DEFINITION OF REGIONS OF THE HUMAN GENOME AFFECTED BY LOSS OF HETEROZYGOSITY IN PRIMARY HUMAN BREAST-TUMORS

We have undertaken a systematic study of primary human breast tumor DN A to identify and characterize frequently occurring somatic mutations. Loss of heterozygosity (LOH) has been the most frequent mutation in o ur panels of primary breast tumor DNA. It is currently thought that LO H reveals recessive mutations within the affected region of the genome . One goal of our studies has been to physically define the target gen es revealed by LOH in primary breast tumors. We have focused our effor ts on chromosome 17, finding five regions of the chromosome which are independently affected by LOH in breast tumors. Two apparent target lo ci are on chromosome 17p; one is the TP53 gene. The other is an as-yet undefined locus telomeric to the TP53 gene. Loss of expression of the nme1 gene on chromosome 17q in tumors was linked to patients with a p oor prognosis (p = 0.018). Although a significant trend (p = 0.05) was found between LOH of the nme1 gene and loss of nme1 expression, no po int mutations were found within the coding region of the nme1 gene by single strand conformational polymorphism (SSCP) or nucleotide sequenc e analysis. These and other results suggest to us that there may be po tential tumor suppressor genes both centromeric and telomeric to the n me1 locus on chromosome 17q. (C) 1993 Wiley-Liss, Inc.