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The DNA Polymerase ß Replication Error Spectrum in the Adenomatous Polyposis Coli Gene Contains Human Colon Tumor Mutational Hotspots¹

Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

We have found a significant concordance between the in vitro replication errors of human DNA polymerase ß and in vivo point mutations of the adenomatous polyposis coli (APC) gene that leads to colon cancer. We determined the error spectrum of DNA polymerase ß in the human APC gene under PCR conditions and compared it with the set of mutations reported in human colon tumors. Polymerase ß created seven hotspot mutations within 141 target bp analyzed in APC exon 15. Three of these polymerase ß hotspots, 2 frameshifts and a bp substitution mutation, were concordant with 3 of 13 APC hotspots detected in human colon cancers in the same DNA sequences. These 3 concordant hotspots accounted for some 54% of reported in vivo APC hotspot mutations. Using the assumption of a hypergeometric distribution of hotspot mutations among bp of the scanned sequences, the probability of this concordance occurring by chance is <4 x 10^-4. These data support the hypothesis that DNA polymerase ß errors are an important fraction of cancer-causing APC mutations.

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