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Somatic Instability of the APC I1307K Allele in Colorectal Neoplasia¹

Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [R. G., N. D., S. G., M. R.], and Departments of Surgery [R. G., S. G.] and Laboratory Medicine and Pathobiology [M. R.], The University of Toronto, Toronto, Ontario, M5G 1X5 Canada

The adenomatous polyposis coli (APC) gene is proposed to function as a gatekeeper of colorectal neoplasia. A germ-line variant of this gene, the APC I1307K allele, is present in 6% of the Ashkenazi Jewish population. To assess the role in tumorigenesis of the variant (A)₈ tract produced by this allele, we undertook a somatic mutation analysis of the region surrounding codon 1307 in colorectal tumors from APC I1307K carriers. Somatic mutations involving the variant (A)₃ tract were identified in 53 of 127 (42%) tumors from APC I1307K carriers compared with 5 of 127 (4%) mutations involving the wild-type allele of these tumors (P < 0.0001). Loss of heterozygosity of the wild-type allele was significantly more common in tumors with APC I1307K allele mutations (25 of 41, 61%) compared with APC I1307K carrier tumors without mutation of the variant (A)₈ tract (12 of 53, 23%; P < 0.0005). This somatic biallelic APC inactivation further confirms the biological importance of the I1307K germ-line variant. The vast majority of APC I1307K somatic mutations consisted of a single adenine insertion (insA) involving the variant (A)₈ tract. This insA mutation was mutually exclusive of the presence of microsatellite instability with 0 of 49 tumors with insA displaying BAT-26 instability compared with 9 of 78 tumors without insA (P = 0.01). These findings support a model where somatic instability of the (A)₈ tract produced by the APC I1307K allele leads to increased APC gene inactivation and directly accounts for 42% of the colorectal neoplasms occurring in APC I1307K carriers.

¹ This research was supported in part by the National Cancer Institute of Canada (to S. G. and M. R.) with funds provided by the Canadian Cancer Society. R. G. is a Terry Fox Research Fellow of the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society.

² To whom requests for reprints should be addressed, at Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 1073A, 600 University Avenue, Toronto, Ontario, M5G 1X5 Canada. E-mail: mredston@mtsinai.on.ca.

Received 4/29/98. Accepted 8/10/98.

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