Interphase cytogenetic analysis of <i>erb</i>B2 and topollα co‐amplification in invasive breast cancer and polysomy of chromosome 17 in ductal carcinoma <i>in situ</i>

Ds, Murphy; McHardy, P; Coutts, J; Ea, Mallon; Wd, George; Kaye, SB; Brown, Robert; Keith, W. Nicol

doi:10.1002/ijc.2910640106

Cited by 48 publications

(36 citation statements)

References 34 publications

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“…Rather, gene dosage changes at the topo I locus, including gene amplification, isochromosome formation and polysomy, are most likely due to selection for alterations to chromosome 20 at for example an oncogene in the proximity of topo I. This situation has been shown to occur for the topo IIcx locus on chromosome 17q, which can be co-amplified along with the erbB2 oncogene in a proportion of breast cancers resulting in high levels of topo Ilo expression, (Coutts et al, 1993;Keith et al, 1993;Murphy et al, 1995). Both allelic imbalances and gene amplification have been detected on chromosome 20 in breast cancer, (Devilee et al, 1991;Keith et al, 1993;Kallioniemi et al, 1994;Tanner et al, 1994).…”

Section: Resultsmentioning

confidence: 99%

“…The sequences present in this clone are not present in the two topo I pseudogenes and do not crosshybridise with them. Probe labelling, in situ hybridisation and probe detection are as previously described, (Coutts et al, 1993;Murphy et al, 1995), using the Hybaid Omnislide system (Hybaid Ltd, Teddington, UK). The topo I probe was localised by fractional length measurements, Flpter, where the Flpter is the distance from the probe location to the end of the short arm of chromosome 20 divided by the total length of the chromosome, (Lichter et al, 1990;Mascio et al, 1995;Sakamoto et al, 1995).…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

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Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity

McLeod

Keith²

1996

Br J Cancer

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Summary DNA topoisomerase I (topo I) is the principle target for camptothecin and its derivatives such as SN38. Levels of topo I expression vary widely between and within tumour types and the basis for this is poorly understood. We have used fluorescence in situ hybridisation to detect the topo I locus in a panel of breast and colon cancer cell lines. This approach has identified a range of topo I gene copies from 1 to 6 between the cell lines as a result of DNA amplification, polysomy and isochromosome formation. Topo I gene copy number was highly correlated with topo I expression, (r, = 0.92), and inversely correlated to sensitivity to a 1 h exposure to SN38 (r, = -0.904). This illustrates the significant impact of altered topo I gene copy number on intrinsic drug sensitivity and influences potential mechanisms for acquisition of drug resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Cytotoxicity Assaymentioning

confidence: 99%

Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity

McLeod

Keith²

1996

Br J Cancer

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“…However, once the general characteristics of an amplicon have been described in terms of position and extent, fine detail analysis of the relative genetic composition of an amplicon is best carried out using locus-specific probes. In addition, REVISH is capable of characterizing an amplification, including the TOPOIIlc locus, which occurs in breast tumour biopsies and which can affect its expression Murphy et al, 1995a).…”

Section: Discussionmentioning

confidence: 99%

“…ERBB-2 sequences were detected using a mixture of two cosmids, cRCNeul and cRCNeu4 (Murphy et al, 1995a). Topoisomerase II alpha (TOPOIIa) sequences were detected using cosmid ICRFC105bO4155 (Murphy et al, 1995b), RARa sequences were detected using cosmid ICRFCl05FI255, NFl sequences were detected using cosmid ICRFC 105c086 1 and NM23 sequences were detected using cosmid ICRFCl05H12160 developed from the Imperial Cancer Research Fund Reference Library (Lehrach, 1990).…”

Section: Cell Linesmentioning

confidence: 99%

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Identification of genetic changes associated with drug resistance by reverse in situ hybridization

Hoare

Freeman²,

Coutts³

et al. 1997

Br J Cancer

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Summary The molecular cytogenetic techniques of comparative genomic hybridization (CGH) and reverse in situ hybridization (REVISH) allow the entire genomes of tumours to be screened for genetic changes without the requirement for specific probes or markers. In order to define the ability of REVISH to detect and map regions of amplification associated with drug resistance, we investigated a panel of cell lines selected for resistance to doxorubicin and intrinsic sensitivity to topoisomerase 11-inhibitory drugs. We have defined a modified REVISH protocol, which involves double hybridizations with genomic DNA from the test cell lines and chromosome-specific whole chromosome paints to identify the chromosomes to which the amplicons localize. Sites of amplification are then mapped by fractional length measurements (Flpter), using published genome databases. Our findings show that amplification of the topoisomerase lla gene is readily detected and mapped, as is amplification of the MDR and MRP loci. Interestingly, REVISH detected a new amplicon in the doxorubicin-resistant lung cancer cell line, GLC4-ADR, which mapped to chromosome 1 q. REVISH is therefore ideally suited to characterize genetic changes specific for drug resistance within a background of genetic anomalies associated with tumour progression.Keywords: molecular cytogenetics; fluorescence in situ hybridization; chromosome painting; drug resistance; gene amplification; gene mapping; reverse in situ hybridization Many tumours respond to a range of cytotoxic agents. However, resistance often develops (van der Zee et al, 1995;Harrison, 1995). Understanding the mechanisms of resistance may provide new therapeutic options (Kastan et al, 1995;FroelichAmmon and Osheroff, 1995). At the cellular level, a number of resistance mechanisms can potentially operate. These mechanisms include drug efflux via membrane pumps, such as p-glycoprotein or multidrug resistance protein (MRP), drug metabolism, including inactivation or failure to activate a prodrug, an alteration in abundance of the target protein, for example topoisomerase II (topoll) enzyme, mutation of target protein and inactivation of pathways leading to cell death, such as apoptotic signalling (Booser and Hortobagyi, 1994;Harrison, 1995;Kastan et al, 1995;van der Zee et al, 1995). It is likely that in any one particular tumour, response to therapy is dependent on concurrent expression of multiple mechanisms. Even for extensively studied drugs, such as etoposide, which is a known topoll inhibitor, resistance is a complex issue (Su et al, 1992;Takano et al, 1992;Booser and Hortobagyi, 1994;Chen and Liu, 1994;Pommier et al, 1994;Sinha, 1995). The recent association of reduced kinesin expression with etoposide resistance, as identified by a genetic suppressor element approach, highlights the usefulness and requirement for new approaches to define potential components of the drug resistance repertoire (Gudkov et al, 1994;Roninson et al, 1995).A major drawback to many of the conventional approaches used to investig...

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Chromosomal aberrations associated with invasion in papillary superficial bladder cancer

et al. 1998

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Non‐invasive and invasive papillary transitional cell carcinomas of stages pTa and pT1 represent the first steps of tumour progression in bladder cancer. In order to analyse different chromosomal alterations of pTa and pT1 superficial bladder cancer, 46 tumour specimens were examined by comparative genomic hybridization (CGH). Losses of chromosome 9 material (11/20) and gains of chromosome 17 material (6/20) were frequently found in pTa tumours. Stage pT1 tumours were characterized by gains of chromosome 1q (14/26; including amplification at 1q21–q24 in three cases) and chromosome 17 material (15/26), as well as by losses of 11p (15/26) and 11q (13/26). Other loci frequently showing losses in pT1 tumours were 2q (9/26), 4q (10/26), 5q (9/26), 8p (10/26), 9p (9/26), 9q (12/26), 10q (8/26), 17p (7/26), and 18q (8/26). Amplifications were detected at 8q21/22, 5q21, 7q36, 10p14, 10p12, 10q25, 12q12, and 12q14. The most striking differences between grade 2 pTa and pT1 tumours were gains of 1q (P<0·01) and losses at 2q (P<0·025), 10q (P<0·05), 11p (P<0·01), 11q (P<0·01), and 17p (P<0·05), as well as the total number of aberrations (pTa grade 2: 4·1; pT1 grade 2: 8·6 aberrations per tumour). These data show characteristic chromosomal aberrations associated with invasion in superficial bladder cancer. © 1998 John Wiley & Sons, Ltd.

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Interphase cytogenetic analysis of erbB2 and topollα co‐amplification in invasive breast cancer and polysomy of chromosome 17 in ductal carcinoma in situ

Cited by 48 publications

References 34 publications

Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity

Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity

Identification of genetic changes associated with drug resistance by reverse in situ hybridization

Chromosomal aberrations associated with invasion in papillary superficial bladder cancer

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