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Amplification and Rearrangement of DNA Sequences from the Chromosomal Region 2p24 in Human Neuroblastomas¹

Mental Retardation Center and Genetics Division, Children's Hospital, Boston, Massachusetts 02115 [Y. S., B. K., K. S., P. H., S. A. L.]; Department of Biochemistry and Institute of Cancer Research, Columbia University College of Physicians and Surgeons, New York, New York 10032 [N. E. K., F. A.]; Department of Anatomy, Tokyo Womens Medical College, Tokyo, Japan [N. K.]; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110 [G. M. B.]; and Children's Cancer Study Group and Department of Pediatrics, University of California at Los Angeles, Los Angeles, California 90024 [R. C. S.]

Seven DNA fragments which map to or very near human chromosome band 2p24 are shown to be differentially amplified in DNA from specific subsets of an enlarged series of human neuroblastoma cell lines and primary neuroblastomas. Of these DNA fragments, the probe NB-19-21 for the oncogene N-myc is the most frequently amplified, with a second expressed sequence (pG21) amplified in 9 of those 11 cell lines and 16 of those 25 tumors exhibiting amplification of N-myc. The remaining probes are in turn each amplified in progressively smaller, nested subsets of the cell lines and tumors in which both N-myc and pG21 are amplified. These data permit construction of models for the organization of a "neuroblastoma amplicon," i.e., an originally amplified DNA domain, with N-myc positioned most central and the other DNA fragments increasingly peripheral; comparable models result for the cell lines and the tumors. Five of the seven probes examined detect novel DNA fragments in these specimens, reinforcing previous observations that extensive DNA rearrangement can occur during DNA amplification in neuroblastoma cell lines and in primary neuroblastomas. Such rearrangements could contribute significantly to the evolution of the neuroblastoma amplicon in different specimens to progressively smaller units, preserving, in the limit, amplification of N-myc.

¹ This study was supported by grants CD-36 (S. A. L.) and CD-269 (F. A.) from the American Cancer Society, HD18658 (S. A. L.), GM33579 (S. A. L.), CA42335 (F. A.), CA22794 (R. C. S.), and CA27678 (R. C. S.) from the NIH.

² Chaim Weizmann postdoctoral fellow. Present address: Department of Human Genetics, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.

³ To whom requests for reprints should be addressed, at Genetics Division, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115.

Received 1/14/86. Revised 4/24/86. Accepted 5/ 2/86.

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