Ever since Knudson

Many publications have documented loss of heterozygosity (LOH) on many diff erent chromosomes in a wide variety of tumours, implicating the existence o f multiple tumour suppressor genes (TSGs). Knudson's two-hit hypothesis pre dicts that these LOH events are the second step in the inactivation of both alleles of a TSG. However, to date the number of TSGs identified that are inactivated mainly at the somatic level in cancers and are not inherited ha s remained disappointingly small. Here we postulate that the accurate mappi ng of LOH events in a series of tumours to define a common LOH region is gr eatly confounded by deficient LOH detection, genetic instability and intert umour heterogeneity. Finding the TSGs in chromosomal regions of frequent LO H might require 'brute-force' genomic approaches.