MICROSATELLITE INSTABILITY AND ALTERATIONS IN THE HMSH2 GENE IN HUMANOVARIAN-CANCER

The role of the replication error-positive (RER(+)) phenotype in the d evelopment of specific subtypes of sporadic ovarian carcinomas was exa mined by screening for the presence of microsatellite instability (MI) in 47 tumors. The overall frequency of ovarian MI was 17% only. Howev er, MI occurred in 50% of the ovarian endometrioid-type tumors, which was significantly more often than in all the other histological subtyp es combined (8%). Five of the 8 RER(+) tumors exhibited most marked ty pe I instability, possibly representing a different mechanism than for the remaining type 2 tumors. The cDNA of the mutation suppression gen e hMSH2, the gene most often associated with MI, was screened for alte rations in 8 MI-positive and 5 MI-negative ovarian tumors. Only 3 chan ges were found. Complete loss of hMSH2 mRNA expression was detected in I tumor, while another expressed only an abnormal transcript containi ng a deletion of exon 3, One additional RER(+) serous adenocarcinoma c ontained a rare polymorphism with a nonconservative amino acid change. One of 8 RER(+) tumors showed loss of heterozygosity at the hMSH2 loc i. Genetic instability, caused in part by alterations in the hMSH2 gen e, may play an important role in the sporadic endometrioid subtype of ovarian tumors. Other mutator-phenotype genes may be responsible for t he remaining cases of RER(+) ovarian tumors. (C) 1995 Wiley-Liss, Inc.