The development of neoplasia has been thought to be associated with genetic alterations for many years. In colorectal cancer two specific types of genetic instability have been defined. One is associated with chromosomal instability and the other with DNA microsatellite instability, also known as replication errors.1 The mechanism underlying tumorigenesis leads to profound differences in the pathological features, prognosis and response to chemotherapy of these two types of colorectal cancer.

The great majority of colorectal cancers are aneuploid with a variable chromosome complement. However, between 10 and 15% of colorectal cancers are near diploid and exhibit DNA microsatellite instability in which replication errors may be demonstrated within repetitive sequences of tumour DNA which are not present in the normal DNA of the individual. Tumours with microsatellite instability occur more frequently in younger patients, are more frequently proximal to the splenic flexure and exhibit exophytic growth, poor differentiation, extracellular mucin production, and a Crohn’s-like lymphocytic reaction.2 The genes mutated during tumorigenesis may be different from those in aneuploid tumours with frequent mutations of tumour growth factor β receptor II and Bax.3 ,4 Cell lines from these tumours are less sensitive to alkylating agents such as N-methyl-N’-nitro-N-nitrosoguanidine (MNNG).5

Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant predisposition to colorectal neoplasia. It has been defined clinically by the Amsterdam criteria of the International Collaborative Group for HNPCC as colorectal cancer affecting at least three members of a family, one of whom must be a first degree relative of the other two, with at least two successive generations affected and one case diagnosed under the age of 50.6 Colorectal carcinomas in HNPCC exhibit microsatellite instability and share the same pathological characteristics.

In HNPCC the microsatellite instability is due to germline mutations of DNA mismatch repair genes. These genes were identified because a similar type of DNA instability had been described in yeast. Mutations of the human homologues of the yeast genes segregate with disease in HNPCC families.1

Brown et al, in this issue (see page 553), have looked at the proportion of cases of familial colorectal cancer associated with microsatellite instability and which, by implication, may be due to the same DNA mismatch repair gene mutations that cause HNPCC. They identified two groups of patients with colorectal cancer. The first group was from follow up of one surgeon’s clinical practice and a careful family history had been taken. The second group was from a regional genetic clinic and the families fulfilled the Amsterdam criteria for HNPCC. In the follow up population only 4/479 (0.8%) had a family history that fulfilled that Amsterdam criteria and only one of these had a tumour that showed microsatellite instability. In the families from the regional genetic centre 8/16 had tumours with microsatellite instability. In four of these families a germline DNA mismatch repair gene mutation had been identified and all of these families had tumours which exhibited microsatellite instability.

These results suggest that only a small proportion of familial colorectal cancer, and possibly only 50% of families fulfilling the Amsterdam criteria for HNPCC, is associated with microsatellite instability. This indicates that there are further inherited predispositions to colorectal cancer yet to be identified.

The majority of colorectal cancers are aneuploid with a variable chromosome number. Genetic alterations involving the loss of chromosomes that occur in tumorigenesis may be demonstrated by comparing normal and tumour DNA from the same individual. Loss of constitutional heterozygosity (allele loss) may indicate areas where tumour suppressor genes have been inactivated. This technique has been used to identify many of the genes which are mutated in colorectal tumorigenesis.

To date, it has not been clear whether aneuploidy is an important mechanism or a by-product of tumorigenesis. However, recent work from Vogelstein’s group indicates that aneuploidy may be significant in pathogenesis.7 A gene that causes aneuploidy in colorectal cancer has been described.8 This is the human homologue of BUBI a yeast gene that is critical in the control of the formation of the mitotic spindle. Mutations of hBUBI are seen in some aneuploid human colorectal cancers. The functional role of hBUBI has been demonstrated by the transfer of the mutant gene to diploid human colon cancer cell lines leading to the development of aneuploidy.

In conclusion, two different genetic pathways may lead to colorectal tumorigenesis due to either chromosomal or DNA microsatellite instability. The molecular basis of these two types of carcinoma have been defined and the two types of tumours shown to have very different biological behaviour. In familial colorectal cancer Brown et al have shown that only a small proportion of cancers have the microsatellite instability characteristic of HNPCC and that there are likely to be other genetic causes.