Loss of Heterozygosity and Mutational Analysis of the PTEN/MMAC1 Gene in Synchronous Endometrial and Ovarian Carcinomas1 w

Mutations of the human putative protein tyrosine phosphatase (PTEN/MMACJ) gene at chromosome 10q23 have been found frequently in type I endometrial carcinomas. Endometrioid adenocarcinoma is the most frequent histol. ogy seen in patients with clinically determined synchronous endometrial and ovarian carcinomas. We report a high incidence of PTEN/MMACJ mutations and 10q23 loss of heterozygosity (LOH) in patients with synchronous endome. trial and ovarian carcinomas. Paraffin-embedded precision microdissected tumors were analyzed for 10 matched synchronous endometrial and ovarian cancers and 1 1 matched control metastatic endometrial cancers. Single-stranded conformation polymorphism analysis was used to screen for mutations in all tumors and corresponding normal lymphocyte DNA. LOH was determined using a panel of four microsatellite markers within the PTEN/MMACJ locus. PTEN/MMACJ mutations were found in 43% (9 of 21) of the endometrial cancers studied, similarly represented in the clinically synchronous group (5 of 10 or 50%) and the advanced metastatic group (4 of 11; 36%; P = 0.53). In two of the five cases of clinically synchronous cancers, identical or progressive PTEN mutations were found in both the Received 6/17/98; revised 8/19/98: accepted 9/2/98. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I Supported in part by the Reproductive Scientist Development Program through NIH Grant K12HD00849, the American Association of Obstetrician Gynecologist Foundation, and Cancer Research Foundation of North Texas. Dr. Muller is an AAOGF-NICHD Fellow of the Reproductive Scientist Development Program. This study was presented at the 27th Annual Meeting of the Western Association of Gynecologic Oncologists, Napa, CA, May 20-23, 1998. 2 To whom requests for reprints should be addressed, at Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9032. Phone: (214) 648-3026; Fax: (214) 648-8404; E-mail: cmulle@mednet. swmed.edu. endometrial and ovarian cancers, suggesting that the ovarian tumor is a mestastasis from the endometrial primary. PTEN/MMACJ mutations in the advanced endometrial cancers were similar in the corresponding metastases. In one case, the mutation was seen in only one of two metastatic lymph nodes. The LOH analysis demonstrated 55% LOH in at least one PTEN/MMACI marker. These findings suggest that the putative tumor suppressor gene PTEN/MMACJ may be a viable molecular marker to differentiate synchronous versus metastatic disease in a subset of clinically synchronous endometrial and ovarian carcinomas.