Retinoblastoma susceptibility gene rb abnormalities in cancer

Retinoblastoma is a paediatric cancer arising in the retina of the eye. This disease occurs in both hereditary and sporadic forms. There are, however, marked differences in their patterns of development and incidence. In the hereditary form the disease is bilateral and multifocal but sporadic retinoblastoma is unilateral and unifocal. The incidence of the familial tumour is higher than the sporadic form. These features of retinoblastoma and statistical analyses of incidence led to the 'two-hit' hypothesis proposed by Knudson (1971). The suggestion was that one mutated rb allele was inherited and occurred in all cells, including germ cells, of the progeny and that a mutation of the second allele would lead to the development of the tumour. It was reported many years ago that retinoblastoma was induced by a bi-allelic inactivation and the retinoblastoma-

susceptibility gene (rb) was identified and cloned (Friend et al, 1986; Fung et al., 1987; Lee et al., 1987a).

The rb gene is expressed in all normal tissues and cell lines (Lee et al., 1987b). It is expressed in a mutated form or absent in retinoblastomas (Lee et al., 1987b, 1990; Horowitz et al., 1990). Abnormalities of this gene have been described in several other human tumours, e.g. small cell lung cancer (SCLC) (Harbour et al., 1988; Hensel et al., 1990; Mori et al., 1990). Harbour et al. (1988) found that 13% of primary SCLC and 18% of SCLC-derived cell lines showed structural abnormalities of rb and 60% of SCLC-derived cell lines showed a loss of the gene. Loss of gene expression has been reported in 30% of primary non-SCLCs (Xu et al., 1991) and it appears also from this study that altered rb expression may be related to tumour stage. Inactivation of rb was reported in two bladder cancer cell lines and lack of expression without gross gene deletion in another cell line (Ishikawa et al., 1991). Of considerable interest is the suggestion of rb inactivation with tumour progression. For these authors failed to detect rb alterations in 16 low-grade non-invasive bladders, whereas only two out of 14 high-grade invasive cancers showed rb protein expression. Wright et al. (1995) have confirmed the association of the absence of rb protein expression with invasive growth and high-grade tumours. In this latter study, tumour growth fraction, as indicated by Ki67 staining, was twice as large in p53+/rb- tumours as in p53-/rb+ tumours. Abnormalities of the gene are also associated with carcinomas of the breast (Lee et al., 1988; T'Ang et al., 1988; Varley et al., 1989), where the gene has been found to be deleted or rearranged. The same abnormalities were detectable in primary breast carcinomas and in metastatic tumour where matching specimens had been examined (Varley et al., 1989). Furthermore, expression of rb appears related to the stage of differentiation of human testicular tumours (Strohmeyer et al., 1991). Mutations in exons 13-22 of the rb sequence have been found in 55% (27 out of 49) of thyroid carcinomas whereas no mutations in these exons were detected in benign tumours. Mutation of both rb and p53 genes appeared to be more frequent in advanced disease (Zou et al., 1994). These data suggest a possible involvement of the gene in tumour growth and progression rather than its initiation.

Loss of heterozygosity at the rb locus occurs frequently in oesophageal cancers (Boynton et al., 1991). Structural changes of the gene are associated with human soft tissue tumours (Friend et al., 1987; Stratton et al., 1989). Other tumour types with rb involvement are cancer of the prostate (Bookstein et al, 1990a), leukaemias (Cheng et al, 1990; Furukawa et al, 1991), and osteocarcinomas (Toguchida et al., 1988; Shew et al., 1989).

The rb gene is located on chromosome 13ql4. Cytogenetic abnormalities of chromosome 13 and loss of heterozygosity at the rb locus have been reported in a variety of human cancers, e.g. lung, bladder, breast, osteosarcomas, etc. Allelic loss at the locus has been found also in ovarian cancers (Li et al., 1991; Cliby etal., 1993). Dodson etal. (1994) also found loss of heterozygosity at the rb locus in 25 out of 48 ovarian cancers, but found that functional rb protein was expressed in 23 out of 25 cancers where loss of heterozygosity had occurred. While loss of heterozygosity was associated with high-grade tumours, again functional rb protein was detectable in a majority of these cases (Kim et al, 1994). This suggests that abnormalities associated with some other gene, but not rb, may be responsible for the aggressiveness of these tumours. Consistent with these thoughts is the observation by Wrede et al. (1991) that no abnormalities of rb or p53 are detectable in human papilloma virus (HPV>positive cervical carcinoma cell lines. The rb protein expressed in these cell lines was of the wild-type (Scheffner et al., 1991), but evidence of abnormalities are found in HPV-negative cell lines. Riou et al. (1992) found that early-stage invasive cervical cancers which over-express the myc oncogene in the absence of HPV show a high risk of distant metastases, thus myc gene over-expression may be deemed as an independent prognostic indicator of metastasis.

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