Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer

Rintaro Yoshida, Kaname Miyashita, Mayuko Inoue, Akiyoshi Shimamoto, Zhao Yan, Akinori Egashira, Eiji Oki, Yoshishiro Kakeji, Shinya Oda, Yoshihiko Maehara

研究成果: ジャーナルへの寄稿記事

45 引用 (Scopus)

抜粋

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.

元の言語英語
ページ(範囲)320-325
ページ数6
ジャーナルEuropean Journal of Human Genetics
19
発行部数3
DOI
出版物ステータス出版済み - 3 1 2011

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

これを引用

Yoshida, R., Miyashita, K., Inoue, M., Shimamoto, A., Yan, Z., Egashira, A., ... Maehara, Y. (2011). Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer. European Journal of Human Genetics, 19(3), 320-325. https://doi.org/10.1038/ejhg.2010.216