Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma

Abstract

Substantial genomic and functional evidence from primary tumors and cell lines indicates that a consistent region of distal chromosome 1p is deleted in a sizable proportion of human neuroblastomas, suggesting that this region contains one or more tumor suppressor genes. To determine systematically and precisely the location and extent of 1p deletion in neuroblastomas, we performed allelic loss studies of 737 primary neuroblastomas and genotype analysis of 46 neuroblastoma cell lines. Together, the results defined a single region within 1p36.3 that was consistently deleted in 25% of tumors and 87% of cell lines. Two neuroblastoma patients had constitutional deletions of distal 1p36 that overlapped the tumor-defined region. The tumor-and constitutionally-derived deletions together defined a smallest region of consistent deletion (SRD) between D1S2795 and D1S253. The 1p36.3 SRD was deleted in all but one of the 184 tumors with 1p deletion. Physical mapping and DNA sequencing determined that the SRD minimally spans an estimated 729 kb. Genomic content and sequence analysis of the SRD identified 15 characterized, nine uncharacterized, and six predicted genes in the region. The RNA expression profiles of 21 of the genes were investigated in a variety of normal tissues. The SHREW1 and KCNAB2 genes both had tissue-restricted expression patterns, including expression in the nervous system. In addition, a novel gene (CHD5) with strong homology to proteins involved in chromatin remodeling was expressed mainly in neural tissues. Together, these results suggest that one or more genes involved in neuroblastoma tumorigenesis or tumor progression are likely contained within this region.

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

“…Whereas breakpoints are widely dispersed along chromosome arms 1p, 2p, 3p and 17q, they lie closer together on chromosome 11q, at 11q23, in accordance with published data (Schleiermacher et al, 2004;Stallings et al, 2004;White et al, 2005;Spitz et al, 2006). Further studies using FISH or high-resolution CGH will be needed to map the breakpoints precisely.…”

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

“…By contrast, we did find that in rare cases of pancreatic cancer, EphA2 protein overexpression may specifically result from amplification of 1p36.12. Chromosomal alterations involving 1p have been reported in a variety of human cancer types, including pancreatic carcinoma [32,33], with most studies implicating the presence of a tumor suppressor gene(s) on this chromosome arm [34,35]. However, the lack of inactivating mutations of EPHA2 reported in this study indicates that EPHA2 functions in a manner unlike that of the other Eph receptor family members targeted by inactivating mutations.…”

CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

“…CASZ1 (1p36.22) localizes to one of the commonly deleted region in NB on chr1p between the markers D1S508 and D1S244. 3 Although the recent study in 184 primary NB with 1p LOH showed that 1p36.3 (minimally between D1S2795 and D1S252) is the shortest region of overlap (SRO), 24 we found in their study that loss of CASZ1 occurs in 180 of the 184 (98%) 1p LOH primary NB tumors. In this study, we provide functional evidence that CASZ1 is a tumor-suppressor gene.…”