Genes, Chromosomes and Cancer

doi: 10.1002/gcc.2870080301pmid: N/A

Scheck, Adrienne C.; Mehta, Bipin M.; Beikman, Melanie K.; Shapiro, Joan Rankin

doi: 10.1002/gcc.2870080302pmid: 7509621

We used standard karyotypic analyses of first‐division cells to identify a subpopulation of cells in primary malignant gliomas with over‐representation of chromosomes 7 and 22. These cells are a minor subpopulation in the primary tumor but become the dominant population after treatment in vitro of the cells with the chemotherapeutic agent 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea (BCNU). The selection for a cell with this specific karyotypic abnormality suggests that these chromosomes contain genes important to the growth of BCNU‐resistant cells. Southern blot hybridization analyses demonstrate an increased copy number of the genes encoding platelet‐derived growth factor (PDGF) A‐chain and B‐chain, which have been mapped to chromosomes 7 and 22, respectively. Reverse transcription followed by polymerase chain reaction (RT‐PCR) analysis demonstrates increased expression of these genes. In addition, these cells secrete a mitogenic factor that stimulates 3H‐thymidine uptake in NIH 3T3 cells. This factor is sensitive to anti‐PDGF antibodies and β‐mercaptoethanol, but not to anti‐EGF antibodies. These data suggest that autocrine and/or paracrine mechanisms occur in human malignant gliomas, and that over‐expression of PDGF may play a role in the growth of BCNU‐resistant cells in these tumors. © 1993 Wiley‐Liss, Inc.

Deweindt, Clotilde; Kerckaert, Jean‐Pierre; Tilly, Hervé; Quief, Sabine; Nguyen, Van Cong; Bastard, Christian

doi: 10.1002/gcc.2870080303pmid: 7509622

In a previous cytogenetic analysis, we showed the recurrence of translocations involving band 3q27 and immunoglobulin gene regions in 20 out of 319 patients with non‐Hodgkin's lymphoma (NHL). We report here the molecular cloning of the translocation breakpoint from tumor cells of a patient (LAR) with t(3;14)(q27;q32) and the isolation of DNA probes which identify a major translocation cluster region (MTC) at band 3q27. A DNA library from LAR tumor cells was screened with a JH probe and several clones were identified corresponding either to a somatic rearrangement of JGH genes (V4‐D2‐J6‐Cμ clonal rearrangement) or to the t(3; 14). Analysis of the t(3; I 4) breakpoint showed that chromosome 3 material was translocated to an inverted 14q32 VH‐containing fragment which was itself translocated to the J3 gene. Chromosome 3‐assigned probes were used to investigate local DNA rearrangements in a series of NHL with 3q27 translocations. Rearrangements were detected in 13 of 17 patients including 9 of 11 with t(3;14)(q27;q32), I of 2 with t(2;3)(P12;q27), I of 2 with t(3;22)(q27;qII), and 2 of 2 NHL with translocations not involving an IG gene, namely, t(3;4)(q27;pII) and t(3;7)(q27;p12). The finding of this MTC should be useful for diagnostic and prognostic studies and for the identification of a novel oncogene at band 3q27 involved in the development of B cell NHL. © 1993 Wiley‐Liss, Inc.

Kao, Chinghai; Wu, Shi‐Qi; Devries, Sandy; Reznikoff, William S.; Waldman, Frederic M.; Reznikoff, Catherine A.

doi: 10.1002/gcc.2870080304pmid: 7509623

The fate of integrated SV40 viral genome in SV40‐immortalized human uroepithelial cells (SV‐HUC) during multistep chemical transformation in vitro was studied. We previously reported that exposure of SV‐HUC at passage (P) 15 to the chemical carcinogens 3‐methylcholanthrene (MCA), 4‐aminobiphenyl (ABP), or the N‐hydroxy metabolites of ABP causes tumorigenic transformation and/or neoplastic progression. We report now that these same chemical carcinogens induce amplification of SV40 DNA in SV‐HUC. We used fluorescence in situ hybridization (FISH) to show that this amplification occurs at the SV40 integration site, which was mapped near a common fragile site at 9q12‐21.1 on the der(9)t(8;9) chromosome that is present in all SV‐HUC at the earliest passage studied. Karyotypic analysis, along with FISH, also revealed that all carcinogen‐induced tumors (T‐SV‐HUCs) had breaks at 9q12‐21.1, deletions of 9q12‐21.1→pter, and new derivative chromosomes containing SV40 in the segment 9q12‐21.1→9q34::8q22→8qter. Southern blot analysis, along with FISH, confirmed SV40 genome rearrangements in T‐SV‐HUCs. In contrast, no 9q12‐21.1 breaks were observed in control SV‐HUC. Thus, these results associate 9q 12‐21.1→pter alterations with HUC tumorigenic transformation. In addition, these results indicate for the first time that (carcinogen‐induced) amplification of chromosome‐integrated viral genes may create sites that are prone to breakage, deletions, and translocations. These results suggest a new mechanism by which chemical carcinogens in synergy with a DNA tumor virus could initiate a cascade of events that contribute to the genomic instability associated with tumorigenesis. © 1993 Wiley‐Liss, Inc.

Akao, Yukihiro; Tsujimoto, Yoshihide; Seto, Masao; Imai, Takashi; Bergeron, Dominique; Berbeau, Benoit; Otsuki, Yoshinori

doi: 10.1002/gcc.2870080305pmid: 7509624

We have previously demonstrated that the RCK gene involved in t(11;14)(q23;q32) and the more centromeric MLL/ALL1 gene involved in t(4;11)(q21;q23) and t(11;19)(q23;p13) are localized on different adjacent Notl fragments by using pulsed‐field gel electrophoresis (PFGE) analysis with the yeast artificial chromosome (YAC) clone yB22B2. The PFGE analysis using the YACs of YTY17 containing the prophobilinogen deaminase (PBGD), CBL2 and THY1 genes and yB22B2 allowed the following ordering of genes and breakpoints from CD3 to THY1 on 11q23: cent‐CD3‐ALL/MLL1‐RCK‐PBGD‐CBL2‐THY1, and the establishment of a long‐range restriction map covering these genes. In addition, we showed that the FLI1 region involved in the t(11;22)(q24;q12) in Ewing's sarcoma was more telomeric region than the THY1 gene by analyzing somatic cell hybrids carrying the 11q‐ and/or 14q+ chromosome of the t(11;14)(q23;q32) translocation, and by PFGE analysis of the YAC clone YTY17. © 1993 Wiley‐Liss, Inc.

Hunter, Stephen; Gramlich, Terry; Abbott, Karen; Varma, Vijay

doi: 10.1002/gcc.2870080306pmid: 7509625

Carcinoma of the esophagus shows a strong male predominance and other epidemiologic differences from cancers arising at other sites. In this study, the prevalence of Y chromosome loss in 29 carcinomas of the esophagus and 53 carcinomas arising elsewhere in the aerodigestive tract was assessed by in situ hybridization of formalin‐fixed paraffin‐embedded tissue sections. Absence of the Y chromosome was defined as (1) negative staining for Y in neoplastic cells with positive staining for Y in immediately adjacent nonneoplastic epithelial and stromal cells, (2) positive staining of neoplastic cells with control probes for chromosomes X and 17, and (3) similar results at different stringencies and levels of protein digestion. According to these criteria, absence of the Y chromosome was observed in 13 of 14 (93%) adenocarcinomas of the esophagus, 8 of 13 (62%) squamous cell carcinomas of the esophagus, and 5 of 53 (9%) carcinomas arising in other sites. For the neoplasms examined, Y chromosome deletion was strongly and selectively associated with carcinomas, particularly adenocarcinomas, of the esophagus (P < .0001). These findings suggest that Y chromosome loss may be pathogenetically significant in these neoplasms. © 1993 Wiley‐Liss, Inc.

Isshiki, Koichi; Elder, David E.; Guerry, Dupont; Linnenbach, Alban J.

doi: 10.1002/gcc.2870080307pmid: 7509626

The involvement of tumor suppressor genes in the progression of melanoma has been suggested by the frequent deletion of specific regions of the genome in melanoma. In this study, a panel of 18 surgically removed melanomas from 15 patients was analyzed for loss of heterozygosity (LOH) at 10 polymorphic loci on chromosome 10. LOH was observed in 7 (50%) of 14 informative patients. LOH data suggested that melanomas from 5 patients had lost entire copies of chromosome 10, and that melanomas from 2 patients had lost copies of 10q. In contrast, LOH was not observed on chromosome 15, 20, or 21. These results are consistent with previous cytogenetic observations and provide indirect evidence that there is a tumor suppressor gene on the long arm of chromosome 10 which is relevant to melanoma development. © 1993 Wiley‐Liss, Inc.

Mohamed, A. N.; Macoska, J. A.; Kallioniemi, A.; Kallioniemi, O.‐P.; Waldman, F.; Ratanatharathorn, V.; Wolman, S. R.

doi: 10.1002/gcc.2870080308pmid: 7509627

A case of acute myeloid leukemia (M‐3) with complex karyotypic aberrations and double minute (dmin) chromosomes is presented. The patient had no history of prior exposure to mutagenic or carcinogenic agents or of other malignancies. She died from CNS involvement six weeks after the initial diagnosis. We used comparative genomic hybridization to identify the amplified sequences presumed to represent the dmin of the leukemic cells; the tumor/normal ratios indicated increased signal intensity at 8q24. This localization prompted investigation by semi‐quantitative PCR that revealed amplification of the MYC oncogene. The extent of chromosome aberrations and the oncogene amplification, both linked with poor prognosis, may relate to the rapid course of this patient's disease. © 1993 Wiley‐Liss, Inc.

Squire, Jeremy; Zielenska, Maria; Thorner, Paul; Tennyson, Shan; Weitzman, Sheila; Pai, K. Mohan; Yeger, Herman; Ng, Y‐Kwan; Weksberg, Rosanna

doi: 10.1002/gcc.2870080309pmid: 7509628

Relatively few variant translocations have been reported in primary Ewing's sarcomas (ES). We report two new variant translocations, both of which involve chromosomal rearrangements of 22q12. Cytogenetic studies of tumor cells from a 12‐year‐old girl revealed a variant translocation, t(7;22)(p22;q12), the second example reported of a simple variant of the 22q12 reciprocal translocation in this type of sarcoma. The identity of this rearrangement was confirmed by in situ hybridization. In addition, a complex translocation was identified in a dysmorphic 15‐year‐old girl, t(4;11;22)(q21q24;q12). No previous cases of variant translocations in ES have involved band 7p22 or 4q21, and there are no previous reports of an association between congenital abnormalities and unusual karyotype abnormalities in ES. Both variant translocations conserve the junction on the der (22), providing additional cytogenetic evidence that the sequences on chromosome 22 are critical. © 1993 Wiley‐Liss, Inc.

Tavassoli, Mahvash; Ruhrberg, Christiana; Beaumont, Vicky; Reynolds, Karina; Kirkham, Nigel; Collins, William P.; Farzaneh, Farzin

doi: 10.1002/gcc.2870080310pmid: 7509629

Chromosomal deletions, associated with the loss of normal function of tumour suppressor genes, have been identified in a variety of both familial and sporadic human cancers. Although the molecular pathology of ovarian cancer is not understood, several studies have reported deletions in chromosome 17 in ovarian tumours. We have used 13 restriction site polymorphic, microsatellite, and variable number tandem repeat markers to make a detailed analysis of chromosome 17 deletions in 12 benign and 19 malignant ovarian tumours. Two benign and 11 malignant tumours were informative for at least one marker on each arm of the chromosome. Loss of heterozygosity (LOH) was detected in both arms (by all informative markers) in 5 malignant tumours from four women (three with the disease at FIGO stage la). In a further bilateral ovarian tumour a partial LOH affecting 17q22‐q25 was present in one ovary only. By contrast to a number of previous studies, none of the 19 malignant and 12 benign tumours showed ERBB2 (17q12ndash;22) amplification. The data presented show that the loss of a whole copy of chromosome 17 is a frequent and relatively early event in the development of some ovarian cancers. This suggests the possible involvement of multiple chromosome 17 loci in the pathogenesis of ovarian cancer. Equally plausible is that the loss of a whole chromosome copy could be the product of chromosomal instabilities induced by loss of the normal allele of tumour suppressors, such as TP53, located on this chromosome. © 1993 Wiley‐Liss, Inc.