LOSS OF HETEROZYGOSITY AND MUTATIONAL ANALYSIS OF THE PTEN MMAC1 GENEIN SYNCHRONOUS ENDOMETRIAL AND OVARIAN CARCINOMAS/

Mutations of the human putative protein tyrosine phosphatase (PTEN/MIM AC1) gene at chromosome 10q23 have been found frequently in type I end ometrial carcinomas, Endometrioid adenocarcinoma is the most frequent histology seen in patients with clinically determined synchronous endo metrial and ovarian carcinomas. We report a high incidence of PTEN/MMA C1 mutations and 10q23 loss of heterozygosity (LOH) in patients with s ynchronous endometrial and ovarian carcinomas. Paraffin-embedded preci sion microdissected tumors were analyzed for 10 matched synchronous en dometrial and ovarian cancers and 11 matched control metastatic endome trial cancers. Single-stranded conformation polymorphism analysis was used to screen for mutations in all tumors and corresponding normal ly mphocyte DNA, LOH was determined using a panel of four microsatellite markers within the PTEN/MMAC1 locus. PTEN/MMAC1 mutations were found i n 43% (9 of 21) of the endometrial cancers studied, similarly represen ted in the clinically synchronous group (5 of 10 or 50%) and the advan ced metastatic group (4 of 11; 36%; P = 0.53), In two of the five case s of clinically synchronous cancers, identical or progressive PTEN mut ations were found in both the endometrial and ovarian cancers, suggest ing that the ovarian tumor is a mestastasis from the endometrial prima ry. PTEN/MIMAC1 mutations in the advanced endometrial cancers were sim ilar in the corresponding metastases, In one case, the mutation was se en in only one of two metastatic lymph nodes. The LOH analysis demonst rated 55% LOH in at least one PTEN/MMAC1 marker. These findings sugges t that the putative tumor suppressor gene PTEN/MMAC1 may be a viable m olecular marker to differentiate synchronous versus metastatic disease in a subset of clinically synchronous endometrial and ovarian carcino mas.