Carcinogenesis Advance Access published online on June 3, 2004
Carcinogenesis, doi:10.1093/carcin/bgh206
© 2004 by Oxford University Press
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1 First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
* To whom correspondence should be addressed. E-mail: hsugimur{at}hama-med.ac.jp.
The MYH gene encodes a DNA glycosylase involved in the excision repair of adenines paired with 8-hydroxyguanines, a major component of oxidative DNA damage, and biallelic germline MYH mutations have been reported to predispose individuals to multiple colorectal adenomas and carcinoma. To determine whether the MYH gene is involved in gastric carcinogenesis, we examined blood specimens from 20 Japanese familial gastric cancer (GC) patients for MYH mutations by PCR-SSCP analysis followed by direct sequencing. Biallelic germline MYH mutations were not found in any of the specimens, but in addition to four known variants, a novel splice-site variant, IVS10-2A>G (c.892-2A>G), was found in two patients as its heterozygote. Reverse transcription-PCR analysis revealed that the IVS10-2A>G variant caused the production of an aberrant mRNA transcript encoding a truncated MYH protein. Immunofluorescence analysis showed that the wild-type MYH protein, but not the variant-type, is localized in the nucleus. We then searched for the IVS10-2A>G variant in 128 digestive tract cancer patients by PCR with confronting two-pair primers, and eight cancers from six patients with the IVS10-2A/G genotype were identified. However, no other germline MYH mutations or inactivation of the remaining wild-type allele was detected. We next tested the presumed correlation of the IVS10-2G allele with GC risk in a case-control study of 148 GC cases and 292 controls, but no significant difference in the distribution of the IVS10-2A>G variant was found between the cases 3 and controls. Interestingly, the homozygote for the IVS10-2G allele was found in one GC case, but not in any controls. These results suggested that the ability to repair 8-hydroxyguanine in nuclear DNA may differ among Japanese individuals due to the splicing abnormality based on the MYH IVS10-2A>G variant, and that the biallelic IVS10-2A>G variation may be responsible for the occurrence of GC.
Revised May 27, 2004
Accepted May 27, 2004
CANCER BIOLOGY
A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus
2 Epidemiology and Biostatistics Division, National Cancer Center, Research Institute East, Chiba 277-8577, Japan
3 Saku General Hospital, 197 Usuda, Usudamachi, Minamisakugun, Nagano 384-1301, Japan
4 Hokushin General Hospital, 1-5-63 Nishi, Nagano 383-0022, Japan
5 Shinonoi General Hospital, 666-1 Shinonoiai, Nagano 388-8004, Japan
6 Nagano Matsushiro General Hospital, 183 Matsushiro, Nagano 381-1231, Japan
7 Department of Pathology, Hamamatsu Medical Center, 328 Tomitsuka-cho, Hamamatsu, Shizuoka 432-8580, Japan
8 Department of Surgery, Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka 540-0006, Japan
9 Biology Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
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