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Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-01-0094.
Submitted January 16, 2003
Accepted August 5, 2003
Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease
Masatoshi Takagi, Rika Tsuchida, Kaoru Oguchi, Teruko Shigeta, Shinichiro Nakada, Kimiko Shimizu, Misao Ohki, Domenico Delia, Luciana Chessa, Yoichi Taya, Makoto Nakanishi, Yukiko Tsunematsu, Fumio Bessho, Keiichi Isoyama, Yoshiki Hayashi, Kazuko Kudo, Jun Okamura, and Shuki Mizutani*
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
Molecular Oncology Division, National Cancer Center Research Institute, Tokyo, Japan
Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy
Department of Experimental Medicine and Pathology, University 'La Sapienza', Rome, Italy
Radiobiology Division, National Cancer Center Research Institute, Tokyo, Japan
Department of Biochemistry, Nagoya City University Medical School, Nagoya, Japan
Department of Hematology/Oncology, National Center for Child Health and Development, Tokyo, Japan
Department of Pediatrics, Kyorin University, Tokyo, Japan
Department of Pediatrics, Showa University of Medical School, Kanagawa, Japan
Department of Pediatrics, Oume Municipal Hospital, Tokyo, Japan
Department of Pediatrics, Nagoya University, Nagoya, Japan
Section of Pediatrics, National Kyushu Cancer Center, Fukuoka, Japan
* Corresponding author; email: smizutani.ped{at}tmd.ac.jp.
There are conflicting reports about the involvement of single nucleotide polymorphisms (SNPs) of the ataxia telangiectasia mutated (ATM) gene with cancer, and the consequences of these SNPs for ATM function remain unclear. We therefore sought to identify SNPs of the ATM gene in pediatric Hodgkin disease (HD) and to analyze ATM function in cells from patients with these SNPs. We have identified SNPs of the ATM gene in 5 of 14 children (S1455R, n = 1, H1380Y, n = 1, N1650S, n = 2; and I1709I, n = 1). One patient had nonsense-associated altered splicing of the ATM gene. Lymphoblastoid cell lines expressing the S1455R and N1650S exhibited defective ATM-mediated p53 phosphorylation and Chk2 activation; cells expressing the H1380Y exhibited defective c-Abl activation after X-irradiation. Expression of the N1650S in ATM-null fibroblasts conferred only partial hyperradiosensitivity. Furthermore, the introduction of N1650S ATM into U2OS cells, which express wild-type ATM, showed reduced p53-Ser15 phosphorylation, suggesting a dominant negative effect of the N1650S over the wild-type ATM protein. We conclude that the rare polymorphic variants of the ATM gene that we identified in children with HD encode functionally abnormal proteins, and we discuss the possible genetic risk factors for childhood HD.
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