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

doi:10.1073/pnas.93.17.9049

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

Simmons Comprehensive Cancer Center

Research output: Contribution to journal › Article › peer-review

298 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	9049-9054
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	93
Issue number	17
DOIs	https://doi.org/10.1073/pnas.93.17.9049
State	Published - Aug 20 1996

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Huang, J., Papadopoulos, N., Mckinley, A. J., Farrington, S. M., Curtis, L. J., Wyllie, A. H., Zheng, S., Willson, J. K. V., Markowitz, S. D., Morin, P., Kinzler, K. W., Vogelstein, B., & Dunlop, M. G. (1996). APC mutations in colorectal tumors with mismatch repair deficiency. Proceedings of the National Academy of Sciences of the United States of America, 93(17), 9049-9054. https://doi.org/10.1073/pnas.93.17.9049

Huang, J, Papadopoulos, N, Mckinley, AJ, Farrington, SM, Curtis, LJ, Wyllie, AH, Zheng, S, Willson, JKV, Markowitz, SD, Morin, P, Kinzler, KW, Vogelstein, B & Dunlop, MG 1996, 'APC mutations in colorectal tumors with mismatch repair deficiency', Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 17, pp. 9049-9054. https://doi.org/10.1073/pnas.93.17.9049

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title = "APC mutations in colorectal tumors with mismatch repair deficiency",

abstract = "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.",

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AU - Zheng, Shu

AU - Willson, James K V

AU - Markowitz, Sanford D.

AU - Morin, Pat

AU - Kinzler, Kenneth W.

AU - Vogelstein, Bert

AU - Dunlop, Malcolm G.

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N2 - 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.

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APC mutations in colorectal tumors with mismatch repair deficiency

Abstract

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