Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization

Abstract

Although it is established that the loss of function of both alleles of the RB1 gene is a prerequisite for the development of retinoblastoma, little is known about the genetic events that are required for tumor progression. We used comparative genomic hybridization (CGH) to search for DNA copy number changes in isolated unilateral retinoblastomas. From a series of 66 patients with retinoblastomas with somatic mutations in both RB1 alleles, tumor samples from 13 children with the youngest (2.0-9.8 months) and 13 with the oldest (36.2-84.1 months) age at operation were studied. Loss at 13q14, the location of RB1, was demonstrated in two tumors only. Recurring chromosome imbalances included gains at 6p (11/26), 1q (10/26), 2p (4/26), and 17q (4/26), gains of the entire chromosome 19 (3/26), and losses at 16q (9/26). A commonly gained region at 1q32 was identified. Increased dosage of GAC1, a candidate oncogene located in 1q32, was found in two of four tumors by Southern blot analysis. Comparison of the CGH findings revealed that retinoblastomas from children with an older age at operation showed significantly more frequent (13/13 cases vs 4/13 cases; P = 0.0005) and more complex genetic abnormalities (median, 5 changes/abnormal tumor vs median, 1.5 changes/abnormal tumor; P = 0.003) than retinoblastomas from children with a young age at operation. Gains at 1q, 2p, 17q, of the entire chromosome 19 and losses of 16q were restricted to the older age group. Our results suggest that the progression of retinoblastomas from older patients follows mutational pathways different from those of younger patients.

KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers

“…The most prevalent karyotypic abnormality in retinoblastoma is gain of portions of the long arm of chromosome 1, seen in 21 of 27 tumors (Squire et al, 1985). At the higher resolution of comparative genomic hybridization (CGH), gain of a minimal region spanning 1q31 is the most common change seen in retinoblastoma in our study (Chen et al, 2001), and was seen cumulatively in 76/162 (47%) tumors across five published studies ( Figure 1a) (Mairal et al, 2000;Chen et al, 2001;Herzog et al, 2001;Lillington et al, 2002;van der Wal et al, 2003).…”

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

“…18 With the copy numbers determined by QMPCR in our study, we could use clustering algorithms to classify tumors according to the pattern of 1q gains. When stratifying according to the classes obtained by this analysis, earlier diagnosis of tumors without 1q gains is evident.…”

“…18 Statistical analysis of genetic findings and clinical manifestation Detailed data on clinical presentation, treatment and follow-up of patients were obtained. We used data warehouse software (Cognos Series 7.1; Cognos Inc., Ottawa, Canada) to link all clinical and genetic data and to set the stage for data mining, which was performed using the tools provided by the software environment.…”

“…[10][11][12] Specifically, chromosome 1q gains have been detected in 40-50% of Rbs. [13][14][15][16][17][18] In one study, the minimal region of gain on the long arm of chromosome 1 was localized to 1q31-q32. 18 This region contains the GAC1 (LRRN5) gene, which was amplified and overexpressed in malignant gliomas.…”

“…[13][14][15][16][17][18] In one study, the minimal region of gain on the long arm of chromosome 1 was localized to 1q31-q32. 18 This region contains the GAC1 (LRRN5) gene, which was amplified and overexpressed in malignant gliomas. 19 However, this is only one of many genes located in the region 1q31-q32, which spans about 25 Mb.…”