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[Cancer Research 62, 4095-4099, July 15, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

Genes Involved in DNA Repair Are Mutational Targets in Endometrial Cancers with Microsatellite Instability1

Vessela Vassileva, Anna Millar, Laurent Briollais, William Chapman and Bharati Bapat2

Samuel Lunenfeld Research Institute [V. V., A. M., L. B., B. B.] and Department of Pathology and Laboratory Medicine, Mount Sinai Hospital [V. V., A. M., B. B.], Toronto, Ontario, M5G 1X5 Canada; University Health Network, The Princess Margaret Hospital [W. C.], Toronto, Ontario, M5G 2C4 Canada; and Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, M5G 1L5 Canada [V. V., A. M., W. C., B. B.]

Microsatellite instability (MSI) is observed in a subset of endometrial cancers (ECs) and is attributed to defects in mismatch repair. Mismatch repair deficiency allows for accumulation of mutations in the coding repeats of key target genes, which may be involved in the initiation and progression of MSI+ EC. We examined genes implicated in DNA repair pathways in 38 MSI-high (MSI-H), 10 MSI-low, 25 microsatellite stable ECs, and a selected panel of associated premalignant hyperplasias. Genetic alterations were correlated to histopathological data, including tumor grade and stage. Somatic frameshift mutations were observed in hMLH3, hMSH3, hMSH6, CHK1, and BAX genes in MSI-H endometrial hyperplasias and cancers, whereas mutations in ATR and CDC25C were observed only in MSI-H ECs. Increased mutation frequency in DNA damage response pathway genes including ATR, CHK1, and BAX demonstrated a significant trend with advancing tumor grade (P < 0.05). Our observations of the same mutations at short coding mononucleotide repeats in both premalignant lesions and tumors and association of increased frequency of mutation accumulation with advancing tumor grade suggest that these alterations may play a role in the development and progression of MSI+ EC.




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