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Deletion Map of Chromosome 9 and p16 (CDKN2A) Gene Alterations in Neuroblastoma¹

Biology Division [J. T., T. K., J. Y.] and Cancer Information and Epidemiology Division [N. Y.], National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104; Department of Pediatrics, Faculty of Medicine, University of Tokyo, 3-1, Hongo 7-chome, Bunkyo-ku, Tokyo 113 [J. T., Y. H.]; and Division of Hematology/Oncology, Saitama Children's Medical Center, 2100, Magome, Iwatsuki 339 [R. H., K. Y.], Japan

We reported previously that loss of heterozygosity (LOH) on chromosomes 2q, 9p and 18q frequently occurs in neuroblastoma and that patients with 9p LOH in the tumors showed statistically significant association with an advanced stage of the disease and poor prognosis. To determine the role of chromosome 9 loss in neuroblastoma, we performed deletion mapping of chromosome 9 in 80 cases of neuroblastoma using 11 polymorphic microsatellite markers and a restriction fragment length porymorphism marker. LOH at one or more loci on chromosome 9 was detected in 33 of 80 cases (41%). Chromosome 9p was lost in 24 of 80 cases (32%), whereas chromosome 9q was lost in 18 of 80 cases (23%). There were two commonly deleted regions mapped to 9p21 between the D9S171 marker and the IFNB1 marker and 9q34-qter distal to the D9S176 marker. In addition, patients with LOH at 9p21 but not at 9q34-qter in the tumors showed statistically significant association with poor prognosis (P = 0.023). Because the commonly deleted regions at 9p21 includes the p16 (CDKN2A) gene, the status of the p16 gene was further examined in 80 fresh tumors and 19 cell lines of neuroblastoma. A missense mutation was detected at codon 52 in a fresh tumor. The p16 gene was not expressed in 13 of 19 cell lines (72%), and 5 of the 13 cell lines displayed methylation of the CpG island surrounding the first exon of the p16 gene. These results suggest that the p16 gene is a candidate tumor suppressor gene for neuroblastoma, and its inactivation may contribute to the progression of neuroblastoma.

¹ This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for the second term Comprehensive 10-Year Strategy for Cancer Control and Grants-in-Aid from the Ministry of Health and Welfare and from the Ministry of Education, Science, Sports and Culture of Japan.

² To whom requests for reprints should be addressed. Phone: 81-3-3542-2511, Ext. 4650: Fax: 81-3-3542-0807.

Received 8/ 5/96. Accepted 1/ 6/97.

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