma in HNPCC patients.

Chromosome Aberrations↗

PubMed1998

Genomic alterations in fallopian tube carcinoma: comparison to serous uterine and ovarian carcinomas reveals similarity suggesting likeness in molecular pathogenesis.

Serous carcinomas of the fallopian tube, uterus, and ovary resemble each other both histologically and in clinical behavior. Comparative genomic hybridization was performed on 20 primary fallopian tube carcinoma specimens to find regions of the genome involved in tubal carcinogenesis and to compare the genomic alterations with those previously detected in serous ovarian and uterine carcinomas. The most frequent changes detected in fallopian tube carcinoma were gains at 3q (70%) and 8q (75%), with high-level amplifications in several cases. Other common gains occurred at 1q, 5p, 7q, 12p, and 20q. The most frequent losses were found at 18q, 8p, 4q, and 5q. The frequency and the pattern of chromosomal changes detected in tubal carcinoma were strikingly similar to those observed in serous ovarian and uterine carcinomas, suggesting common molecular pathogenesis.

Chromosome Aberrations↗

PubMed1998

A cloned human germ cell tumor-derived cell line differentiating in culture.

We have derived a clonal cell line (HGCT-1) from a lymph node metastasis of a primary testicular germ cell tumor (GCT). The tumor was negative for the embryonal carcinoma (EC) cell marker BerH2 but positive for vimentin, cytokeratin (CK) and desmin. Comparative genomic hybridization (CGH) revealed a high-level amplification at 12p that was observed in both the metastatic tumor and in the cultured HGCT-1 cells. In vitro, the phenotype of HGCT-1 cells was modulated by the culture conditions. In the presence of 10% fetal calf serum (FCS), the majority of HGCT-1 cells lacked CK and desmin. If cultured in 0.5% FCS, HGCT-1 cells acquired a uniform co-expression of vimentin, CK and desmin. Upon treatment with retinoic acid (RA), HGCT-1 cells lost the expression of desmin, but exhibited abundant CK filaments. Simultaneously, they started to express desmoplakin, form desmosomes and flatten on the culture substratum. The RA-induced changes were irreversible, whereas those following the culture in 0.5% FCS were at least partially reversible. When xenografted into an immunosuppressed rat, HGCT-1 cells formed a tumor consisting of epithelial- and mesenchymal-like structures. HGCT-1 cells thus represent a pluripotential cell system with a capacity for reversible phenotypic modulation and for irreversible differentiation into epithelial-type cells. The behavior of this novel cell line, distinct from established EC cell models, suggests a complex regulation of GCT cell differentiation.

Animals↗

PubMed1998

Genetic changes in inherited and sporadic ovarian carcinomas by comparative genomic hybridization: extensive similarity except for a difference at chromosome 2q24-q32.

Germ-line mutations in the BRCA1 and BRCA2 genes confer a predisposition to breast as well as ovarian carcinoma. Except for loss of the respective wild-type allele, somatic genetic changes needed for the progression of inherited ovarian tumors are unknown. A genome-wide search for such alterations was performed by comparative genomic hybridization analysis on BRCA1 and BRCA2 mutation-positive (n = 20) ovarian carcinoma specimens. Comparison with sporadic ovarian carcinomas (n = 20) revealed extensive genetic similarity between the inherited and sporadic carcinomas with the sole exception of a frequent gain of 2q24-q32 in the inherited group, suggesting the presence of an oncogene at 2q24-q32 operating in the absence of BRCA1 function. The overall similarity of gains and losses by comparative genomic hybridization suggests a common main pathway in tumor progression of both inherited and sporadic ovarian carcinomas.

Adolescent↗

PubMed1998

Cytogenetic chromosomal preparations using 2-methoxyestradiol.

The antimitotic drug 2-methoxyestradiol is an end metabolite of catechol estrogens. In vivo, it arrests cells in mitosis by interfering with the dynamics of the mitotic spindle without disrupting tubulin formation. It has a mitotic index similar to that of Colcemid in different cell lines. Here we report that 2-methoxyestradiol can be used for making cytogenetic preparations of comparable quality to that of colcemid. In addition, 2-methoxyestradiol is devoid of the toxicity associated with Colcemid, which may make 2-methoxyestradiol useful in slowly growing samples often found in primary solid tumor cultures where a sufficient number of mitotic cells is difficult to obtain.

2-Methoxyestradiol↗

PubMed1998

Distinct chromosomal imbalances in uterine serous and endometrioid carcinomas.

Endometrial carcinoma shows various histological types that differ in their clinical presentation and prognosis. Comparative genomic hybridization was used to detect gains and losses of DNA sequences along all chromosome arms in 24 uterine serous and 24 uterine endometrioid carcinomas. In serous carcinomas, extensive genetic aberrations were detected in 17 of the 24 specimens, with a mean of 5.7 changes per tumor. The most frequent gains occurred at 3q (50%), 8q (33%), 5p (29%), 6p (29%), and 1q (29%), and the most common losses were located at 4q (17%), 15q (17%), and 18q (17%). Tumors exhibiting DNA copy number changes were associated with shorter overall survival. In endometrioid carcinomas, genetic aberrations were less frequent and simpler than in serous carcinomas. DNA sequence copy number changes were observed in 12 of the 24 cases, with a mean of 1.5 changes per tumor. The most frequent aberrations were gains at 1q (29%), 2q (13%), and 8q (13%). Losses were rarely observed. The diverging pattern of genetic changes observed in uterine serous and endometrioid carcinomas suggests different pathways of carcinogenesis in these tumor types.

Chromosome Aberrations↗

PubMed1998

Comparison of fluorescein isothiocyanate- and Texas red-conjugated nucleotides for direct labeling in comparative genomic hybridization.

In this study, we investigated whether fluorescein isothiocyanate (FITC)-labeling of test DNA and Texas-red (TR) labeling of reference DNA in comparative genomic hybridization (CGH) experiments cause the results to differ from those obtained using the opposite combination (reverse labeling). Analysis was performed on a total of 20 DNA specimens consisting of 13 frozen bone marrow aspirates from patients with acute myeloid leukemia, and fresh peripheral blood samples from seven healthy donors. For CGH, one aliquot from each test DNA sample was labeled using nick-translation with FITC-dUTP and another with TR-dUTP. Afterwards, the FITC-dUTP and TR-dUTP-labeled test DNAs were hybridized to TR-dUTP- and FITC-dUTP-labeled normal reference DNAs, respectively. The results using the two combinations were compared with each other and with the results of G-banding karyotype analysis. Karyotype data was used to detect artifacts known to occur in some chromosome regions in CGH analysis. The control DNAs labeled with FITC or TR showed no DNA copy number changes. Regardless of the fluorochrome employed for labeling, no DNA copy number changes were detected using CGH in patients with normal karyotypes, nor in patients whose karyotype aberrations were present in less than 40% of cells. In the remaining patients, CGH revealed DNA copy number changes that coincided with the results of the G-banding analysis. Hybridization artifacts known to occur in CGH experiments affecting chromosome regions 1p33-pter, 16p, 17p, 19, and 22 were observed in 15-23% of the tumor samples labeled with FITC, but not in samples labeled with TR. In addition, other previously unreported overrepresentations affecting 7q21, 9q34, 16q, 17q, and chromosome 20 were observed at very low frequencies in up to 10% of the samples when FITC was used to label test DNA. However, when TR was used, overrepresentations were observed at 4q13-q21, 11q21-q23, 13q21-qter, and Xq21-q22, whereas 19p was underrepresented. The results demonstrate that TR-labeling confirms abnormalities detected using FITC-labeling and reduces hybridization artifacts in the known problematic regions of the human genome.

Adult↗

PubMed1998

Comparative genomic hybridization study on pooled DNAs from tumors of one clinical-pathological entity.

Comparative genomic hybridization (CGH) was performed using DNAs pooled from numerous specimens from tumor categories studied case-by-case. The series of six DNA pools consisted of 28 diffuse centroblastic lymphomas (DCL), 28 gastrointestinal stromal tumors (GIST), 21 primary chondrosarcomas (CS), 17 samples from the Ewing family of tumors (ET), 14 liposarcomas (LS), and 14 mesotheliomas (MS). Losses and gains present in at least 50% of the individual specimens were always detected in the pooled DNAs. The loss of the whole p-arm of chromosome 1 was observed even when the affected proportion of individual specimens was only 25%. Gains were also detected at frequencies lower than 50%, but with a high-level amplification in one or more specimens. In conclusion, the present pooled DNA study revealed the following changes: DCL had a gain at 18q22-qter; GIST had losses at 14 and 22q12, and gains at 5p, 8q22-24, 17q22-qter, and 19q13; ET had gains at 1q and 8q13-qter; LS had gains at 1q21-25 and 12q; and MS had a loss at 9p22-pter. No changes were observed in the CS DNA pool. The results from individual specimens also stressed the importance of these chromosomal regions to the tumorigenesis in the corresponding malignancies. This pooled DNA approach can thus be used for fast screening of recurrent DNA copy number in a specific tumor entity.

DNA, Neoplasm↗

PubMed1998

Radiation therapy for breast cancer and clonal chromosome translocations: a fluorescence in situ hybridization study.

The frequency of chromosomal translocations was analyzed in skin fibroblast cell cultures derived from irradiated and nonirradiated skin biopsies from five cases of breast adenocarcinoma in women, who had undergone radiotherapy after surgery. The study was performed at the first annual check-up. Chromosomal in situ suppression (CISS) hybridization was performed using metaphase nonisotopic fluorescence in situ hybridization (FISH) with library probes specific for chromosomes 1, 2, 3, 4, 5, 7, 8, 13, 19, and 20. The results showed that the frequency of clonal translocations in metaphases obtained from irradiated areas was significantly higher than in metaphases from the nonirradiated tissue samples.

Aged↗

PubMed1998

Consistent genetic alterations in xenografts of proximal stomach and gastro-esophageal junction adenocarcinomas.

The genetic alterations underlying the development of gastric and gastro-esophageal carcinoma remain largely undefined. DNA copy number changes were determined by comparative genomic hybridization in eight xenografts of proximal gastric and gastro-esophageal junction adenocarcinomas of the intestinal type. All tumors exhibited DNA copy number changes, with a total of 139 changes detected (range, 11-24 per tumor; mean = 17), indicating numerous and widespread alterations within these cancers. Gains (65%) in DNA copy number were more frequent than losses (35%). Our most striking finding was gain (all eight cases) or high-level amplification (four cases) in 20q, with a minimal common overlapping region at 20q13. Other frequent gains were observed at 6p, 7q, and 17q (six cases each) and at 1q, 2q, and 8q (five cases each). Frequent losses were observed at 4q and 5q (six cases each) and at 9p (five cases). No differences in DNA copy number changes were seen in tumors arising from the gastro-esophageal junction compared to those of the proximal stomach. The presence of common and consistent DNA copy number changes in these tumors implicate a number of chromosomal regions that may harbor important genes that are involved in tumorigenesis of the proximal stomach and gastro-esophageal junction.

Adenocarcinoma↗

PubMed1998

Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics.

Approximately 45% of adults with acute myeloid leukemia (AML) have normal cytogenetics and therefore lack structural abnormalities that can assist in the localization and characterization of molecular defects. The partial tandem duplication of the ALL1 (MLL) gene has been found in several such cases of AML, yet its frequency and clinical significance are unclear. We performed Southern analysis of the ALL1 gene in pretreatment samples from 98 AML patients with normal cytogenetics. Eleven of 98 such patients (11%; 95% confidence interval, 6-19%) showed rearrangement of ALL1 at diagnosis. The partial tandem duplication of ALL1 was responsible for ALL1 rearrangement in all such cases examined, making it a frequent molecular defect in adult AML patients with normal cytogenetics. Furthermore, patients with ALL1 rearrangement had a significantly shorter duration of complete remission when compared to patients without ALL1 rearrangement (P = 0.01; median, 7.1 versus 23.2 months). This defect defines for the first time a subset of AML patients with normal cytogenetics who have short durations of complete remission and thus require new therapeutic approaches.

Acute Disease↗

PubMed1998

A novel splice site mutation of the EXT2 gene in a Finnish hereditary multiple exostoses family. Mutations in brief no. 197. Online.

Hereditary multiple exostoses is a dominantly inherited disease characterized by multiple benign osteochondromas. The affected individuals have an increased risk of developing sarcoma. A large Finnish family with hereditary multiple exostosis was analyzed to find the disease-causing mutation. Blood samples were obtained from 35 family members, including 21 affected and 14 unaffected individuals. Using 2-point linkage analysis the EXT phenotype was shown to be linked to the recently cloned EXT2 gene on chromosome 11p11. The coding region of the gene was sequenced and a previously unreported splice site mutation found. This G to T transversion within a 5-prime splice donor site following exon 6 was shown to cause aberrant splicing of RNA. The described change is considered to be a novel disease-causing mutation in the EXT2 gene.

Alternative Splicing↗

PubMed1998

Gain of 3q and deletion of 11q22 are frequent aberrations in mantle cell lymphoma.

We used comparative genomic hybridization (CGH) to screen for DNA copy number changes in 34 specimens from 27 cases of mantle cell lymphoma (MCL). The most common gains were detected at 3q (52%), 8q (30%), and 15q (26%), whereas the most frequent losses involved 13q (41%), 1p (33%), 6q (30%), 9p (30%), and 11q (30%). The gain of 3q, with a minimal common region at 3q26.1-27, appeared in more than half of the lymphomas, suggesting the location of an important oncogene here. A common deleted region at 11q22 was found in one-third of the patients, which suggests that this region may harbor a tumor suppressor gene important in the tumorigenesis of MCL. The mean number of changes was higher in more aggressive blastoid variants of MCL than in lymphomas with typical morphology. Our results show that the chromosomal regions affected in MCL are highly consistent and are different from those seen in other types of non-Hodgkin's lymphoma.

Aged↗

PubMed1998

Chromosome band 1q21 is recurrently gained in desmoid tumors.

DNA sequence copy number changes were studied by comparative genomic hybridization (CGH) in 28 desmoid tumors. Changes were detected in 12 tumors (43%) with a mean of 1.4 changes per sample (range: 1 to 7). Out of 12 tumors associated with pregnancy or Gardner's syndrome, only two displayed changes. The minimal common regions of the most frequent gains were 1q21 (39%), chromosome 20 (32%), and 9p12 (21%). No high-level amplifications were detected. Losses of DNA sequences were two times less frequent than gains and the minimal common regions of the most frequent losses were 6q16-q21 (14%), 5q14 (11%), and 13q21-q31 (11%).

Adolescent↗