Originally published as JCO Early Release 10.1200/JCO.2005.06.055 on April 18 2005

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Molecular Analysis of Familial Endometrial Carcinoma: A Manifestation of Hereditary Nonpolyposis Colorectal Cancer or a Separate Syndrome?

From the Departments of Medical Genetics, and Biological and Environmental Sciences, University of Helsinki; Laboratory of Molecular Genetics, and Department of Obstetrics and Gynecology, Helsinki University Central Hospital; and Family Federation of Finland and Finnish Cancer Society, Helsinki, Finland

Address reprint requests to Päivi Peltomäki, MD, Department of Medical Genetics, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014, University of Helsinki, Helsinki, Finland; e-mail: Paivi.Peltomaki{at}Helsinki.fi

PURPOSE: Familial clustering of endometrial carcinoma (EC) may occur as part of hereditary nonpolyposis colorectal cancer (HNPCC), a multiorgan cancer syndrome with mismatch repair (MMR) deficiency. Clustering of EC alone, termed as familial site-specific EC, may constitute a separate entity. Because its genetic basis is unknown, our purpose was to characterize such families molecularly.

MATERIALS AND METHODS: Twenty-three families with site-specific EC were identified among 519 consecutive patients diagnosed with EC during 1986 to 1997. Tumor tissues were examined for MMR protein expression by immunohistochemical (IHC) analysis, and MMR genes pinpointed by IHC changes were screened for germline mutations by exon-by-exon sequencing, multiplex ligation-dependent probe amplification, and direct tests for mutations common in the population.

RESULTS: Among 33 ECs from 23 families, MLH1 protein was lost in seven tumors (21%), MSH2 together with MSH6 was lost in four tumors (12%), and MSH6 alone was lost in five tumors (15%). A truncating germline mutation in MSH6 (3261insC) was identified in one family and a likely pathogenic missense mutation in MSH2 (D603N) was identified in another family. Among the original 519 patients, nine (all with colon cancer in the family) were diagnosed with HNPCC at the outset—six with MLH1 and three with MSH2 mutations.

CONCLUSION: Our study gives a minimum overall frequency of 2.1% (11 of 519) for germline MMR defects ascertained through EC in the index patients. The fact that only two of 23 families with site-specific EC (8.7%) had germline mutations in MMR genes suggests another as yet unknown etiology in most families with site-specific EC.

Supported by the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Cancer Foundation, the Finnish Cultural Foundation, the Paulo Foundation, and the Oskar Öflund Foundation.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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