Genomic gains on chromosome 1q in retinoblastoma: Consequences on gene expression and association with clinical manifestation

Abstract

Many retinoblastomas (Rbs) show genomic alterations in addition to mutational loss of both normal RB1 alleles. The most frequent of these changes are gains on chromosomes 1q and 6p and losses on 16q. To identify the genes targeted by gains on chromosome 1q, we used quantitative-multiplex PCR to determine DNA copy number changes in 76 primary tumors and 6 Rb cell lines. In addition, in 21 of these tumors, gene expression was analyzed by cDNA microarray hybridization. Increased copy numbers of loci on chromosome 1q were present in 34 (45%) primary tumors and in all 6 cell lines. Two regions of gain emerged, one in 1q32 and another in 1q21. Tumors with 1q gains showed higher RNA expression of several genes in these 2 regions. The clinical manifestation of tumors with and without gains was similar with regard to many aspects, including size, necrosis and calcification. However, the distribution of age at diagnosis was remarkably distinct, with earlier diagnosis in tumors without gains. This suggests that these tumors either are initiated earlier or grow faster than tumors with gains. This association with clinical manifestation indicates that gains on 1q are significant for the biology of Rb. The genes on 1q with copy number gains and overexpression are candidates that need to be tested for their individual contribution to the progression of Rb. ' 2005 Wiley-Liss, Inc.

Allelic Loss in a Minimal Region on Chromosome 16q24 Is Associated with Vitreous Seeding of Retinoblastoma

“…Informed consent was obtained from all patients or their parents. Storage and processing of samples as well as extraction of nucleic acids was done as previously described (10). Material from 58 patients (54 unilateral and 4 bilateral cases) with known mutations in the RB1 gene was used for the present study.…”

“…Intermarker distances were even (1-2 Mb along 16q) except a gap of 15 Mb between markers D16S3080 and D16S3050 (at 16q12.1 and 16q21, respectively). PCR with labeled forward primers (FAM, PET, or NED fluorescent dyes at the 5 ¶-end, Applied Biosystems, Weiterstadt, Germany) was done in multiplexed assays and analyzed as described (10). If loss of one allele in the tumor was incomplete, the allele ratio was determined as follows: (PI allele 1 tumor / PI allele 2 tumor) / (PI allele 1 blood / PI allele 2 blood), where PI is the peak integral.…”

Emerging Roles of Atypical Dual Specificity Phosphatases in Cancer

“…dusp12 is up-regulated or amplified in a variety of cancers including neuroblastoma, retinoblastoma, intracranial ependymoma, and chronic myelogenous leukemia [56][57][58][59]. Additionally, dusp12 is one of only two candidate genes for the target of a 1q21-1q23 amplification found in invasive liposarcomas [60] leading to the hypothesis that dusp12 is an oncogene.…”

“…Transient over-expression of dusp12 in HEK293 cells resulted in an increase in the percentage of cells in the G2/M phase and polyploidy and knock-down resulted in cell cycle arrest and senescence [66]. Since, dusp12 is amplified in several cancers [56,57,60], it is possible that DUSP12 may promote cancer by increasing genomic instability. Unlike the pro-survival properties described above, DUSP12's effect on the cell cycle was independent of its phosphatase activity and required the CRD domain [66].…”

Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma

“…Amplification of these genes would be expected to functionally inactivate the p53 pathway and may explain the lack of genetic alterations observed at the p53 locus in human RB. However, some reports have demonstrated a lack of correlation between genomic amplification of MdmX and levels of its expressed mRNA (96). Nevertheless, amplification of MdmX has been shown to suppress p53-mediated cell death in retinoblasts lacking RB1 and to promote their clonal cell proliferation (83).…”