APC mutations in colorectal tumors with mismatch repair deficiency

Jian Huang, Nickolas Papadopoulos, Aileen J. Mckinley, Susan M. Farrington, Lucy J. Curtis, Andrew H. Wyllie, Shu Zheng, James K V Willson, Sanford D. Markowitz, Pat Morin, Kenneth W. Kinzler, Bert Vogelstein, Malcolm G. Dunlop

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298 Scopus citations


We have investigated the influence of genetic instability [replication error (RER) phenotype) on APC (adenomatous polyposis coli), a gene thought to initiate colorectal tumorigenesis. The prevalence of APC mutations was similar in RER and non-RER tumors, indicating that both tumor types share this step in neoplastic transformation. However, in a total of 101 sequenced mutations, we noted a substantial excess of APC frameshift mutations in the RER cases (70% in RER tumors versus 47% in non-RER tumors, P < 0.04). These frameshifts were characteristic of mutations arising in cells deficient in DNA mismatch repair, with a predilection for mononucleotide repeats in the RER tumors (P < 0.0002), particularly (A)(n) tracts (P < 0.00007). These findings suggest that the genetic instability that is reflected by the RER phenotype precedes, and is responsible for, APC mutation in RER large bowel tumors and have important implications for understanding the very earliest stages of neoplasia in patients with tumors deficient in mismatch repair.

Original languageEnglish (US)
Pages (from-to)9049-9054
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Aug 20 1996

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