Using loss of heterozygosity data in affected pedigree member linkage tests

Linkage analysis can be used to test the hypothesis that a marker locus of known location segregates independently from a presumed disease gene. One way to test this hypothesis is to measure the similarity of marker alleles among pairs of relatives affected with the disease. When the disease under consideration is cancer, it is possible to take advantage of the marker alleles in tumors to revise the similarity measure obtained from the observations made in constitutional tissue. Only cancers that arise through the model of recessive oncogenesis are amenable to this revised analysis. This model postulates that cancer is caused by somatic genetic changes which result in the loss of one or both copies of a normal allele at a tumor suppressor locus. If an individual's inherited genotype is heterozygous at the marker locus, the model of recessive oncogenesis suggests that we may observe loss of constitutional heterozygosity at the marker locus in the tumor. In this report, we show how to incorporate this loss of heterozygosity data into affected pedigree member linkage tests. The revised procedure is illustrated using data obtained from relatives with breast cancer. Substantial improvement in the power to reject the different chromosome hypothesis is obtained when loss of heterozygosity is observed in multiple relatives with the same marker alleles retained in the tumors. ©1995 Wiley‐Liss, Inc.