USING LOSS OF HETEROZYGOSITY DATA IN AFFECTED PEDIGREE MEMBER LINKAGETESTS

Linkage analysis can be used to test the hypothesis that a marker locu s of known location segregates independently from a presumed disease g ene. One way to test this hypothesis is to measure the similarity of m arker alleles among pairs of relatives affected with the disease. When the disease under consideration is cancer, it is possible to take adv antage of the marker alleles in tumors to revise the similarity measur e obtained from the observations made in constitutional tissue. Only c ancers that arise through the model of recessive oncogenesis are amena ble to this revised analysis. This model postulates that cancer is cau sed 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 individu al's inherited genotype is heterozygous at the marker locus, the model of recessive oncogenesis suggests that we may observe loss of constit utional heterozygosity at the marker locus in the tumor. In this repor t, we show how to incorporate this loss of heterozygosity data into af fected pedigree member linkage tests. The revised procedure is illustr ated using data obtained from relatives with breast cancer. Substantia l improvement in the power to reject the different chromosome hypothes is is obtained when loss of heterozygosity is observed in multiple rel atives with the same marker alleles retained in the tumors. (C) 1995 W iley-Liss, Inc.