bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular evidence that childhood monosomy 7 syndrome is distinct from juvenile chronic myelogenous leukemia and other childhood myeloproliferative disorders
Authors: Butcher Mark , Frenck Robert , Emperor John , Paderanga Dorothy , Maybee David , Olson Kristin , Shannon Kevin
Published: February 2007

The observation that juvenile chronic myelogenous leukemia (JCML) and childhood bone marrow monosomy 7 syndrome (Mo 7) are similar in many clinical and epidemiologic respects suggests a shared pathogenic basis and raises the possibility that the bone marrows of patients with JCML might lose chromosome 7 alleles by mechanisms that do not result in detectable cytogenetic deletions. We used a series of polymorphic markers mapped to chromosome 7 to test this hypothesis in 22 children with MPS and MDS, including 19 with JCML. All MPS and MDS samples demonstrated allelic heterozygosity with at least one chromosome 7 marker; 16 were heterozygous with probes from both 7p and 7q. Furthermore, the percentage of patient bone marrow samples heterozygous at each locus tested was similar to the frequency observed in the normal population. Whereas these data demonstrate that submicroscopic loss of large segments of chromosome 7 alleles is uncommon in children with MPS and MDS who do not have Mo 7, they do not exclude small deletions around an uncharacterized tumor‐suppressor locus. Our results suggest that a number of distinct molecular events contribute to leukemogenesis, and we propose a multistep model to explain the similarities and differences between the major subtypes of childhood MPS and MDS.
Allelic losses on chromosome band 11q13 in aldosterone‐producing adrenal tumors
Authors: Iida Aritoshi , Nakamura Yusuke , Imai Takashi , Blake Kirsten , Tunny Terry , Klemm Shelley , Stowasser Michael , Gordon Richard , Hayward Nicholas
Published: February 2007

We examined loss of heterozygosity (LOH) in 14 aldosterone‐producing adrenal tumors, with six linearly ordered restriction fragment length polymorphism (RFLP) markers that map within a 12‐cM region containing the MEN 1 locus on 11q13. Among 11 tumors that were informative for at least one marker, five showed LOH at one or more loci, and two distinct regions of deletion were identified. The proximal region overlapped with the location of the MEN 1 locus previously predicted by linkage analyses in MEN 1 families and the commonly deleted region in hyperparathyroid tumors. This suggests that one of the genes associated with development of aldosterone‐producing adrenal tumors may coincide with the MEN 1 locus, and that a second gene, distal to the MEN 1 locus, may also play a role in the development of this type of tumor.
Frequent Loss of Chromosome Arms 8p and 13q in Collecting Duct Carcinoma (CDC) of the Kidney
Authors: Schoenberg Mark , Brooks James D. , Marshall Fray F. , Epstein Jonathan I. , Isaacs William B. , Cairns Paul , Sidransky David
Published: February 2007

Collecting duct carcinoma (CDC) is a malignant renal neoplasm that is believed to arise from the epithelium of the ducts of Bellini in the distal nephron. These tumors are clinically aggressive and more often occur in a younger population than is typical of the more common clear cell renal carcinoma (RCC). Using highly informative polymorphic microsatellite markers on chromosome arms 3p, 5q, 6q, 8p, 9p, 9q, 11p, 13q, 17p, and 18q, we analyzed DNA from nonmalignant and tumor tissue in 6 cases of CDC. We found no evidence of 3p loss of heterozygosity (LOH) in these renal tumors by using multiple markers, a finding that distinguishes CDC from RCC in which 3p LOH has frequently been observed. We found LOH of 8p in 50% of the tumors examined; in addition, we observed LOH of 13q in 50% of the tumors studied. Interestingly, 8p LOH may be associated with high stage and poor clinical prognosis. These data suggest that the molecular events responsible for the development of CDC differ from those associated with the origin of RCC, and that tumor suppressor genes on 8p and 13q may be involved in the pathogenesis of CDC.
Expression of the wilms' tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet‐derived growth factor A and insulin‐like growth factor 2 expression
Authors: Langerak Anthonie W. , Williamson Kathleen A. , Miyagawa Kiyoshi , Hagemeijer Anne , Versnel Marjan A. , Hastie Nicholas D.
Published: February 2007

Mutations in the WT1 tumor suppressor gene are known to contribute to the development of Wilms' tumor (WT) and associated gonadal abnormalities. WT1 is expressed principally in the fetal kidney, developing gonads, and spleen and also in the mesothelium, which lines the coelomic cavities. These tissues develop from mesenchymal components that have subsequently become epithelialized, and it has therefore been proposed that WT1 may play a role in this transition of cell types. To test the possible involvement of this gene in malignant mesothelioma, we have first studied its expression in a panel of human normal and malignant mesothelial cell lines. WT1 mRNA expression levels varied greatly between the cell lines and no specific chromosomal aberration on 11p, which could be related to the variation in WT1 expression in these cell lines, was observed. Furthermore, no gross deletions, rearrangements, or functionally inactivating point mutations in the WT1 coding region were identified. All four WT1 splice variants were observed at similar levels in these cell lines. The WT1 gene encodes a zinc‐finger transcription factor and the four protein isoforms are each believed to act as transcriptional repressors of certain growth factor genes. Lack of WT1 expression is thus predicted to result in growth stimulation of tumor cells. Binding of one particular WT1 isoform construct to the insulin‐like growth factor 2 (IGF2) and platelet‐derived growth factor A (PDGFA) gene promoters has been demonstrated to result in repression of these genes in transient transfection studies. Analysis of IGF2 and PDGFA mRNA expression levels compared with WT1 mRNA expression levels failed to demonstrate an inverse correlation in the mesothelial cell lines, which endogenously express these genes. Finally, the putative role of WT1 in the transition of cell types was investigated. No obvious correlation between WT1 expression levels and cell morphology of the malignant mesothelial cell lines was evident from this study. Moreover, no change in WT1 expression was observed in normal mesothelial cells which were, by alteration of culture conditions, manipulated to switch from the mesenchymal to epithelial morphology.
N‐ and KRAS mutations in primary testicular germ cell tumors: Incidence and possible biological implications
Authors: Olie Robert A. , Looijenga Leendert H. J. , Boerrigter Lucie , Top Bert , Rodenhuis Sjoerd , Langeveld An , Mulder Maarten P. , Oosterhuis J. Wolter
Published: February 2007

Recently, conflicting results have been reported on the incidence of RAS mutations in primary testicular germ cell tumors of adults (TGCTs). In four studies a low incidence of mutations (less than 15%) in a variety of TGCTs or derived cell lines was found, whereas in two other studies a high incidence of N‐ or KRAS mutations (over 40%) was shown. A total of 62 testicular seminomas (SE) and 34 nonseminomatous TGCTs (NS) were studied thus far. The largest series consisted of 42 TGCTs, studied on paraffin embedded tissue. We present the results of analysis for the presence of N‐ and KRAS mutations, in codons 12, 13, and 61, in snap frozen samples of 100 primary TGCTs, comprising 40 SE and 60 NS. Using the polymerase chain reaction (PCR) and allele specific oligonucleotide hybridization (ASO), mutations were found in five SE (three in NRAS and two in KRAS, all codon 12), and in one NS (KRAS, codon 12). To exclude underestimation of the incidence of RAS mutations in TGCTs due to the presence of an excess of wild type alleles in the analyzed sample, a PCR technique preferentially amplifying KRAS alleles with a mutation in codon 12 was applied to all SE. This approach, allowing a 250 times more sensitive assay, resulted in the detection of only one additional SE with a mutation. Based on a critical analysis of published data and on our results from the largest series of frozen samples investigated thus far, we conclude that N‐ or KRAS mutations are rare and apparently not essential for initiation or progression of TGCTs.
Screening for germ‐line mutations in the NF2 Gene
Authors: Mérel Philippe , Hoang‐Xuan Khé , Sanson Marc , Bijlsma Emilia , Rouleau Guy , Laurent‐Puig Pierre , Pulst Stephan , Baser Michael , Lenoir Gilbert , Sterkers Jean Marc , Philippon Jacques , Resche François , Mautner Victor F. , Fischer Georges , Hulsebos Theo , Aurias Alain , Delattre Olivier , Thomas Gilles
Published: February 2007

Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease that predisposes to the development of tumors of the nervous system, particularly meningiomas and schwannomas. The gene which, when altered, causes NF2, is localized on chromosome 22 and has recently been identified. The NF2 gene is also the site of somatic mutation in tumors, suggesting that it might have a tumor suppressor activity. We here report a screening method for the detection of point mutations in NF2 which takes advantage of denaturing gradient gel electrophoresis (DGGE). This method efficiently screens 95% of the coding sequence and 90% of intron/exon junctions. When applied to 91 unrelated NF2 patients, it enabled the identification of 32 germ‐line mutations. Since mutations are found in only one third of the patients, it is expected that mutations or deletions affecting the promoter and/or intronic regions of the NF2 gene occur frequently. The characterized mutations are preferentially located within the 5° half of the gene. Most of them are predicted to lead to the synthesis of a truncated protein. A search for genotype/phenotype correlations showed that, at least in this series of patients, mild manifestations of the disease were associated with mutations which preserve the C‐terminal end of the protein.
A genetic model of melanoma tumorigenesis based on allelic losses
Authors: Walker Graeme J. , Palmer Jane M. , Walters Marilyn K. , Hayward Nicholas K.
Published: February 2007

Previous karyotypic studies have indicated a possible series of non‐random chromosomal events involved in progression of melanoma. We sought to verify and augment this model of melanocyte tumorigenesis by studying allelic deletions of markers mapping to these regions in 30 matched pairs of melanoma and constitutional DNA samples. Polymorphic loci on chromosomes 1, 7, 10, 11, 17, and 21 were analyzed and data combined with those previously obtained for chromosome arms 6q and 9p in the same series of tumours. The most frequent and earliest deletions were found on 9p (57%) and 10q (32%). With the exception of one case, no sample had loss of markers on another chromosome without concomitant loss of markers on 9p or 10q. Losses on 6q were also a frequent (31%) and early event whereas losses of loci on distal 1p (22%) or 11q (26%) occurred only in metastatic melanomas. A “background” rate (0–17%) of allele loss was seen on chromosomes 7, 17, and 21. These data strongly support the previous model based on karyotypic findings in melanocytic lesions. However, we have been able to further augment that model by delimiting the regions of loss on 10q, to that distal to D10S254, and on 1p, to between D1S243 and D1S160.
Chromosome analysis of 97 primary breast carcinomas: Identification of eight karyotypic subgroups
Authors: Pandis Nikos , Jin Yuesheng , Gorunova Ludmila , Petersson Catarina , Bardi Georgia , Idvall Ingrid , Johansson Bertil , Ingvar Christian , Mandahl Nils , Mitelman Felix , Heim Sverre
Published: February 2007

Chromosome banding analysis of 97 short‐term cultured primary breast carcinomas revealed clonal aberrations in 79 tumors, whereas 18 were karyotypically normal. In 34 of the 79 tumors with abnormalities, two to eight clones per case were detected; unrelated clones were present in 27 (34%) cases, whereas only related clones were found in seven. These findings indicate that a substantial proportion of breast carcinomas are of polyclonal origin. Altogether eight abnormalities were repeatedly identified both as sole chromosomal anomalies and as part of more complex karyotypes: the structural rearrangements i(1)(q10), der(1;16)(q10;p10), del(1)(q11–12), del(3)(p12–13p14–21), and del(6)(q21–22) and the numerical aberrations +7, +18, and +20. At least one of these changes was found in 41 (52%) of the karyotypically abnormal tumors. They identify a minimum number of cytogenetic subgroups in breast cancer and are likely to represent primary chromosome anomalies in this type of neoplasia. Other candidates for such a role are translocations of 3p12–13 and 4q21 with various partner chromosomes and inversions of chromosome 7, which also were seen repeatedly. Additional chromosomal aberrations that give the impression of occurring nonrandomly in breast carcinomas include structural rearrangements leading to partial monosomies for 1p, 8p, 11p, 11q, 15p, 17p, 19p, and 19q and losses of one copy of chromosomes X, 8, 9, 13, 14, 17, and 22. The latter changes were seen consistently only in complex karyotypes, however, and we therefore interpret them as being secondary anomalies acquired during clonal evolution.
Detection of the t(2;13)(q35;q14) and PAX3‐FKHR fusion in alveolar rhabdomyosarcoma by fluorescence in situ hybridization
Authors: Biegel Jaclyn A. , Nycum Lynn M. , Valentine Virginia , Barr Frederic G. , Shapiro David N.
Published: February 2007

Cytogenetic studies of the pediatric solid tumor alveolar rhabdomyosarcoma have demonstrated the presence of a consistent chromosomal translocation, t(2;13)(q35;q14). We recently identified PAX3 and FKHR as the genes on chromosomes 2 and 13, respectively, that are juxtaposed by this translocation. As one means of detecting the t(2;13) translocation in clinical specimens, we have developed a fluorescence in situ hybridization (FISH) assay that may be used for both interphase and metaphase cells. Translocation of the 5′ region of the FKHR gene to the derivative chromosome 2, and retention of the 3′ region of FKHR on the derivative chromosome 13 [(der(13)], were demonstrated in metaphase cells from a rhabdomyosarcoma cell line with a previously identified t(2;13) translocation. A 5′ PAX3 cosmid probe was shown to localize to 2q35 in normal cells, and to translocate to the der(13) in the rhabdomyosarcoma cell line. In order to detect the der(13) in interphase nuclei, we labeled the 3′FKHR and the 5′PAX3 cosmid probes with digoxigenin and biotin, respectively, and used these in a two‐color FISH assay. The presence of the der(13) was visualized as juxtaposed or overlapping red and green signals in metaphase and interphase tumor cells. The PAX3‐FKHR FISH assay was then applied to a series of cytogenetically characterized pediatric sarcoma cell lines. The presence of the der(13) was demonstrated by FISH in all cases containing a cytogenetically detectable t(2;13). The FISH assay was then applied to a series of 20 embryonal and alveolar rhabdomyosarcoma samples. All 10 of the alveolar rhabdomyosarcoma specimens demonstrated a der(13) with the FISH assay. We did not detect a PAX3‐FKHR fusion in 10 embryonal rhabdomyosarcoma cases. Thus, the two‐color FISH assay is a sensitive and rapid means of identifying the t(2;13) in rhabdomyosarcoma specimens, and it will be a useful adjunct for the diagnosis of pediatric small round cell tumors. The cosmid probes for the 5′ and 3′ regions of FKHR, as well as the probe for PAX3, will be useful for molecular cytogenetic studies of variant translocations in rhabdomyosarcoma, such as the t(1;13)(p36;q14).
Comparative genomic hybridization in the investigation of myeloid leukemias
Authors: Bentz Martin , Döhner Hartmut , Huck Karin , Schütz Barbara , Ganser Arnold , Joos Stefan , Manoir Stanislas Du , Lichter Peter
Published: February 2007

Comparative genomic hybridization (CGH) was used for the examination of ten cases of myeloid leukemia (eight acute myeloid leukemias and two myelodysplastic syndromes). In five cases, genomic gains or losses were identified, which mapped to chromosomal regions known to be involved in this group of malignancies. In comparison to the results obtained by banding analysis, discrepancies were found in three of the ten cases; in two cases, chromosomal imbalances were not identified by CGH because they were present only in small subclones. In the other case, there were no evaluable metaphase cells for banding analysis; CGH revealed an overrepresentation of chromosome 8, which was confirmed by interphase cytogenetics with a chromosome 8‐specific alphoid probe. All abnormalities revealed by CGH were confirmed by G‐banding or subsequent interphase cytogenetic analysis, which demonstrates the high specificity of the method. Furthermore, in all cases, CGH identified the chromosomal imbalances present in the major clone as detected by banding analysis. The good correlation between CGH and chromosome banding results in myeloid leukemias makes this tumor a good model for the assessment of tools that are developed for automated and quantitative CGH analysis.
Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma
Authors: Eng Charis , Mulligan Lois M. , Smith Darrin P. , Healey Catherine S. , Frilling Andrea , Raue Friedhelm , Neumann Hartmut P. H. , Pfragner Roswitha , Behmel Annemarie , Lorenzo Maria J. , Stonehouse Timothy J. , Ponder Margaret A. , Ponder Bruce A. J.
Published: February 2007

Medullary thyroid carcinoma (MTC) occurs sporadically or as part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. In MEN 2A, germline missense mutations are found in one of five cysteine codons within exons 10 and 11 in the extracellular domain of the RET protooncogene. In MEN 2B, germline mutations occur in codon 918 (exon 16) within the catalytic core of the tyrosine kinase domain. To determine if RET mutations similar to those in MEN 2A and 2B play a role in the pathogenesis of sporadic MTC, we analysed 71 sporadic tumours comprising 68 primary tumours and three cell lines, for mutations in RET exons 10, 11, and 16. We found that 23% of sporadic MTC had RET codon 918 mutations, while only 3% had exon 10 mutations, and none had mutations in exon 11. We found no exon 16 mutations in MTC from 14 MEN 2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN 2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumourigenesis of a significant minority of sporadic MTC but not MEN 2A tumours. In addition to their biological interest, these findings may have some clinical application in determining whether a patient presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome.
Cytogenetic and histologic findings in 17 pulmonary chondroid hamartomas: Evidence for a pathogenetic relationship with lipomas and leiomyomas
Authors: Fletcher Jonathan A. , Longtine Janina , Wallace Kristin , Mentzer Steven J. , Sugarbaker David J.
Published: February 2007

Pulmonary chondroid hamartomas (PCH) are benign tumors that contain mesenchymal and epithelial components. In this series, we identified clonal chromosome aberrations in mesenchymal cells from 10 of 17 PCH. Chromosome band 12q15 was rearranged most frequently (N = 4), and one case had a t(12;14)(q15;q24) that was identical cytogenetically to the characteristic translocation in uterine leiomyomas. Histologic review revealed diverse mesenchymal populations, including undifferentiated cells, cartilage, adipose tissue, and smooth muscle, in most of the PCH. These findings suggest that PCH result from neoplastic transformation of a primitive mesenchymal cell that differentiates along chondroid, adipose, and smooth muscle pathways.
Interphase cytogenetics of prostatic adenocarcinoma and precursor lesions: Analysis of 25 radical prostatectomies and 17 adjacent prostatic intraepithelial neoplasias
Authors: Alers Janneke C. , Krijtenburg Pieter Jaap , Vissers Kees J. , Bosman Fré T. , van der Kwast Theodorus H. , Van Dekken Herman
Published: February 2007

Twenty‐five radical prostatectomy specimens were screened for the presence of numerical chromosome changes within the adenocarcinoma as well as in 17 adjacent prostatic intraepithelial neoplasias (PIN) by means of interphase in situ hybridization (ISH) to routinely processed tissue sections. To this end a defined alfoid repetitive DNA probe set was used, specific for the centromeres of chromosomes 1, 7, 8, 10, 15, and Y. The cytogenetic information was correlated with histopathological and clinical features as well as with DNA ploidy. Numerical aberrations of at least one chromosome were shown in 13 of 25 cases (52%). Alterations of chromosome 8 and loss of the Y chromosome were the most frequent findings (both 20%), followed by loss of chromosomes 15 (16%) and 10 (12%). Gain of chromosome 7 was seen in 8% of cases. No aberrations of chromosomes 7, 8, 10, and 15 were found in the adjacent PIN lesions, whereas loss of the Y chromosome in both PIN and tumor occurred in two cases. Also, (low level) aneuploidy was observed in 76% of these PIN lesions. Ploidy of the carcinomas as assessed by ISH correlated well with ploidy measured by DNA flow cytometry (FCM; P < 0.02). Due to the more specific correspondence between ISH and tumor pathology, pathologic grade correlated with ISH aneuploidy (P < 0.05), whereas FCM ploidy did not. Furthermore, genetic heterogeneity within a tumor was seen, as judged by the focal appearance of chromosomal aberrations. Chromosomal alterations occurred in all grades and stages, although loss of chromosome 10, gain of chromosome 7, and aberrations of chromosome 8 tended to predominate in more advanced cancers.
Suppression of endometrial carcinoma cell tumorigenicity by human chromosome 18
Authors: Yamada Hideto , Sasaki Masahiro , Honda Tsuyoshi , Wake Norio , Boyd Jeff , Oshimura Mitsuo , Barrett J. Carl
Published: February 2007

Presumptive tumor suppressor genes may be localized to specific chromosomes by the procedure of microcell fusion, whereby individual chromosomes derived from normal human cells are introduced into tumor cells. Allelic loss on chromosome I 8 is commonly seen in endometrial carcinoma, and the DCC gene on chromosome arm 18q is a potential human tumor suppressor gene. In this study, we investigated the hypothesis that a gene on chromosome 18, possibly DCC, is capable of suppressing the tumorigenicity of endometrial carcinoma cells. Microcells from the mouse A9 cell clone containing one human chromosome I8 tagged with the pSV2‐neo plasmid were fused with the highly tumorigenic endometrial carcinoma cell lines HHUA and Ishikawa, and G418‐resistant microcell hybrids containing an extra copy of chromosome I8 were isolated. Clones isolated from the HHUA cell line were completely suppressed for tumorigenicity in nude mice, and clones from the lshikawa line were suppressed or inhibited for tumorigenicity. In contrast, growth rates in vitro were not significantly affected in clones from either parental cell line. DCC expression was elevated in most of the suppressed hybrids. These results indicate that a gene on human chromosome I 8 is capable of suppressing the tumorigenicity of endometrial carcinoma cells, and that DCC is a candidate for this endometrial carcinoma tumor suppressor gene. © 1995 Wiley‐Liss, Inc.
dic(9; 20): A new recurrent chromosome abnormality in adult acute lymphoblastic leukemia
Authors: Rieder Harald , Schnittger Susanne , Bodenstein Heinrich , Schwonzen Martin , Wörmann Bernhard , Berkovic Dinko , Ludwig Wolf‐Dieter , Hoelzer Dieter , Fonatsch Christa
Published: February 2007

Loss of chromosome 20 and rearrangement of the short arm of chromosome 9 were identified by banding analysis of three adult patients with acute lymphoblastic leukemia (ALL). The G‐banding pattern suggested and identical deletion of 9p, but, also, an unbalanced translocation with chromosome 20 was taken into consideration. Dual‐color chromosome painting with probes for chromosomes 9 and 20 revealed the presence of material from chromosome 20 at the short arm of the abnormal chromosome 9 in all three cases. Centromeric alpha‐satellite DNA of both chromosome 9 and chromosome 20 was demonstrated by fluorescence in situ hybridization and indicated the presence of a dicentric chromosome. The hybridization of a YAC clone of the short arm of chromosome 20 proved that the dicentric chromosome contained the short arm of chromosome 20, which had been suspected from the G‐banding pattern. Thus, the rearrangement was interpreted as dic(9; 20)(pl I;qi I . ? I). Because this was the sole chromosome abnormality in two patients, dic(9; 20) may be a primary chromosome aberration in ALL. In one case, a 9q+ chromosome derived from a Philadelphia (Ph) translocation was involved in the formation of the dicentric chromosome. Immunophenotyping revealed CD 1o+ B‐cell precursor ALL in all three cases. Whereas the two patients in whom dic(9; 20) was the sole cytogenetically detectable change are in continuous complete remission for 10 and 45 months, respectively, the Ph+ patient relapsed with leukemia and died 8 months after diagnosis. © 1995 Wiley‐Liss, Inc.
Involvement of chromosomes 17 and 22 in dermatofibrosarcoma protuberans
Authors: Minoletti Fabiola , Miozzo Monica , Pedeutour Florence , Sard Laura , Pilotti Silvana , Azzarelli Alberto , Turc‐Carel Claude , Pierotti Marco A. , Sozzi Gabriella
Published: February 2007

Literature on the cytogenetics of dermatofibrosarcoma protuberans (DFSP) is limited; only I0 cases with chromosome aberrations have been reported. They are karyotypically characterized by the presence of supernumerary ring(s), either as the sole cytogenetic abnormality or together with a few additional structural or numerical changes. We report the cytogenetic and fluorescence in situ hybridization (FISH) analysis of three new DFSP, one primary and two recurrent tumors. In two cases we found a supernumerary ring as the sole change, whereas the third had two copies of a marker chromosome and monosomy of chromosome 22. Sequences of chromosomes I7 and 22 were identified by FISH in the supernumerary rings and in the markers. The fluorescence pattern suggested that additional sequences were present in the two rings, but showed that the marker chromosomes were entirely painted by chromosome 17 and 22 probes. The findings indicate that juxtaposition and/or amplification of chromosome 17 and 22 sequences could be crucial in the pathogenesis of DFSP. © 1995 Wiley‐Liss, Inc.
Cytogenetic and molecular studies on the neuroblastoma cell line NGP: Identification of a reciprocal t(I;I5) involving the “consensus region” Ip36. I
Authors: Muresu Rosella , Casciano Ida , Volpi Emanuela V. , Siniscalco Marcello , Romani Massimo
Published: February 2007

A reciprocal t(I; 15)(p36.1–36.3;q25‐26) has been identified in an established neuroblastoma cell line (NGP) that earlier studies had shown to carry, among others, a rearrangement at the Ip subtelomeric region. Though it has not been possible to establish whether this translocation was constitutional, it is of interest to note that one of the breakpoints is located within the well‐known Ip consensus site of tumor‐associated chromosomal rearrangements where, as a result of the reciprocal translocation, the FES oncogene has been transferred from autosome IS. It is to be expected that the molecular cloning of the I p and I 5q translocation breakpoints may yield crucial data for understanding the association between specific chromosomal rearrangements and malignant tumor progression.
Molecular basis of IIq23 rearrangements in hematopoietic malignant proliferations
Authors: Bernard Olivier A. , Berger Roland
Published: February 2007

Chromosomal abnormalities of the 11q23 band occur frequently in various hematopoietic malignant disorders. Because numerous partner chromosomes have been previously described, it is now important to determine the number of genes involved at 11q23 and to clarify the role of the partner genes. Recent efforts in several laboratories have identified a trithorax‐related gene that is involved in most of the 11q23 abnormalities. The aim of this review is to summarize the recent data concerning these 11q23 rearrangements and the understanding of their consequences.
Correlation between the proportion of Philadelphia chromosome‐positive metaphase cells and levels of BCR‐ABL mRNA in chronic myeloid leukaemia
Authors: Lin Feng , Chase Andrew , Bungey Julie , Goldman John M. , Cross Nicholas C. P.
Published: February 2007

We have sought to define the relationship between the proportion of marrow metaphases showing the Philadelphia chromosome (Ph) and levels of BCR‐ABL mRNA assessed by quantitative polymerase chain reaction (PCR) in patients with chronic myeloid leukaemia (CML). From a total of 141 patients, 164 PCR assays were performed on peripheral blood samples taken within 2 weeks of a bone marrow specimen analysed by cytogenetics. BCR‐ABL mRNA was quantified in all 106 PCR‐positive samples by competitive PCR; results ranged from < 10 to 3.4 × 106 transcripts/μg RNA. Twenty‐one chronic‐phase patients had a median of 5.0 × 105 BCR‐ABL transcripts/μg RNA; no difference in levels of the fusion mRNA was found between 15 Ph‐positive and six Ph‐negative, BCR‐ABL‐positive patients. Ph‐positive metaphases were not detected in any individual who was PCR negative (n = 58) and in only a single patient who was PCR positive with < 103 BCR‐ABL transcripts/μg RNA (n = 44). Conversely, of 41 samples from patients in haematological remission who had >103 BCR‐ABL transcripts/μg RNA, 30 had at least one Ph‐positive metaphase. The highest level of BCR‐ABL transcripts at which Ph‐positive metaphases were not detected was 1.5 × 104. For the 46 patients who had at least one Ph‐positive metaphase, a good correlation (Spearman coefficient = 0.83, P <0.0001) was found between the percentage of Ph‐positive metaphases and BCR‐ABL transcript levels. We conclude that quantitative PCR for BCR‐ABL is an effective method for monitoring CML patients after bone marrow transplantation and is less invasive than conventional cytogenetic studies of bone marrow. © 1995 Wiley‐Liss, Inc.
Molecular analysis of a t(II;22) translocation junction in a case of Ewing's sarcoma
Authors: Bhagirath Thounaojam , Abe Syuiti , Nojirna Takayuki , Yoshida Michihiro C.
Published: February 2007

Polymerase chain reaction (PCR)‐directed sequence analysis was performed to characterize the genomic and cDNA breakpoint junctions of t(11; 22) (q24; q12) translocation in a case of Ewing's sarcoma, in which the EWS gene located on chromosome 22 is rearranged with the FLII gene located on chromosome 11. RNA‐PCR revealed the novel chimeric product of EWS/FLII gene on the derivative chromosome (der) 22, resulting from a probable fusion of EWS exon 7 to FLII exon 9. Sequencing of the PCR‐amplified genomic fragments of the fusion genes showed that the breakpoints on der(22) occurred in EWS intron 7 and, most probably, in FLII intron 8. Those of the untranxribed counterpart on der(11) were located in the same FLII intron and in EWS exon 11, with deletion of a considerable amount of sequences from both genes. These findings indicate asymmetric junction at the molecular level in the present t(11; 22). None of the reported conserved sequences that mediate other cancer chromosome translocations was observed around the genomic junctions. Instead, a palindromic hexamer 5′‐GCTAGC‐3′ was found to flank the breakpoints of both genes on der(22), which may have a functional significance in the genesis of the t(11; 22). © 1995 Wiley‐Liss, Inc.
BCR/ABL fusion located on chromosome 9 in chronic myeloid leukemia with a masked Ph chromosome
Authors: Mohamed Anwar N. , Koppitch F. , Varterasian M. , Karanes C. , Yao Kai‐Ling , Sarkar F. H.
Published: February 2007

A reciprocal translocation, t(10; 22) (q22; q11), resulting in a masked Ph chromosome was identified in a patient diagnosed with chronic myeloid leukemia (CML). Both homologs of chromosome 9 were of the normal pattern. Two signals for the ABL probe, both of them hybridized to chromosome 9, were demonstrated via fluorescence in situ hybridization (FISH). Furthermore, cohybridization with two differently labeled BCR/ABL translocation DNA probes indicated a BCR/ABL fusion apparently located on 9q34. Molecular studies revealed a rearrangement of the BCR region and expression of a chimeric BCR/ABL mRNA of CML configuration. These findings indicate that the BCR/ABL fusion resulted from an unusual relocation of the BCR gene from its normal position on 22ql I to 9q34 adjacent to the ABL gene.
The t(II; 22)(pI5.5; qII.23) in a retroperitoneal rhabdoid tumor also includes a regional deletion distal to CRYBB2 on 22q
Authors: Besnard‐Guérin Corinne , Cavenee Webster , Newshams Irene
Published: February 2007

Translocations and deletions involving chromosomal band 22q 11 are common genetic aberrations in malignant rhabdoid tumors. Previous molecular analyses of a t(11; 22) in the malignant rhabdoid tumor cell line TM87‐16 localized the breakpoint distal to BCR on 22q 11. In the present report, we have further refined the map position of this breakpoint between CRYBB2 and D22S258. Moreover, the D22S258, CRYBA4, D22S300, D22SI, and D22S310 loci, which lie between CRYBB2 and D22S42, were found to be deleted, presumably as a result of the translocation event. The identification of this deletion of at least 2 Mb on the long arm of chromosome 22 should be helpful for mapping the gene(s) in the region involved in the development of malignant rhabdoid tumors as well as providing insights into the mechanisms of chromosomal translocation in human solid tumors.
Localization of a tumor suppressor gene associated with progression of human prostate cancer within a 1.2 Mb region of 8p22‐p21.3
Authors: Suzuki Hiroyoshi , Emi Miburu , Komiya Akira , Fujiwara Yoshiyuki , Yatani Ryuichi , Nakamura Yusuke , Shimazaki Jun
Published: February 2007

Human prostate cancers frequently show loss of heterozygosity at loci on the short arm of chromosome 8. In order to take a step toward isolation of the putative tumor suppressor gene(s) on 8p via positional cloning, we performed high‐resolution deletion mapping in 46 prostate cancers (stage B, 20 cases; stage C, 8 cases; endocrine therapy‐resistant cancer death, 18 cases) using new 12 restriction fragment length polymorphism markers for this chromosomal region. Allelic losses were observed in 25 of the 44 cases (57%) that were informative with at least one locus. Detailed deletion mapping defined a 1.2 Mb commonly deleted region at 8p22‐p2 1.3 flanked by markers cMSR‐32 and C18‐ 105 1. A second region of common deletion was identified between C18‐1312 and C18‐494 at 8p21‐8p11.22, suggesting that at least two tumor suppressor genes associated with prostate cancer are present on chromosome arm 8p. Allelic losses on 8p were observed more frequently in the cancer death cases (14/17, 82%) than in early‐stage tumors (11/27, 40%; P < 0.01, Fisher's exact test). In two out of 7 patients for whom DNA was available from metastatic cancers as well as from normal tissues and primary tumors, the primary cancer foci had no detectable abnormality of 8p, but the metastatic tumors showed loss of heterozygosity. These results suggest that inactivation of tumor suppressor genes on 8p plays an important role in the progression of prostate cancer. © 1995 Wiley‐Liss, Inc.
Identification of novel regions of altered DNA copy number in small cell lung tumors
Authors: Levin Nikki A. , Bnorka Piur M. , Warnock Martha L. , Gray Joe W. , Christman Michael F.
Published: February 2007

Identification of the genetic alterations that occur in tumors is an important approach to understanding tumorigenesis. We have used comparative genomic hybridization (CGH), a novel molecular cytogenetic method, to identify the gross DNA copy number changes that commonly occur in small cell lung cancer (SCLC). We analyzed ten SCLC tumors (seven primary tumors and three metastases) from eight patients. We found frequent increases in DNA copy number on chromosome arms Sp, 8q, 3q, and Xq and frequent decreases in copy number on chromosome arms 3p. 17p, Sq, 8p, 13q, and 4p. The increase in copy number at 8q24 (MYC) and decreases at 17p 13 (TP53), 13q 14 (RB), and 3p have previously been identified in SCLC with other methods. Many of the other regions in which we detected common copy number changes have not been reported to be regions of common alteration in SCLC tumors. Comparison of copy number changes between a primary tumor and a metastasis from the same patient showed that they were more closely related to each other than to any of the other tumors. The results of direct CGH analysis of SCLC tumors reported here confirm the existence of copy number changes that we identified previously by using cell lines. © 1995 Wiley‐Liss, Inc.
High allele loss rates at I7q I2‐q2I in breast and ovarian tumors from BRCAI‐linked families
Authors: Cornelis R. S. , Neuhausen S. L. , Johansson O. , Arason A. , Kelsell D. , Ponder B. A. J. , Tonin P. , Hamann U. , Lindblom A. , Lalle P. , Longy M. , Olàh E. , Scherneck S. , Bignon Y. ‐J. , Sobol H. , Chang‐Claude J. , Larsson C. , Spurr N. , Borg A. , Barkardottir R. B. , Narod S. , Devilee P.
Published: February 2007

Loss of heterozygosity (LOH) was evaluated in 174 breast and ovarian tumors derived from 94 families with at least 3 first‐degree relatives affected with either of these cancers. By linkage analysis 26 families were identified as having a high posterior probability of being due to BRCAI (the breadovarian cancer susceptibility locus on 17q 12–21) with lod scores varying from 0.5 1 to 9.49. Tumor genotypes were determined at at least 2 constitutionally heterozygous markers flanking BRCA I in a total of 58 tumors from these families. These tumors were derived from 52 patients, the BRCAI mutation carrier status of which was evidenced by DNA sequencing in 20, and inferred by reconstructing haplotypes in the remainder. LOH was detected in 50 (86%) tumors. and invariably involved the wild‐type allele. Where informative, this allele was of paternal origin in 33 cases and of maternal origin in I0 cases. These results strongly suggest that BRCA I is a tumor suppressor gene and that LOH is greatly favored to fully inactivate it. © 1995 Wiley‐Liss, Inc.
Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas
Authors: Mérel P. , Hoang‐Xuan K. , Sanson M. , Moreau‐Aubry A. , Bijlsma E. K. , Lazaro C. , Moisan J. P. , Resche F. , Nishisho I. , Estivill X. , Delattre J. Y. , Poisson M. , Theillet C. , Hulsebos T. , Delattre O. , Thomas G.
Published: February 2007

The NF2 gene is a putative tumor‐suppressor gene that, when it is altered in the germline, causes neurofibromatosis type 2, a tumor‐susceptibility disease that mainly predisposes to schwannomas and meningiomas. The recent isolation of the NF2 gene on chromosome 22 allows the identification of somatic mutations in human tumors. We have searched for mutations of the NF2 gene in 331 primary human tumors using a screening method based on denaturing gradient gel electrophoresis, which allows the detection of mutations in 95% of the coding sequence. Mutations were observed in 17 of 57 meningiomas and in 30 of 89 schwannomas. No mutations were observed for 17 ependymomas, 70 gliomas, 23 primary melanomas, 24 pheochromocytomas, 15 neuroblastomas, 6 medulloblastomas, 15 colon cancers, and 15 breast cancers. All meningiomas and one‐half of the schwannomas with identified NF2 mutations demonstrated chromosome 22 allelic losses. We conclude that the involvement of the NF2 gene in human tumorigenesis may be restricted to schwannomas and meningiomas, where it is frequently inactivated by a two‐hit process. © 1995 Wiley‐Liss, Inc.
U937 cell line has a t(I0;II)(pI3–I4;qI4–2I) rather than a deletion of IIq
Authors: Kobayashi Hirofumi , Thirman Michael J. , Rowley Janet D.
Published: February 2007

The U937 cell line was studied with the fluorescence in situ hybridization (FISH) technique using phage and cosmid probes which were mapped and ordered on IIq. Although this cell line was thought to have a del(IIq), FISH demonstrated that IIq was translocated to lop and that the breakpoint on IIq is centromeric to the MLL gene. This I0; II translocation appears to be a t(I0;II)(p I3‐I4;q I4–2I), which was recently reported to be a recurring translocation in malignant hematologic disease. This cell line will be a good tool for the study of this chromosomal rearrangement.
BCL6 encodes a sequence‐specific DNA‐binding Protein
Authors: Baron Beverly W. , Stanger Regan R , Hume Ellen , Sadhu Annamma , Mick Rosemarie , Kerckaert Jean‐Pierre , Deweindt Clotilde , Bastard Christian , Nucifora Giuseppina , Zeleznik‐Le Nancy , McKeithan Timothy W.
Published: February 2007

Chromosomal rearrangements of BCL6 are commonly associated with diffuse large‐cell lymphomas. We set out to determine the DNA‐binding site of a glutathione‐S‐tranderase fusion protein containing the BCL6 zinc finger region by employing cyclic amplification and selection of targets (CASTing). From oligonucleotides containing 16 central random bases, sequences binding to the protein on glutathione‐coated beads were repeatedly selected and amplified by polymerase chain reaction (PCR). The binding sites were cloned and sequenced. A consensus, TTTNNNGNNATNCTTT, was obtained. Protein binding studies of double‐stranded oligomen containing point mutations within the 3′ CTTT confirmed the binding specificity of this part of the consensus. In addition, evidence indicated that some of the base pairs held constant in the oligonucleotides used for CASTing also contributed to binding. © 1995 Wiley‐Liss, Inc.
Loss of heterozygosity on chromosome arms 5q, IIp, IIq, I3q, and I6p in Human Testicular Germ Cell Tumors
Authors: Al‐Jehani Rajai M. A. , Povey Susan , Delhanty Joy D. A. , Parrington Jennifer M.
Published: February 2007

To identify common regions of deletion in human testicular germ cell tumors (TGCTs), we have screened tumors from 33 patients for loss of heterozygosity (LOH) using Southern blot analysis with 39 polymorphic markers covering 21 chromosome arms. Losses in more than 2 tumors and occurring at a frequency of > 10% were found on chromosome arms 5q, 11p, 11q, 13q, and 16p, the highest being on chromosome arm 5q (19%). It is suggested that tumor suppressor genes on 5q among others may be involved in testicular tumorigenesis and that LOH in this region requires further investigation. No losses were found on 12q and 17p despite the fact that the most common cytogenetic abnormality in TGCTs is an i( 12p) and that the TP53 gene on 17p is the most frequently mutated gene in human cancers. The level of allelic imbalance varied considerably from one chromosome region to another (0–80%) and did not generally reflect the pattern of LOH. It tended to be high in overrepresented regions of the genome, 1q, 7p, and 12p. The tumor from one patient had a seminomatous component and a less differentiated component. We provide evidence for a common origin of both components and show that it is likely that this tumor has progressed from the seminoma to the less differentiated histology. © 1995 Wiley‐Liss, Inc.
In situ hybridization analysis of the Y chromosome in gonadoblastoma
Authors: Sultana Razia , Myerson David , Disteche Christine M.
Published: February 2007

Gonadoblastoma is a rare tumor arising in the streak gonads of about 30% of 46, XY sex‐reversed females. Because gonadoblastoma develops only in patients who have Y‐chromosome material and dysgenetic gonads, it has been hypothesized that positive expression of a gene (or genes) on the Y chromosome (GBY) is involved in the etiology of the tumor. To examine the Y chromosome directly in tumors, we performed nonisotopic in situ hybridization of a biotin‐labeled Y‐specific probe for the DYZI locus on formalin‐fixed, paraffin‐embedded sections of tumor samples from four different patients.

After hybridization to DYZI, the Y chromosome was found to be present in all gonadoblastoma foci in the four patients studied, and the gonadoblastoma foci showed an average of 85% cell nuclei positive for the Y chromosome on tissue sections. Normal male and female control tissues showed an average of 78% and 0% positive nuclei, respectively. One patient with bilateral gonadoblastoma had previously been shown to be mosaic, with a 45, X/46, XY karyotype in lymphocytes, skin fibroblasts, and cultures from both gonads. Examination of sections of this patient's gonads showed 79% positive nuclei within the gonadoblastoma foci, whereas the nontumor stromal tissue had 19% positive nuclei. These results indicate that, in this mosaic gonad, tumor foci developed only from cells that had a Y chromosome. Our results support the hypothesis that there is a GBY locus on the Y chromosome and that the Y chromosome is retained in the gonadoblastoma foci during the development of the tumor. © 1995 Wiley‐Liss, Inc.
Genomic DNA and messenger rna expression alterations of the CDKN2B and CDKN2 genes in esophageal squamous carcinoma cell lines
Authors: Zhou Xiaoling , Suzuki Hiroyuki , Shimada Yutaka , Imamura Masayuki , Yin Jing , Jiang Hai‐Yan , Tarmin Lila , Abraham John M. , Meltzer Stephen J.
Published: February 2007

The genes CDKN2B (MTS2) and CDKN2 (MTSI) encoding the proteins p15 and p16 are both located on chromosomal band 9p21, a locus at which frequent homozygous and heterozygous deletions occur in many primary human tumors, including esophageal carcinoma. CDKN2 and CDKN2B belong to a family of cyclin‐dependent kinase 4 inhibitors (INK41) and control cell proliferation during the GI phase of the cell cycle. Their inactivation may contribute to uncontrolled growth in human cancers. To investigate whether CDKN2B and CDKN2 are involved in esophageal tumorigenesis, we studied homozygous deletion, intragenic mutation, and messenger RNA (mRNA) expression of CDKN2 and CDKN2B in nine esophageal squamous cancer cell lines. Polymerase chain reaction (PCR) amplification revealed that five of the nine cell lines (55%) manifested homozygous deletions of CDKN2B, CDKN2, and/or flanking loci on chromosomal band 9p21. Reverse transcriptase‐PCR (RT‐PCR) was used to examine CDKN2 and CDKN2B mRNA in the nine cell lines. Lack of CDKN2 and CDKN2B mRNA correlated perfectly with homozygous deletion involving these genes. No subtle intragenic mutations of CDKN2B or CDKN2were detected by DNA sequencing of their entire coding sequences in any cell lines lacking homozygous deletion. Two of the cell lines manifested homozygous deletions excluding CDKN2; one of these two deletions also excluded CDKN2B. These results suggest that inactivation of CDKN2B and CDKN2 may contribute to the malignant phenotype in esophageal cells and that homozygous deletion may be the predominant mechanism for inactivation of CDKN2B and CDKN2. Alternatively, a gene or genes adjacent to CDKN2B/CDKN2 may constitute the target(s) of deletion at this locus. © 1995 Wiley‐Liss, Inc.
Patterns of loss of heterozygosity at loci from chromosome arm 13q suggest a possible involvement of BRCA2 in sporadic breast tumors
Authors: Kerangueven Fabienne , Allione Florence , Noguchi Teburo , Adélaïde José , Sobol Hagay , Jacquemier Jocelyne , Birnbaum Daniel
Published: February 2007

Loss of heterozygosity (LOH) at loci from chromosome I3 is frequently observed in breast cancer. Chromosome 13 contains at least two cancer genes, the well‐characterized RB1 gene located at 13q 14 and the breast cancer‐susceptibility gene, BRCA2, recently localized to 13q 12. To investigate the possible involvement of BRCA2 in sporadic breast tumors, we looked at LOH at eight microsatellite (CA)n markers distributed along chromosome 13 in a panel of 59 primary breast carcinomas. We show that some LOH does not include the RB1 locus and is associated with the BRCA2 gene region.