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(American Journal of Pathology. 2002;160:1503-1506.)
© 2002 American Society for Investigative Pathology

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PolyA Deletions in Hereditary Nonpolyposis Colorectal Cancer

Mutations Before a Gatekeeper

Kyoung-Mee Kim^*, Reijo Salovaara, Jukka-Pekka Mecklin, Heikki J. Järvinen, Lauri A. Aaltonen^¶ and Darryl Shibata^*

From the Department of Pathology,^* Norris Cancer Center,University of Southern California School of Medicine, Los Angeles,California; the Departments of Pathology and MedicalGenetics, Haartman Institute, Helsinki,Finland; Jyvaskyla Central Hospital,Jyvaskyla, Finland; the Second Department ofSurgery, Helsinki University Central Hospital,Helsinki, Finland; and the Department of MedicalGenetics,^¶ Haartman Institute, University ofHelsinki, Helsinki, Finland

Microsatellite instability (MSI) secondary to loss of DNA mismatch repair (MMR) is present in adenomas and colorectal carcinomas from individuals with hereditary nonpolyposis colorectal cancer (HNPCC). To better characterize when MMR loss occurs during HNPCC progression, the extent of deletions in noncoding polyA sequences were compared between 6 adenomas (all 1.0 cm in size) and 10 cancers. Numbers of deleted bases reflect time since loss of MMR because polyA deletions are stepwise. Adenoma deletions were nearly the same (85%) as the cancers with sum total deletions at four different polyA loci of -32.7 bases in adenomas and -38.4 bases in cancers. Intervals between negative clinical examinations and tumor removal (average of 2.1 years) were known for six tumors. There were no significant differences in the extent of deletions in tumors removed under clinical surveillance (-34.8 bases) versus tumors removed without prior negative examinations (-36.5 bases). These findings illustrate that MSI is extensive in both small adenomas, and tumors which appear after negative clinical examinations, consistent with an early loss of MMR in HNPCC, even before a gatekeeper mutation.

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