THE HUMAN PLAKOGLOBIN GENE LOCALIZES ON CHROMOSOME 17Q21 AND IS SUBJECTED TO LOSS OF HETEROZYGOSITY IN BREAST AND OVARIAN CANCERS

The gene encoding human plakoglobin was mapped to chromosome 17q12-q22 . An intragenic restriction fragment length polymorphism was used to l ocalize the plakoglobin gene distal to locus KRT10 and proximal to the marker D17S858. The plakoglobin gene colocalizes with the polymorphic 17q21 marker UM8 on the same cosmid insert. This subregion of chromos ome 17 is known to be particularly subjected to genetic alterations in sporadic breast and ovarian tumors. We show loss of heterozygosity of the plakoglobin gene in breast and ovarian tumors. We have identified a low-frequency polymorphism in the plakoglobin coding sequence which results in an arginine to histidine substitution at amino acid positi on 142 of the protein, as well as a silent mutation at nucleotide posi tion 332 of the coding sequence. This polymorphism allowed us to demon strate an allelic association of plakoglobin with predisposition to fa milial breast and ovarian cancers. Our results, together with the pres ent knowledge about the biological function of plakoglobin, suggest th at plakoglobin might represent a putative tumor suppressor gene for br east and ovarian cancers.