Genes, Chromosomes and Cancer

doi: 10.1002/gcc.2870080101pmid: N/A

Saglio, Giuseppe; Borrello, Maria Grazia; Guerrasio, Angelo; Sozzi, Gabriella; Serra, Anna; Celle, Paola Francia Di; Foa, Robin; Ferrarini, Manlio; Roncella, Silvio; Pignatti, Caterina Borgna; Marradi, Pierluigi; Izzo, Pietro; Soler, Jesus; Pierotti, Marco

doi: 10.1002/gcc.2870080102pmid: 7691153

We have analyzed the type of MYC/IG heavy‐chain locus (IGH) rearrangement present in 15 patients affected by t(8; 14)‐positive primary Burkitt's lymphoma or acute lymphoblastic leukemia of the L3 type in an attempt to map in detail the locations of the chromosome 8 and chromosome 14 breakpoints. The almost constant position of the chromosome 8 breakpoint (within or immediately 5′ of the MYC gene) together with two distinct clusters of breakpoints on chromosome 14 resulted in two main types of MYC/IGH (present in 12 of 15 cases). In the first type (six cases), the MYC gene or at least its coding portion was joined with the JH region on chromosome 14, whereas in the second, present in another six cases, the MYC gene and the Cαl region were juxtaposed. Physical linkage between the translocated MYC and a known enhancer element of the IGH locus is the common feature in the two types of rearrangement, suggesting that a high‐level constitutive expression plays a prominent role in MYC activation. Interestingly, the chromosome 14 break site within the switch α1 region, which has been only occasionally described in other cases, is present in 40% of our patients, suggesting the existence of preferential breakpoint cluster regions in cases of similar geographic origin. © 1993 Wiley‐Liss, Inc.

Alvarez, Luis; Evans, James W.; Wilks, Rebecah; Lucas, Joe N.; Brown, J. Martin; Giaccia, Amato J.

doi: 10.1002/gcc.2870080103pmid: 7691162

Telomeric DNA is composed of highly conserved sequences which are present at the termini of chromosomes as well as at intrachromosomal locations. Here, we studied a Chinese hamster ovary (CHO) cell line, BL‐10, with highly stable amplified telomeric DNA at the termini as well as at intrachromosomal locations. We show that intrachromosomal or interstitial telomeric sites in this cell line and in another CHO cell line, HA‐1, are radiosensitive in that they are more prone to breakage than would be expected based on the percentage of the genome composed of telomeric sequences. The frequency of breakage at interstitial telomeric sites is 4.3 to 8.3 times higher than that in the CHO genome overall. These conclusions are reached by both conventional cytogenetic analysis of two CHO cell lines which have the same survival rates after exposure to ionizing radiation, and by use of double fluorescence in situ hybridization (FISH) with a pan‐telomere‐specific probe and a CHO chromosome‐specific library in the same metaphase cells after irradiation. © 1993 Wiley‐Liss, Inc.

Akiyama, Kiyotaka; Kanda, Naotoshi; Yamada, Masao; Kato, Mieko; Tadokoro, Keiko; Matsunaga, Tadashi; Nishi, Yoshisuke

doi: 10.1002/gcc.2870080104pmid: 7691154

We characterized differences in the structural organization of the MYCN amplicons of a number of neuroblastomas by analyzing 8 contigs spanning 330 kb cloned from the MYCN amplicon of a neuroblastoma cell line. Some regions were amplified in almost all specimens, the conserved regions (CRs), and others were differentially amplified in some subsets, the non‐conserved regions (NCRs). CRs constituted only 20% of the 330 kb region, with the remainder being NCRs. The regions that inevitably co‐segregate with the MYCN gene make up the core, whereas flanking regions are retained at random. If a histogram of the frequency with which the amplified NCR sequences from one specimen match those of the cell line MC‐NB‐1 shows a random distribution, the NCRs would co‐segregate with MYCN as a result of random events. However, both the tumors and cell lines/xenografts showed a distribution with two distinct peaks; one from a group containing a small number of sequences with a fairly high degree of homology to the NCRs of MC‐NB‐1, and the other from a group containing a large number of sequences with little homology. These results indicate that the flanking segments are preferentially co‐segregated with MYCN by a non‐random mechanism. © 1993 Wiley‐Liss, Inc.

König, Josée J.; Teubel, Wilma; Van Dongen, Jan Willem; Hagemeijer, Anne; Romijn, Johannes C.; Schröder, Fritz H.

doi: 10.1002/gcc.2870080105pmid: 7691155

The frequency of aneuploid cells in cultured prostate carcinoma specimens was investigated. Ploidy distribution of the original tissue was established by flow cytometry (FCM). Fluorescence in situ hybridization (FISH) of chromosome I was applied to directly isolated and cultured cells to investigate whether any modifications in the ploidy distribution of chromosome I took place during tissue culture. In six tumor specimens that were diploid by FCM and FISH, no differences were found in the ploidy distribution of chromosome I before and after tissue culture. In eight tumors that were aneuploid by FISH, the percentage of aneuploid nuclei was significantly reduced from 28.0 ± 15.0 (range 13ndash;59%) in uncultured cells to 9.1 ± 4.4 (range 4ndash;18%) after tissue culture. The reduction of aneuploid nuclei ranged from 44 to 85%, which means that the majority of the aneuploid cell populations that were observed in the original specimens were undetectable in cultured samples. This suggests a preferential growth of normal epithelial cells. The data presented can explain the high percentage of diploid karyotypes usually found in short‐term cultured prostate carcinoma specimens. © 1993 Wiley‐Liss, Inc.

Tricoli, James V.; Yao, Joyce L.; D'Souza, Sharon A.; Bracken, R. Bruce

doi: 10.1002/gcc.2870080106pmid: 7691156

The human sex‐region Y (SRY) gene maps to Yp 11.3 and encodes a protein that shares significant sequence homology with a conserved DNA binding motif found in the nonhistone high‐mobility group (HMG) proteins. In the mouse, Sry is required for normal testicular development and is expressed in the developing male gonadal ridge as well as in the adult testis. In man, SRY expression has been observed in the adult testis, but not in other adult male tissues. We have analyzed samples from human prostate adenocarcinoma and benign prostatic hypertrophy (BPH) for the expression of the SRY gene. We found expression of SRY in 60% of malignant prostate tumors and in three of six samples of BPH. We did not find expression in male or female colon mucosa, or in tissue from a cystic ovary. Malignant and atrophic testicular tissue both contained SRY transcript and served as positive controls in these experiments. We also found SRY transcript in the DU‐145 prostate adenocarcinoma cell line. Interestingly, SRY expression is absent in the Tera‐2 teratocarcinoma cell line. The potential for the SRY gene product to bind HMG core response elements in vitro suggests that SRY could participate in the cascade of gene regulatory events that result in aberrant cell growth or malignancy. © 1993 Wiley‐Liss, Inc.

Hanash, Samir M.; Beretta, Laura; Barcroft, Christine L.; Sheldon, Susan; Glover, Thomas W.; Ungar, David; Sonenberg, Nahum

doi: 10.1002/gcc.2870080107pmid: 7691157

Recent evidence suggests that the human interferon‐inducible double‐stranded RNA‐dependent protein kinase may function as a tumor suppressor. Here we describe the mapping of the gene for this kinase to chromosome region 2p21‐22 by fluorescence in situ hybridization. A combined analysis of cytogenetic data from a series of 341 patients with hematologic disorders that exhibited cytogenetic abnormalities and from published reports indicates that abnormalities involving 2p21‐22 occur nonrandomly and are observed among patients with acute myelogenous leukemia, raising the possibility of a role for this protein kinase in leukemogenesis. © 1993 Wiley‐Liss, Inc.

Lestou, Valia S.; De Braekeleer, Marc; Strehl, Sabine; Ott, German; Gadner, Helmut; Ambros, Peter F.

doi: 10.1002/gcc.2870080108pmid: 7691158

In order to examine the role of Epstein‐Barr virus (EBV) in the immortalization of human 6 lymphocytes and in the pathogenesis of lymphoid malignancies, we investigated whether the EBV integration into the human genome is randomly distributed or whether the virus integrates preferentially at certain sites. Twelve in vitro immortalized human lymphoblastoid cell lines (LCLs), two in vivo infected LCLs, and one Burkitt's lymphoma cell line (EB2) were examined by non‐radioactive in situ hybridization (ISH) with a biotinylated EBV probe. Recurrent hybridization sites were detected in all 15 cell lines. The chromosomes frequently carrying the EBV genome were chromosomes 1, 2, 4, and 5. In more than 70 chromosomal bands, a greater number of integration sites than expected was found (p < 0.05). Approximately half of these bands were involved in the majority of the cell lines (for example, 1p31, 1q43, 2p22, 3q28, 4q13, 5p14, 5q12, and 11p15) whereby band 5p14 was involved in all LCLs analyzed. Virtually no viral integrations were found on the sex chromosomes (X, Y). The majority of the EBV integrations was found in G‐band‐positive material (p < 0.0001). Thus, our findings clearly show that EBV integrates into the human genome in a non‐random manner. © 1993 Wiley‐Liss, Inc.

Crossen, Peter E.; Tully, Sandra M.; Benjes, Suzanne M.; Hollings, Peter E.; Beard, Michael E. J.; Nimmo, Joy C.; Morrison, Mary J.

doi: 10.1002/gcc.2870080109pmid: 7691159

Cytogenetic analysis of unstimulated cultures from a female patient with chronic B‐cell leukemia (CLL) revealed three cytogenetically distinct clones, suggesting that the patient's leukemia was oligoclonal. Immunoglobulin heavy chain gene rearrangement studies revealed 1 germline and 4 rearranged bands, indicative of an oligoclonal leukemc population. Further evidence of oligoclonality was provided by X‐linked RFLP studies. This is the first report of oligoclonality in CLL demonstrated by cytogenetic, immunoglobulin gene rearrangement, and X‐chromosome inactivation studies. In addition to oligoclonality, the patient's leukemk cells exhibited telomere association, a Robertsonian translocation, and clonal evolution, suggesting an underlying genomic instability. © 1993 Wiley‐Liss, Inc.

Crossen, Peter E.; Kennedy, Martin A.; Heaton, David C.; Morrison, Mary J.

doi: 10.1002/gcc.2870080110pmid: 7691160

The t(14;19) is a recurring translocation found in a small number of cases of chronic B‐cell leukemia (CLL). We have cloned and sequenced the breakpoint in a patient with a t(14;19) and shown that the breakpoint on chromosome 14 occurred in the Cμ switch region, and that the breakpoint on chromosome 19 occurred in the 5′ untranslated region of the BCL3 gene. This is in contrast to all the other reported cases with a t(14;19) in which the breakpoints on chromosome 14 occurred in the Cαl or Cα2 switch region, and the breakpoints on chromosome 19 occurred upstream of the BCL3 gene. Our results further emphasize the importance of the switch region in the t(14;19) translocation. © 1993 Wiley‐Liss, Inc.