Prognostic significance of the DNA content of human breast cancer

Dowle, C. S.; Owainati, A.; Robins, Adrian; Burns, Karen; Ellis, Ian O.; Elston, C. W.; Blamey, R.W.

doi:10.1002/bjs.1800740221

Cited by 99 publications

(35 citation statements)

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“…Most authors agree that DNA aneuploidy is associated with poor histological grade (Thorud et al, 1986;Moran et al, 1984;Spyratos et al, 1987;Olszewski et al, 1981;Jakobsen et al, 1984;Hedley et al, 1984;McDivitt et al, 1986;Kute et al, 1985;Kallioniemi et al, 1987;Feichter et al, 1988;Dowle et al, 1987), and the mitotic count, nuclear pleomorphism and degree of tubule formation describe much the same thing. The amount of elastin and the extent of necrosis have been associated with histological grade too (Fisher et al, 1984;Kuhajda et al, 1985).…”

Section: Discussionmentioning

confidence: 97%

“…Most authors (Thorud et al, 1986;Coulson et al, 1984;Hedley et al, 1987;Kallioniemi et al, 1987;Dowle et al, 1987;Cornelisse et al, 1987;Ewers et al, 1984;Stal et al, 1989), but not all (van der Linden et al, 1989;Uyterlinde et al, 1988;Owainati et al, 1987), agree that DNA aneuploidy is associated with unfavourable survival in breast cancer. In most studies this association has, however, been weak.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that breast carcinomas with an abnormal (non-diploid or aneuploid) nuclear DNA content are associated with less favourable prognosis than carcinomas with a normal (diploid) DNA content (Hedley et al, 1984(Hedley et al, , 1987Coulson et al, 1984;Ewers et al, 1984;Thorud et al, 1986;Baildam et al, 1987;Cornelisse et al, 1987;Kallioniemi et al, 1987;Stal et al, 1989). Similarly, the DNA index (DI, the relative DNA content of an aneuploid stemline of cells as compared with diploid cells) and the percentage of S-phase cells in the DNA histogram (S-phase fraction, SPF) have been found by some to be of prognostic significance (Dowle et al, 1987;Hedley et al, 1987;Kallioniemi et al, 1988;Stal et al, 1989;McDivitt et al, 1986;Klintenberg et al, 1986). However, the prognostic value of nuclear DNA content analysis is still unsettled.…”

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confidence: 99%

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The prognostic significance of nuclear DNA content in invasive breast cancer – a study with long-term follow-up

Toikkanen

Joensuu²,

Klemi³

1989

Br J Cancer

117

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Summary The nuclear DNA content of 351 breast carcinomas was determined by flow cytometry from paraffin-embedded tissue to assess the prognostic significance of DNA ploidy, the DNA index (DI) and the S-phase fraction (SPF). The minimum follow-up of the patients was 22 years, and they were all from a defined urban population. DNA ploidy correlated with histological type and grade, mitotic count and nuclear pleomorphism (P<0.0001), and also with axillary nodal status (P=0.0005), tumour necrosis (P=0.001), primary tumour size (P = 0.03), menopausal status (P = 0.004) and the presence of distant metastases at the time of the diagnosis (P = 0.04). Survival corrected for intercurrent deaths of the patients with a diploid tumour was better than that of the patients with a non-diploid tumour (P = 0.0001, 48% vs 28% at 25 years). SPF Leatham & Brooks, 1987; Slamon et al., 1987).The nuclear DNA content determined by flow cytometry has recently emerged as a new prognostic factor in breast cancer. The technique has gained some popularity, since flow cytometric histograms are rapid to produce and often easy to interpret. It has been suggested that breast carcinomas with an abnormal (non-diploid or aneuploid) nuclear DNA content are associated with less favourable prognosis than carcinomas with a normal (diploid) DNA content (Hedley et al., 1984(Hedley et al., , 1987Coulson et al., 1984;Ewers et al., 1984;Thorud et al., 1986;Baildam et al., 1987;Cornelisse et al., 1987;Kallioniemi et al., 1987;Stal et al., 1989). Similarly, the DNA index (DI, the relative DNA content of an aneuploid stemline of cells as compared with diploid cells) and the percentage of S-phase cells in the DNA histogram (S-phase fraction, SPF) have been found by some to be of prognostic significance (Dowle et al., 1987;Hedley et al., 1987;Kallioniemi et al., 1988;Stal et al., 1989;McDivitt et al., 1986;Klintenberg et al., 1986). However, the prognostic value of nuclear DNA content analysis is still unsettled. Some authors report DNA content to be the most important prognostic variable in breast cancer, and to have independent prognostic value in a multivariate analysis , whereas others find it to have prognostic value only in a univariate analysis (Stal et al., 1989;Hedley et al., 1984), and yet a few fail to find any prognostic significance at all when overall survival is concerned (van der Linden et al., 1989;Uyterlinde et al., 1988;Owainati et al., 1987

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The prognostic significance of nuclear DNA content in invasive breast cancer – a study with long-term follow-up

Toikkanen

Joensuu²,

Klemi³

1989

Br J Cancer

117

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“…Flow cytometric measurement of DNA content per nucleus provides information both about DNA ploidy status and about proliferative activity as represented by the fraction of cells in the S-phase of the cell cycle, The prognostic value of DNA ploidy has been demonstrated in many studies (6,8,9,20,24,42), as has that of the S-phase fraction (SPF; 13,15,16,22,31,37), though others have failed to confirm the independent prognostic value of these variables (12,21,30). sults.…”

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confidence: 99%

One or multiple samplings for flow cytometric DNA analyses in breast cancer‐prognostic implications?

Fernö¹,

Baldetorp²,

Ewers³

et al. 1992

Cytometry

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Flow cytometric assessments of DNA ploidy status and the S-phase fraction (SPF) have been shown to yield prognostic information in breast cancer. The aim of the present investigation was to elucidate the reproducibility of results with regard to tumor DNA heterogeneity, and to ascertain whether the prognostic value of DNA measurements might be enhanced by analyzing two pieces of a tumor instead of one.Agreement with regard to ploidy status (diploid versus non-diploid) was obtained in 90% of cases (71/79) when two adjacent sections of the tumor were investigated, and in 77% of cases (10/13) when four biopsies from different quadrants of the tumor specimen were investigated. The corresponding figures for agreement in SPF (divided into three categories, < 7.0%, 7.0-11.9%, and > 12%) were 75% 69/79; 2-sample series) and 55% (7/13; 4-biopsy series).The main reason for variance in ploidy results was the difficulties in distinguishing near diploid cell populations. Discrepancies in SPF categories could be explained by minor fluctuations in SPF values near the cut-off levels, or by variance in ploidy status, the fraction of nondiploid nuclei, and background noise due to cell debris.There was a stepwise increase in recurrence rate (RR) among patients with increasing SPF category (RR: 20%, 41%, and 53%). Patients whose SPF categories varied, from low or intermediate in one part of the tumor to high in another, seemed to have a poor prognosis (RR = 57%).We conclude that the variation in ploidy status and SPF between different parts of the same tumor specimen is largely to be explained by uncertainty in the interpretation of the DNA histograms and by difficulties inherent in the estimation of SPF, rather than by the existence of DNA tumor heterogeneity. Evaluation of a different part of the same tumor specimen may be of value, especially in the case of SPF, as this may yield additional prognostic information. These findings also emphasize the need for good quality control of FCM DNA analysis.

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DNA signal splitting improves detection and analysis of tetraploid populations

Weaver

Bagwell

1992

Cytometry

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There are no currently published guidelines for establishing a diagnosis of DNA tetraploidy; however, many studies have examined DNA tetraploidy as a separate variable from non-tetraploid DNA aneuploidy for determining patient outcome (1,(3)(4)(5)631. Confirming the presence of a tetraploid cell population is not a trivial task. Tetraploid cells in G, or G, of the cell cycle have the same nuclear DNA content (4C) as diploid cells in G2 or M of the cell cycle. Furthermore, an aggregate of two G,G, nuclei would also appear in the 4C peak. A 4C peak containing greater than 10-20% of the cells in the sample usually first suggests the possibility of a tetraploid population (2,7,9). Confirmation is generally obtained by establishing the presence of an 8C peak in the absence of a 6C peak or a n 8C peak that is greater in area than a 6C peak. A low doublet count as visualized with a fluorescence microscope assists in eliminating aggregated nuclei. Additional helpful findings are the presence of cycling cells (S-phase cells) with a DNA content between 4C and 8C and/or a n abnormal orthogonal light scatter pattern (DNA fluorescence vs. log 90 scatter). All of the corroborating features necessitate examining the hypertetraploid area of the DNA histogram. This paper describes a simple, inexpensive modification to the flow cytometer that is currently in use in several laboratories and that allows simultaneous acquisition of data optimized for both the diploid (< 4C) and hypertetraploid (> 4C) region of the DNA histogram. MATERIALS AND METHODSThe amplifier lead was disconnected from the photomultiplier tube (PMTj used for collection of the DNA fluorophore signal and a n in-line T-connector (type UG-274 BNC #278-112, Radio Shack, Tandy Corp, Ft. Worth, TX) installed on the PMT. The amplifier lead was then re-connected to one side of the T-connector. The amplifier lead from a n unused PMT was disconnected and re-connected to the other side of the T-connector. The resulting PMT output signal was processed by two different amplifiers (Fig. 1). The gain setting on one amplifier was optimized for analysis of diploid or near-diploid cells and the other amplifier was optimized for tetraploid or near-tetraploid cells. This was accomplished on a n EPICS Profile cytometer (Coulter Corporation, Hialeah, FL) by installing the Tconnector directly on the F1,2 PMT output and re-connecting the FL2 amplifier lead to the T-connector. The FL3 amplifier was disconnected from the FL3 PMT and connected to the T-connector on the FL2 PMT. The gain was set to 5 on the FL3 amplifier and to 2 on the FL2 amplifier. The PMT voltage was then adjusted to optimize histogram placement. Placing the diploid peak

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Prognostic significance of the DNA content of human breast cancer

Cited by 99 publications

References 10 publications

The prognostic significance of nuclear DNA content in invasive breast cancer – a study with long-term follow-up

The prognostic significance of nuclear DNA content in invasive breast cancer – a study with long-term follow-up

One or multiple samplings for flow cytometric DNA analyses in breast cancer‐prognostic implications?

DNA signal splitting improves detection and analysis of tetraploid populations

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