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Sverre Heim

Publications and source records attributed to Sverre Heim.

34 records · Page 2Linked to original sources
PubMed2003

Cytogenetic and molecular genetic analyses of endometrial stromal sarcoma: nonrandom involvement of chromosome arms 6p and 7p and confirmation of JAZF1/JJAZ1 gene fusion in t(7;17).

Endometrial stromal sarcomas (ESS) are rare neoplasms with the capacity both to invade the myometrium locally and to give rise to extrauterine metastases. Cytogenetic abnormalities have been reported in 22 cases of ESS, mostly involving rearrangements of chromosomes 6, 7, and 17. The most characteristic translocation of this tumor type, t(7;17)(p15 approximately p21;q12 approximately q21), was recently shown to generate a JAZF1/JJAZ1 fusion gene. We report three additional cases of ESS with abnormal karyotypes, whose interpretation was based on the combined analysis by conventional cytogenetics and cross-species color banding FISH (RxFISH). The combination of G-banding and RxFISH in every case gave additional information beyond that obtained by either technique alone, determining the identity of even complex inter- as well as intrachromosomal rearrangements. In one of the three tumors, a t(7;17) was seen; molecular genetic studies identified the JAZF1/JJAZ1 fusion gene in this case. Two tumors had aberrations that included structural changes of chromosome arms 6p and 7p. Evidently, karyotypic, and hence pathogenetic, heterogeneity exists for tumors classified as endometrial stromal sarcomas based on their phenotypic features.

Adult↗
PubMed2003

8q24 Copy number gains and expression of the c-myc mRNA stabilizing protein CRD-BP in primary breast carcinomas.

The coding region determinant binding protein (CRD-BP) was isolated by virtue of its high affinity to the c-myc mRNA coding region stability determinant and shown to shield this message from nucleolytic attack, prolonging its half-life. CRD-BP is normally expressed during fetal life but is also activated de novo in tumors. Considering that aberrant CRD-BP expression may represent an additional mechanism interfering with c-myc regulation, we screened 118 primary breast carcinomas for CRD-BP expression, 60 of which had also been analyzed by comparative genomic hybridization (CGH). Copy number gains encompassing 8q24, the chromosome band that contains the c-myc locus, were detected in 48.3% (29/60) of tumors, whereas gains involving band 17q21, which contains the CRD-BP locus, were observed in 18.3% (11/60) of tumors. CRD-BP expression was detected in 58.5% (69/118) of tumors, implying mechanisms of activation alternative to gene amplification. Altogether, some 75% of the tumors had alterations pertaining to c-myc since they either harbored 8q24 gains and/or expressed CRD-BP. Significant associations were detected between CRD-BP expression and the absence of estrogen receptors (p = 0.005) and between the presence of 8q24 gains and an increased number of genomic changes as measured by CGH (p = 0.0017). Tumors were divided into 4 groups according to CRD-BP expression and 8q24 gains. The odds for tumors having both characteristics to be classified as poorly differentiated (grade III vs. grade I and II) were 19.6 times the corresponding odds for tumors neither expressing CRD-BP nor harboring 8q24 gains. For tumors either harboring 8q24 gains only or expressing CRD-BP alone, the corresponding odds were 6.4 and 3, respectively.

Adult↗
PubMed2003

Cytogenetic characterization of tumors of the vulva and vagina.

Neoplasms of the vulva and vagina account for less than 5% of all female genital tract cancers. Squamous cell carcinoma (SCC) represents more than 70% of the cases in both locales, followed by melanoma, basal cell carcinoma, Paget's disease, and other carcinoma subtypes. Until recently, only few cases had been analyzed by chromosome banding techniques and karyotyped, and also the number subjected to molecular cytogenetic analysis remains low. To understand better the genetic changes harbored by the neoplastic cells in cancer of the vulva and vagina, we analyzed cytogenetically 51 such tumors, finding karyotypic abnormalities in 37. All tumors were analyzed by G-banding, sometimes supplemented by multicolor fluorescence in situ hybridization, and a subset of tumors was also analyzed by comparative genomic hybridization. The two cytogenetically abnormal cases of Paget's disease both had two clones, one with gain of chromosome 7 as the sole change, the other with loss of the X chromosome among, in one case, other aberrations. The four cytogenetically abnormal malignant melanomas (three of the vulva, one of the vagina) presented complex karyotypes with aberrations involving different chromosomes but most often chromosome 1, specifically 1p12-q41. In the 31 cytogenetically abnormal SCCs, different clonal karyotypic abnormalities were seen. Intratumor heterogeneity with multiple clones was observed in 11 cases. The clones were cytogenetically unrelated in eight tumors but related in three, indicating that in the latter clonal evolution had taken place from a single malignantly transformed cell. The main chromosomal imbalances were gains of, or from, chromosome arms 3q, 5p, 8q, 9q, and 19q, and loss from 11q. Breakpoint clusters were seen in 11q13-23, 2q22-35, and 19q13, as well as in the centromeres and pericentromeric bands of chromosomes 3, 8, 9, 13, 14, and 22.

Carcinoma in Situ↗
PubMed2003

Genome profiles of bilateral dysgerminomas, a unilateral gonadoblastoma, and a metastasis from a 46, XY phenotypic female.

We present a case report of a 16-year-old, phenotypic female with bilateral dysgerminomas, a unilateral gonadoblastoma, and a peritoneal metastasis. The patient's constitutional karyotype was 46,XY. The chromosomal copy number, examined by the comparative genomic hybridization technique, showed 3 gains in the dysgerminoma of the right ovary, 6 gains in the dysgerminoma of the left ovary, and 2 gains and 1 loss in the gonadoblastoma of the left ovary. The metastasis showed 5 gains of which 4 were also observed in the dysgerminoma of the left ovary. The DNA ploidy classifications of the gonadoblastoma and the dysgerminoma in the right ovary were tetraploid, whereas the dysgerminoma in the left ovary and the metastasis were aneuploid. We therefore propose that the metastasis most probably developed from the dysgerminoma of the left ovary.

Adolescent↗
PubMed2003

Chromosomal abnormalities in inflammatory pseudotumor of the urinary bladder.

Inflammatory pseudotumors of the urinary bladder are rare, benign, nonepithelial tumors. Fewer than 30 have been reported, and no data are available on their karyotypic characteristics and/or the molecular mechanisms of pathogenesis. We performed short-term culturing and cytogenetic analysis of an inflammatory pseudotumor of the bladder, finding a der(20)t(12;20)(q13 approximately q15;q13) as the only cytogenetic aberration. The detection of a 12q13 approximately q15 rearrangement in the inflammatory pseudotumor indicates that this lesion is pathogenetically related to other benign mesenchymal tumors displaying, for example, lipogenic or leiomyomatous differentiation, something that is in sharp contrast to the karyotypic profile of epithelial tumors of the urinary bladder mucosa.

Chromosome Aberrations↗
PubMed2003

Comparative cytogenetic and DNA flow cytometric analysis of 242 primary breast carcinomas.

The cytogenetic and DNA flow cytometric findings in 242 breast carcinomas were compared. The combined use of both techniques improved the detection of abnormal cell populations from 65% by cytogenetic analysis alone and 59% by DNA flow cytometric analysis alone to 84%. Informative and comparable cytogenetic and flow cytometric data were obtained for 155 tumors. Among these 155 tumors, there was good concordance (64%) between the estimates of genomic changes by the two methods. Most discrepancies were among the DNA-diploid cases, where cytogenetic analysis detected small genomic changes. There were, however, also some exceptions in which large genomic changes detected by one method were missed by the other. Of the specific breast cancer-associated cytogenetic aberrations subjected to separate correlation analysis, polysomy for chromosome 20 was significantly associated with a high S-phase fraction, whereas loss of the long arm of chromosome 16 and/or the presence of a der(1;16) were significantly associated with a low S-phase fraction. Our data show that cytogenetic and DNA flow cytometric analyses of breast carcinomas give largely comparable results, and that combining data from both methods significantly improves the information obtained by either technique used alone on the genetic abnormalities in these tumors.

Breast Neoplasms↗
PubMed2003

CD7 expression by CD34+ cells in CML patients, of prognostic significance?

The purpose of the study was to identify a unique immunophenotype of normal or Philadelphia chromosome positive (Ph+) CD34+ cells that might be used to purify normal CD34+ cells from chronic myelogenous leukemia (CML) patients. An immunophenotypical study of CD34+ bone marrow cells of 20 patients with CML at diagnosis and during hydroxyurea treatment, and 39 controls were performed. All patients were Ph+, two patients had variant translocations and three patients displayed cytogenetic signs of clonal evolution. The immature progenitor cell compartment (CD34+ HLA-DR- and CD34+ CD38- cells) was comparable. The CD34+ AC133+ progenitor cell compartment was decreased in CML patients. We found no difference for any of the adhesion molecules examined except for CD62L, where the percentage of CD34+ CD62L+ cells was decreased in CML patients. The number of myeloid progenitors (CD34+ CD33+) was increased at the expense of B-lymphoid progenitors (CD34+ CD10+ and CD34+ CD19+) in CML patients indicating that B-lymphopoiesis is inhibited in CML. The megakaryocytic (CD34+ CD61+) and erythroid (CD34+ CD71+) progenitors were increased in CML patients. The number of CD34+ CD7+ cells was also significantly increased (mean 25.3% vs. 4.9%). However, the level of CD7 expression was quite heterogeneous, and the patients could be separated into two populations according to CD7 expression (more or less than 20% CD7+ CD34+ cells). The Sokal and Hasford risk scores did not differ between CD34+ CD7- CML and CD34+ CD7+ CML, but all patients with signs of disease progression clustered in the CD34+ CD7+ population indicating that the level of CD7 expression on CD34+ cells may be of prognostic importance in CML.

Adult↗
PubMed2003

Cytogenetic abnormalities in childhood acute myeloid leukaemia: a Nordic series comprising all children enrolled in the NOPHO-93-AML trial between 1993 and 2001.

Between 1993 and 2001, 318 children were diagnosed with acute myeloid leukaemia (AML) in the Nordic countries. The patient group comprised 237 children < 15 years of age with de novo AML, 42 children < 15 years with Down syndrome (DS) and de novo AML, 18 adolescents 15-18 years of age with de novo AML, and 21 children < 15 years with treatment-related AML (t-AML). The first group was all-inclusive, yielding an annual childhood de novo AML incidence of 0.7/100 000. Cytogenetic analyses were successful in 288 cases (91%), and clonal chromosomal abnormalities were detected in 211 (73%). The distribution of ploidy levels were pseudodiploidy (55%), hyperdiploidy (34%) and hypodiploidy (11%). The most common aberrations (> 2%) were + 8 (23%) (as a sole change in 6.2%), 11q23-translocations, including cryptic MLL rearrangements (22%) [t(9;11)(p21-22;q23) in 11%], t(8;21)(q22;q22) (9.0%), inv(16)(p13q22) (6.2%), -7/7q- (5.2%), and t(15;17)(q22;q12) (3.8%). Except for +8, these abnormalities were rare in group 2; only one DS patient had a t(8;21) and none had 11q23-translocations, t(15;17) or inv(16). In the t-AML group, three cases displayed 11q23-rearrangements, all t(9;11); and there were no t(8;21), t(15;17) or inv(16). Overall, the observed frequencies of t(8;21) and t(15;17) were lower, and frequencies of trisomy 8 and 11q23-translocations higher, than in previous studies. Furthermore, seven abnormalities that were previously reported as only single AML cases were also seen, meaning that der(4)t(4;11)(q26-27;q23), der(6)t(1;6)(q24-25;q27), der(7)t(7;11)(p22;q13), inv(8)(p23q11-12), t(11;17)(p15;q21), der(16)t(10;16)(q22;p13) and der(22)t(1;22)(q21;q13) are now classified as recurrent abnormalities in AML. In addition, 37 novel aberrations were observed, 11 of which were sole anomalies.

Acute Disease↗
PubMed2002

Chromosomal aberrations in benign and malignant bilharzia-associated bladder lesions analyzed by comparative genomic hybridization.

BACKGROUND: Bilharzia-associated bladder cancer (BAC) is a major health problem in countries where urinary schistosomiasis is endemic. Characterization of the genetic alterations in this cancer might enhance our understanding of the pathogenic mechanisms of the disease but, in contrast to nonbilharzia bladder cancer, BAC has rarely been the object of such scrutiny. In the present study, we aimed to characterize chromosomal imbalances in benign and malignant post-bilharzial lesions, and to determine whether their unique etiology yields a distinct cytogenetic profile as compared to chemically induced bladder tumors. METHODS: DNAs from 20 archival paraffin-embedded post-bilharzial bladder lesions (6 benign and 14 malignant) obtained from Sudanese patients (12 males and 8 females) with a history of urinary bilharziasis were investigated for chromosomal imbalances using comparative genomic hybridization (CGH). Subsequent FISH analysis with pericentromeric probes was performed on paraffin sections of the same cases to confirm the CGH results. RESULTS: Seven of the 20 lesions (6 carcinomas and one granuloma) showed chromosomal imbalances varying from 1 to 6 changes. The most common chromosomal imbalances detected were losses of 1p21-31, 8p21-pter, and 9p and gain of 19p material, seen in three cases each, including the benign lesion. CONCLUSION: Most of the detected imbalances have been repeatedly reported in non-bilharzial bladder carcinomas, suggesting that the cytogenetic profiles of chemical- and bilharzia-induced carcinomas are largely similar. However, loss of 9p seems to be more ubiquitous in BAC than in bladder cancer in industrialized countries.

Animals↗
PubMed2002

Genome profiling of breast cancer cells selected against in vitro shows copy number changes.

About 20% of breast carcinomas show no clonal chromosome abnormalities when analyzed after short-term culturing. An interesting question is whether this subset of breast carcinomas really is karyotypically normal or if selection for normal cells occurred in vitro. To address this issue, 26 breast carcinomas that had shown no cytogenetic changes by chromosome banding analysis were examined by comparative genomic hybridization (CGH), a technique that does not require culturing or tumor metaphase cells. All but one case showed copy number changes by CGH (median, four). A comparison of these findings with those of a karyotypically abnormal series analyzed using the same CGH protocol found that the cytogenetically "normal" cases were typically genetically less complex (median, four and eight, respectively; P = 0.0058). Although largely the same alterations were found in both series, some differences with respect to the frequencies of specific imbalances were seen. Gains of 3p and 6q and losses of 10q, 14q, and 17p more often were found in the cytogenetically abnormal series than in the normal tumors. We conclude that in most instances cells found to be normal by chromosome banding analysis after short-term culture do not belong to the tumor parenchyma. Furthermore, when we compared the distribution of the number of imbalances detected by CGH in the total data set according to the mitotic index in vivo (scored from 1 to 3), the median values were three, seven, and 18, respectively (P < 0.001). These data indicate not only that karyotypically normal breast carcinomas may represent a genetically simpler subgroup that grows poorly in vitro but also that this subset of tumors already has a slow growth rate in vivo.

Breast Neoplasms↗
PubMed2002

Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is a soft-tissue neoplasm cytogenetically characterized by the translocations t(9;22)(q22;q11-12) or t(9;17)(q22;q11), generating EWS/CHN or RBP56/CHN fusion genes, respectively. In the present study, 18 EMCs were studied both cytogenetically and at the molecular level. Chromosomal aberrations were detected in 16 samples: 13 with involvement of 9q22 and 22q11-12, and three with rearrangements of 9q22 and 17q11. Fifteen cases had an EWS/CHN fusion transcript and three had an RBP56/CHN transcript. The most frequent EWS/CHN transcript (type 1; 10 tumors), involved fusion of EWS exon 12 with CHN exon 3, and the second most common (type 5; two cases) was fusion of EWS exon 13 with CHN exon 3. In all tumors with RBP56/CHN fusion, exon 6 of RBP56 was fused to exon 3 of CHN. By genomic XL PCR and sequence analyses, the breakpoints from 14 cases were mapped in the EWS, RBP56, and CHN genes. In CHN, 12 breakpoints were found in intron 2 and only two in intron 1. In EWS, the breaks occurred in introns 7 (one break), 12 (eight breaks), and 13 (one break), and in RBP56 in intron 6. Repetitive elements such as Alu and LINE sequences seem to have limited, if any, importance in the genesis of EWS/CHN and RBP56/CHN chimeras. Furthermore, there were no chi, chi-like, topoisomerase II, or translin consensus sequences in the introns harboring the translocation breakpoints, nor could the number of topo I sites in EWS, RBP56, and CHN introns explain the uneven distribution of the breakpoints among EWS or CHN introns. Additional genetic events, such as nucleotide insertions, homologies at the junction, deletions, duplications, and inversions, were found to accompany the translocations, indicating that the chromosomal translocations do not require sequence-specific recombinases or extensive homology between the recombined sequences.

Adult↗
PubMed2002

Cytogenetic clues to breast carcinogenesis.

The somatic mutation theory of cancer maintains that tumorigenesis is driven by genetic alterations, many of which are visible cytogenetically. We have examined breast cancer by chromosome banding analysis after short-term culturing of tumor cells and here review our findings in 322 karyotypically abnormal samples obtained since 1992 from 256 patients. The screening capabilities of this technique enabled us to identify several cytogenetic subgroups of breast cancer, to study the intratumor heterogeneity of breast carcinomas, and to compare primary tumors with their metastases. Using chromosome abnormalities as clonality markers, we could determine on an individual basis when multiple, ipsilateral or bilateral breast, tumors were independent de novo carcinomas and when they resulted from the spreading of a single malignant clone within one breast or from one breast to the other. The distribution of chromosomal breakpoints and genomic gains and losses is clearly nonrandom in breast cancer, something that can guide further investigations using molecular methods. Based on the total dataset, we propose a multipathway model of mammary carcinogenesis that takes into consideration the genetic heterogeneity revealed by the karyotypic findings and review the karyotypic-pathologic correlations and the possible clinical applications of the cytogenetic knowledge.

Breast Neoplasms↗
PubMedDate not supplied

Telomerase activity and genetic alterations in primary breast carcinomas.

It has been proposed that the structural and numerical chromosome abnormalities recorded in breast cancer could be the result of telomere dysfunction and that telomerase is activated de novo to provide a survival mechanism curtailing further chromosomal aberrations. However, recent in vivo and in vitro data show that the ectopic expression of telomerase promotes tumorigenesis via a telomere length-independent mechanism. In this study, the relation between telomerase expression and the extent of chromosomal aberrations was investigated in 62 primary breast carcinomas. Telomerase activity was measured using a polymerase chain reaction-based telomeric repeat amplification protocol assay and 92% of the tumors were found to express telomerase with a relative activity ranging from 0 to 3839.6. Genetic alterations were determined by G-banding and comparative genomic hybridization analysis and 97% of the tumors exhibited chromosomal aberrations ranging from 0 to 44 (average: 10.98). In the overall series, the relationship between telomerase activity levels and genetic changes could be best described by a quadratic model, whereas in tumors with below-average genetic alteration numbers, a significant positive association was recorded between the two variables (coefficient=0.374, P=.017). The relationship between telomerase activity levels and the extent of genetic alteration may reflect the complex effect of telomerase activation upon tumor progression in breast carcinomas.

Adult↗
PubMedDate not supplied

Molecular cytogenetic characterization of tenosynovial giant cell tumors.

Tenosynovial giant cell tumor (TSGCT) is a disease of disputed etiology and pathogenesis. Some investigations indicate a neoplastic origin of the tumors; others indicate that they are polyclonal and inflammatory. The cytogenetic and molecular genetic features of TSGCTs are largely unknown, as only some 20 localized and 30 diffuse tumors with cytogenetic aberrations have been reported. The most common karyotypic aberrations have been trisomy for chromosomes 5 and 7 and translocations involving chromosomal area 1p11-13. We decided to screen the genomes of TSGCTs by comparative genomic hybridization (CGH) to perform interphase fluorescence in situ hybridization (IP-FISH), looking for numerical aberrations of chromosomes 1, 5, and 7, and to analyze the tumors for microsatellite instability. Except for two diffuse TSGCTs that came fresh to us, and which, by karyotyping, exhibited t(1;22)(p13;q12) and a t(1;1)(q21;p11) and +7, respectively, all studies had to be performed on formalin-fixed, paraffin-embedded material. DNA was extracted from 51 localized and nine diffuse TSGCTs. CGH was successful for 24 tumors, but none of them showed copy number changes. The IP-FISH studies showed trisomy 7 in 56% of the tumors (15/27), whereas chromosomes 1 and 5 seemed to be disomic in all TSGCTs. All informative tumors were wild-type by microsatellite instability analysis.

Adolescent↗