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Carcinogenesis Advance Access published online on August 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh267
© 2004 by Oxford University Press
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Received May 1, 2004
Revised July 29, 2004
Accepted August 10, 2004

CANCER BIOLOGY

Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer

Kazuya Shinmura 1, Hong Tao 1, Masanori Goto 1, Hisaki Igarashi 1, Terumi Taniguchi 2, Masato Maekawa 2, Toshiro Takezaki 3, Haruhiko Sugimura 1*

1 First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
2 Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
3 Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan

* To whom correspondence should be addressed. E-mail: hsugimur{at}hama-med.ac.jp.


  Abstract

Oxidized DNA base lesions, such as thymine glycol (Tg) and 8-hydroxyguanine, are often toxic and mutagenic and have been implicated in carcinogenesis. To clarify whether NEIL1 protein, which exhibits excision repair activity towards such base lesions, is involved in gastric carcinogenesis, we examined 71 primary gastric cancers from Japanese patients and 4 gastric cancer cell lines for mutations and genetic polymorphisms of the NEIL1 gene. We also examined 20 blood samples from Chinese patients for NEIL1 genetic polymorphisms. Three mutations (c.82_84delGAG:p.Glu28del, c.936G>A and c.1000A>G:p.Arg334Gly) and two genetic polymorphisms were identified. When the excision repair activity towards double-stranded oligonucleotide containing a Tg:A base-pair was compared among six types of recombinant NEIL1 proteins, p.Glu28del-type NEIL1, found in a primary case, was found to exhibit an extremely low activity level. Moreover, c.936G>A, located in the last nucleotide of exon 10 and detected in the KATO-III cell line, was shown to be associated with a splicing abnormality using an in vivo splicing assay. An immunofluorescence analysis showed that the wild-type NEIL1 protein, but not the truncated protein encoded by the abnormal transcript arising from the c.936G>A mutation, was localized in the nucleus, suggesting that the truncated protein is unlikely to be capable of repairing nuclear DNA. An expression analysis revealed that NEIL1 mRNA expression was reduced in 6/13 (46%) of the primary gastric cancer. These results suggest that low NEIL1 activities arising from mutations and reduced expression may be involved in the pathogenesis in a subset of gastric cancers.


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