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particular (parts ot) chromosomes in human tumors. The latter approach uses the frequent
occurrence of restriction fragment length polymorph isms (RFLPs) of some DNA probes or
polymorphic microsatellites in the human genome. This technique takes advantage of the
heterozygous state of a patient's normal (constitutional) DNA for a particular polymorphic
marker, loss of that part of the chromosome is the case when tumor tissue of the same patient
shows reduction or loss of one of the alleles (Fig. I).
LOH study
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Figure 1.
The most commonly observed inactivation scheme for a recessive tumor suppressor gene. The
normal (wild-type) copies of the tumor suppressor gene are shown with the open boxes. In the
tumor both copies of the gene are inf'lctivated by a small mutation in one allele (black box) and
loss of the portion of the chromosome that harbours the second allele. Loss of heterozygosity
(LOH) of this chromosomal part can be detected on a Sonthern blot. This analysis uses the ability
of a polymorphic DNA marker, specific for the relevant region of the chromosome, to detect both
the maternal and paternal alleles (A I and A2). The comparison of normal and tumor DNA from
the same individual can distinguish whether one allele is lost in the tumor.
A comprehensive list of consistently observed allele losses in solid tumors has been described
by Seizinger et al. (1991). A combination of linkage analyses in cancer families and LOH
studies in both sporadic and familial tumors have led to the localization of a large number
of (mostly) tumor suppressor gene loci. The 'positional cloning' (Collins, 1992) andlor
candidate gene approach eventually resulted in the cloning of some of these genes. A number
of examples are listed in Table 1. In the following sections these genes are briefly described.
The products of tumor suppressor genes may be involved in the negative regulation
of cell growth, induction of terminal differentiation and/or apoptosis. The gene can contribute
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