Detailed molecular analysis of 1p36 in neuroblastoma.

Abstract

Several lines of evidence es tablish that chromosome band 1p36 is frequently deleted in neuroblastoma primary tumors and cell lines, suggesting that a tumor suppressor gene within this region is involved in the development of this tumor. We analyzed the status of 1p36 in primary neuroblastomas and cell lines to define the region of consistent rearrangement. Loss of heterozygosity (LOH) studies of primary neuro blastomas identified allelic loss in 135 of 503 tumors (27%), with the smallest region of overlap (SRO) defined distal to D15214 (1p36.3). No homozygous deletions were detected at 120 loci mapping to 1p36.1-p36.3 in a panel of 46 neuroblastoma cell lines. A recently identified patient with neuroblastoma was found to have a constitutional deletion within 1p36.2-p36.3, and this deletion, when combined with the LOH results, defined a smaller SRO of one megabase within 1p36.3. We constructed a comprehensive integrated map of chromosome 1 containing 11,000 markers and large-insert clones, a high-resolution radiation hybrid (RH) map of 1p36, and a P1-artificial chromosome (PAC) contig spanning the SRO, to further characterize the region of interest. Over 768 kb (75%) of the SRO has been sequenced to completion. Further analysis of distal 1p identified 113 transcripts localizing to 1p36, 21 of which were mapped within the SRO. This analysis will identify suitable positional candidate transcripts for mutational screening and subsequent identification of the 1p36.3 neuroblastoma suppressor gene.