Chromosomal abnormalities in cancer

The abnormal nature of chromosomes of cancer cells was recognised many years ago, but the potential significance of chromosomal aberrations was realised only after the discovery by Nowell and Hungerford (I960) of the Philadelphia chromosome in patients with chronic myeloid leukaemia. The virtual invariability of the association of this abnormal chromosome with a form of human cancer served to emphasise the significance of chromosomal aberrations in the pathogenesis of cancer. The importance of cytogenetics as a major discipline of cancer biology has been strengthened by the non-random nature of chromosomal changes. Most of the abnormalities are restricted to a few sites of the human genome (Heim and Mitelman, 1987). Sutherland (1979) showed the presence of non-staining gaps in both chromatids, which are inherited in a Mendelian fashion. These have been called the fragile sites. These fragile sites appear to be the major targets of mutagens and carcinogens (Yunis et al., 1987). In some tumour cell lines, the incidence of sister chromatid recombination shows marked association with certain chromosomes and it is also predominantly associated with these fragile sites (Lakshmi and Sherbet, 1990). Reciprocal chromosomal translocations as well as sister chromatid recombination are now known to involve specific oncogenes, suggesting a mechanism by which the rearrangement of chromosome might bring these oncogenes into play. Transposition of genes by chromosomal rearrangement can result in inappropriate gene activation which can initiate and mediate pathogenesis. Sister chromatid recombination is strongly associated with the presence of double minute chromosomes, and has therefore been implicated in the process of gene amplification (Lakshmi and Sherbet, 1989; see pages 11-13).

Chromosomal and DNA ploidy is an important parameter which has served as a marker of prognosis in breast cancer (Hedley et al., 1987; Clark et al., 1989; Ferno et al., 1992; Grant et al., 1992; Wenger et al., 1993), as well as in other forms of cancer such as pancreatic adenocarcinoma (Porschen et al., 1993), melanoma (Karlsson et al., 1993), endometrial cancer (Rosenberg et al., 1989), and gastric leiomyosarcoma (Suzuki and Sugihira, 1993). An image cytometric study carried out in the authors' laboratory on breast cancer aspirate cells has also revealed a highly significant relationship between ploidy and prognosis (see Table 2) (G. V. Sherbet et al., unpublished data). Nevertheless, it should be noted that a dissenting view has been expressed with regard to the significance of aneuploidy as a prognostic indicator (Lanigan et al., 1992; Lipponen et al., 1992). Aneuploidy may be a consequence of cells entering the S-phase of the cell cycle prematurely. This can be inferred from the close association often observed between aneuploidy and the size of the S-phase fraction in tumours. Aneuploid

Table 2. Relationship between DNA aneuploidy in breast cancer aspirate cells1 and tumour progression

DNA ploidy2

Number of samples

Non-malignant

M-

M+3

2 n-4n

22

17

5

0

4n-8n

15

0

13

2

8ยป-12w

17

0

7

10

1 Source: Sherbet GV, Lakshmi, MS, Wadehra V, and Lennard TWJ (unpublished data).

2 DNA content was measured by image cytometry as described in Parker et al. (1994a).

3 M-, node negative (no distant metastases); M+, node positive (with/without distant metastases). The relationship of degree of DNA ploidy to nodal/distant metastasis was statistically significant at P < 0.009 in Fisher exact probability test.

1 Source: Sherbet GV, Lakshmi, MS, Wadehra V, and Lennard TWJ (unpublished data).

2 DNA content was measured by image cytometry as described in Parker et al. (1994a).

3 M-, node negative (no distant metastases); M+, node positive (with/without distant metastases). The relationship of degree of DNA ploidy to nodal/distant metastasis was statistically significant at P < 0.009 in Fisher exact probability test.

tumours have been reported to show a virtual doubling of the S-phase fraction (Wenger et al., 1993); in that study no information is available about the S-phase fractions of hypodiploid tumours. In contrast, Balslev et al. (1994) found that hypodiploidy correlated with a high S-phase fraction. D'Agnano et al. (1996) reported that 68% of aneuploid breast cancers and only 25% of diploid tumours contained >8.2% cells in the S-phase. The cut-off of 8.2% used in that analysis is somewhat arbitrary and one can conceivably obtain a totally different distribution using another cut-off level. However, in some tumour systems the prognostic value of S-phase fraction could be dissociated from DNA aneuploidy (Sigurdsson et al., 1990; Lipponen et al., 1991,1992; Arnerlov et al., 1992; Suzuki and Sugihara, 1993). Some data obtained in our study of human breast cancer aspirate cells have revealed no correlation between the size of the S-phase fraction and the degree of ploidy (Figure 2) (G. V. Sherbet et al., unpublished data). Thus, there is not only a serious conflict in the views concerning both the value of DNA ploidy and S-phase fraction as markers of prognosis, but also about the possible relationship between degree of DNA aneupoidy and the size of the S-phase fraction. Despite this, one ought to take into account the observations from several quarters that DNA ploidy is associated with expression of growth factor and hormone receptors (Coulson et al., 1984; Stal et al., 1991; Visscher et al., 1991; Schimmelpenning et al., 1992). The increase in S-phase fraction could be a consequence of events such as gene amplification. Amplification of genes such as c-erbB2, myc, mdm2 but notp53 has been reported in adenocarcinoma of the breast (Latham et al., 1996). Schimmelpenning et al. (1992) also make the interesting statement that mammary carcinomas in situ that express c-erbB2 (encoding a growth factor receptor with similarities to the epidermal growth factor receptor, see page 148) proto-oncogene and possess anueploid DNA show a significantly greater predilection to develop into infiltrating mammary carcinoma. The clonogenic ability of cells derived from certain human tumours has been found to correlate with DNA aneuploidy (Verheijen et al., 1985), but this might represent an adaptive phenomenon determined by the properties relating to the adhesion of cells to the substratum. However, clonal expansion of

15 105 0

1 I I I I I I I I I I I I r cJcviriricricO'tri^'t't^^uiioKoio

Ploidy (n)

Figure 2. Relationship between ploidy and the size of the S-phase fraction in human breast cancer aspirate cells. The ploidy and S-phase fractions were measured by using image cytometric methods. DNA profiles were constructed and ploidy was calculated from the DNA levels of G0Gj cells, and the size of the S-phase fraction by integrating cell numbers in the region between G0G! and G2M peaks. No relationship has emerged from this study between DNA ploidy and the size of the S-phase fraction. (From Sherbet GV, Lakshmi MS, Wadehra V, and Lennard TWJ, unpublished observations.)

tumour subpopulations may be an authentic phenomenon, dependent upon how the component cells of a tumour respond to paracrine signals. Thus, even in the face of a degree of scepticism, DNA aneuploidy may be deemed to have some bearing on the progression of cancer.

0 0

Post a comment