TY - JOUR
T1 - Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer
AU - Yoshida, Rintaro
AU - Miyashita, Kaname
AU - Inoue, Mayuko
AU - Shimamoto, Akiyoshi
AU - Yan, Zhao
AU - Egashira, Akinori
AU - Oki, Eiji
AU - Kakeji, Yoshishiro
AU - Oda, Shinya
AU - Maehara, Yoshihiko
N1 - Funding Information:
We are most grateful to P Karran, H Maki and M Sekiguchi for their helpful advice. The expert assistance in DNA sequencing by Y Baba, K Funatsu, Y Ikematsu and K Miyamoto is also gratefully acknowledged. This study was supported by a Grant-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare, and grants from the Ministry of Education, Science, Sports and Culture of Japan.
PY - 2011/3
Y1 - 2011/3
N2 - Genomic sequences encoding the 3′ exonuclease (proofreading) domains of both replicative DNA polymerases, pol delta and pol epsilon, were explored simultaneously in human colorectal carcinomas including six established cell lines. Three unequivocal sequence alterations, including one previously reported, were found, and all these were considered as dysfunctional mutations in light of the local amino-acid sequences. In particular, the F367S mutation found in the POLE gene encoding the pol epsilon catalytic subunit, which includes the proofreading domain, is the first found in human diseases. Surprisingly, the tumours carrying these proofreading domain mutations were all defective in DNA mismatch repair (MMR). In addition to the two cell lines with acknowledged MMR gene mutations, the third tumour was also demonstrated to harbour a distinct mutation in MLH1, and indeed exhibited a microsatellite- unstable phenotype. These findings suggest that, in concert with MMR deficiency, defective polymerase proofreading may also contribute to the mutator phenotype observed in human colorectal cancer. Our observations may suggest previously unrecognised complexities in the molecular abnormalities underlying the mutator phenotype in human neoplasms.
AB - Genomic sequences encoding the 3′ exonuclease (proofreading) domains of both replicative DNA polymerases, pol delta and pol epsilon, were explored simultaneously in human colorectal carcinomas including six established cell lines. Three unequivocal sequence alterations, including one previously reported, were found, and all these were considered as dysfunctional mutations in light of the local amino-acid sequences. In particular, the F367S mutation found in the POLE gene encoding the pol epsilon catalytic subunit, which includes the proofreading domain, is the first found in human diseases. Surprisingly, the tumours carrying these proofreading domain mutations were all defective in DNA mismatch repair (MMR). In addition to the two cell lines with acknowledged MMR gene mutations, the third tumour was also demonstrated to harbour a distinct mutation in MLH1, and indeed exhibited a microsatellite- unstable phenotype. These findings suggest that, in concert with MMR deficiency, defective polymerase proofreading may also contribute to the mutator phenotype observed in human colorectal cancer. Our observations may suggest previously unrecognised complexities in the molecular abnormalities underlying the mutator phenotype in human neoplasms.
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U2 - 10.1038/ejhg.2010.216
DO - 10.1038/ejhg.2010.216
M3 - Article
C2 - 21157497
AN - SCOPUS:79951811449
VL - 19
SP - 320
EP - 325
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 3
ER -