Molecular Vision 2003; 9:502-507 <>
Received 16 December 2002 | Accepted 6 September 2003 | Published 7 October 2003

Genetic alterations on Chromosome 19, 20, 21, 22, and X detected by loss of heterozygosity analysis in retinoblastoma

Qing Huang,1,2 Kwong Wai Choy,1 Kin Fai Cheung,1 D. S. C. Lam,1 Wei Ling Fu,2 Chi Pui Pang1

1Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; 2Department of Clinical Laboratory Centre, Southwestern Hospital, The Third Military Medical University, Chongqing, China

Correspondence to: Prof. Chi Pui Pang, Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, Hong Kong; Phone: (852) 2762 3169; FAX: (852) 2715 9490; email:


Purpose: To explore the presence of common genetic alterations in retinoblastoma and to localize the altered genomic regions.

Methods: Genetic analysis included determinations of the loss of heterozygosity (LOH) and microsatellite instability (MSI) on chromosomes 19, 20, 21, 22, and X. Investigations were carried out among 15 microdissected retinoblastoma tumors and corresponding genomic DNA specimens.

Results: Among the 15 retinoblastoma cases, 73% (11/15) showed genome instability (LOH and/or MSI) at one or more loci on the 5 chromosomes, although loci with recurrent LOH was infrequent. The loss of a single allele was more frequent in chromosomes 19 (33%) and 20 (27%) than the other 3 chromosomes. Five loci with recurrent allelic loss were identified, among them the most frequent allelic losses were between D19S902 and D19S571 on 19q13 and were identified in 3 out of the 15 tumor specimens. The results suggested that gene loci in the 19q13 region may be associated with tumor development in retina. In addition, 3 specimens showed moderate frequency of LOH and/or MSI in more than 6 microsatetillete markers, indicating genomic instability to occur at least in a subset of retinoblastoma.

Conclusions: Our results provide the first evidence of LOH in chromosomes 19 and 20 in retinoblastoma. They also support the proposition that presence of genome instability in retinoblastoma may play a role in the tumorigenesis or progression of retinoblastoma.


It has been known that aberration of the genome is associated with human cancers and genetic instability is a hallmark of the human cancer genome. Two common mutant phenotypes, multiplex chromosomal aberration and multiple microsatellite alteration, indicated such genomic instability [1,2]. Mutations and/or allelic loss of the retinoblastoma gene (Rb1), located on chromosome band 13q14, are essential for the tumorigenesis of retinoblastoma. The inactivation of Rb1 can either be inherited through the germ line (hereditary retinoblastoma) or somatically (nonhereditary retinoblastoma) acquired at the Rb1 locus [3]. Analysis of multi-generation pedigrees has shown that homozygous deletion of the Rb1 gene always leads to development of retinoblastoma. According to Knudson's two-hit theory, Rb1 gene inactivation is a prerequisite for tumorigenesis, and other alterations are secondary or are participating in tumor development [4]. Apart from genetic or epigenetic inactivation of the Rb1 gene and allelic loss on chromosome 13q14, other recurrent genomic alterations have been frequently discovered on retinoblastoma, including the isochromosome 6p [i(6p)] [5], trisomy 1q [6], monosomy 16 or del(16q) [7,8]; monosomy 17 or del(17p), i(17p) [7,9], complete absence of pericentromoric heterochromomatin on chromosome 9 [10], and loss of X or Y sex chromosome [8]. Such chromosomal aberrations in retinoblastoma have been well documented by fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH).

Presence of abnormal amplifications of genes has been discovered in retinoblastoma including the N-myc [11] and INT-1[12] cellular oncogenes [8], tumor necrosis factor-alpha (TNF-α) [13], and RBKIN/KIF13A [14]. Also, concomitant alterations in p53 and Rb1 have been shown to give further negative effects, resulting in increased tumor recurrence and poor survival of patients. However, so far no p53 mutation in retinoblastoma has been detected [15,16]. In addition, cytogenetic karyotype abnormalities have been reported in a few retinoblastoma cases, such as 13qXp translocation and chromosomal aberration on chromosome 19, 21 and 22 [17-26]. Among them, only 13qXp translocation was considered a potential factor in tumorigenesis of retinoblastoma. Although cytogenetic and CGH studies on chromosomes 19, 21, 22, and X have been suggested to play roles in the pathogenesis of retinoblastoma, the results were ambiguous. Meanwhile, several lines of evidence point to the presence of one or more putative suppressor gene(s) located on the short arm of chromosome 20 and allelic loss and unbalanced translocation in its long arm. The subsequent loss of function likely contributes to the pathogenesis of cancer including multiple myeloid and prostate malignancies [27,28].

In order to narrow the genomic regions and ultimately aid to identify the critical genes involved in development of human retinoblastoma, we performed LOH analysis on chromosomes 19, 20, 21, 22, and X with 55 microsatellite markers to identify additional loci involved in retinoblastoma tumorigenesis.


Tumor and blood specimens, genomic DNA preparation

Tumor tissues and corresponding peripheral blood samples were collected from 15 patients treated at the Hong Kong Eye Hospital between 1990 and 2000 (Table 1). All patients and controls were ethnic Chinese with no family history of cancer. Informed consent had been obtained from all of them. Peripheral blood samples were obtained from all study subjects. Formalin-fixed paraffin embedded specimens of retinoblastoma tissue of these 15 patients were retrieved for analysis. The study protocol has been approved by the Ethic Committee for human research, the Chinese University of Hong Kong. Tissue cells in the paraffin embedded sections were H&E stained. Our histopathologists were able to visually differentiate intact cancerous from normal cells under the microscope. We ensured presence of more than 90% tumor cells in tissue samples by using laser-capture microdissection system (P.A.L.M., Bernried, Germany) on slides to select cancerous tissue cells according to manufacturers protocols. Genomic DNA was extracted from 15 microdissected formaline-fixed, paraffin-embedded retinoblastoma specimens, as well from corresponding blood samples of each patient using QIAmp DNA Mini Kit (Qiagen, Valencia, CA, USA).

Fluorescence-based semi-automated microsatellite analysis

LOH analysis was performed by PCR amplification of microsatellite DNA on chromosomes 19, 20, 21, 22, and X using fluorescence-labeled primers from the ABI Prism Linkage Mapping Set-MD-10 (PE Biosystems, Foster City, CA, USA), which consisted of 55 dinucleotide repeats microsatellite markers distributed throughout the five tested chromosomes. PCR amplifications were performed using approximately 15 ng of genomic DNA as template in a total volume of 7.5 μl. Reactions contained 0.4 units of polymerase (PE Biosystems), 3.0 pmol fluorescence-labeled and unlabeled primer, 2.5 mM MgCl2, 1 x buffer (10 mM Tris-HCl, pH 8.3, 50 mM KCl, 0.001% w/v gelatin) and dNTPs (0.2 mM each). PCR reactions were performed for 12 min at 95 °C to activate the polymerase, followed by 15 cycles of 94 °C for 15 s, 55 °C for 15 s, and 72 °C for 30 s, and 35 cycles of 89 °C for 15 s, 55 °C for 15 s, and 72 °C for 30 s, with a final extension at 72 °C for 12 min. PCR products of different sizes and/or labeled with different fluorescent dyes were pooled, and 1.2 μl pooled products were mixed with 1.2 μl loading cocktail [0.86 μl deionized formamide + 0.17 μl blue dextran/EDTA loading buffer + 0.17 μl GenScanTM-400HD [ROX] Size Standard (PE Biosystems)]. After denaturing at 94 °C for 2 min before quick cooling on ice, the fluorescence-labeled PCR products were analyzed by automated ABI Prism 377 DNA Sequencer (PE Biosystems) with GeneScan V2.1 (PE Biosystems) and GenoTyper V2.0 (PE Biosystems).

Analysis of LOH and MSI

The microsatellite markers used in this study are listed in Figures 1 and 2. For each marker, the corresponding normal blood DNA sample was used to determine the allelic size and heterozygosity for patients, and the Centre d'Etude du Polymorphisme Humain individual 1347-02 (Applied Biosystems) was used as an internal control DNA. Details of all makers, such as allele heterozygosity frequencies, primer sequences, cytogenetic localization and location on genetic maps relative to other genes and loci, can be found at the following database: the Center for Medical Genetics, the Genetic Location database, the Human Genome Database, ABI Prism products, and ABI Prism Integrated Genetic Maps on CHLC web. A given informative marker was considered to display LOH when a 3-fold or greater relative allele intensity ratio was seen between the tumor DNA and normal DNA (Figure. 1). The allele ratio was assessed based on the allelic imbalance factor (AIF) which was calculated using a normalized equation in which AIF=(T1/N1)/(T2/N2), where T1 and T2 are the heights of the alleles from tumor, and N1 and N2 are the heights of the alleles from the corresponding blood DNA [29,30]. In subsequent data analysis, the allelic imbalance was represented by AIF or the reciprocal (1/AIF) if AIF was >1 (to give a range of 0.00-1.00). The threshold range of AIF for allelic retention (normal or retained heterozygosity) was defined as >0.5. The range for allelic loss (LOH) was defined as <=0.5. All LOH cases were verified by repetition. The mean AIF values were used for data analysis. Homozygous alleles were considered not informative for allelic loss and AIF assessment. The status of microsatellite instability (MSI) was designated positive if one or both alleles in the tumor exhibited expansion or contraction of the repeat sequences when compared with paired normal tissue from the same individual (Figure 1). We defined genomic instability as when either LOH or MSI was detected in the retinoblastoma genome.

Statistical Analysis

All the informative heterozygous loci were used to calculate the proportion of genome instability in form of LOH and MSI. Fisher's exact test (2-tail) was used to assess the significance of associations between genome instability versus pathological and clinical manifestations of retinoblastoma. All reported p values are 2-sided; statistical significance was set at the 0.05 level.


Determination of LOH and MSI

The average heterozygosity was 82% for the 37 autosomal markers, of which 78% (29/37) markers showed >75% heterozygosity, yielding a stable estimation of LOH frequency for this study. Among the 15 patients, 11 cases (73%) showed genome instability (LOH and/or MSI) at one or more loci on chromosomes 19, 20, 21, 22, and X. Seven of the 15 patients (46%) showed allele loss in one or more microsatellite marker regions among the four autosomal chromosomes. The frequencies of LOH were 33% (5/15) on chromosome 19, 27% (4/15) on chromosome 20, and 13% (2/15) on chromosomes 21, 22, and X. Therefore higher frequency of allelic loss was observed on chromosomes 19 and 20 than the other 3 chromosomes (Figure 2). Five allelic loci displayed LOH in more than one patients: D19S902 (2/13), D19S571 (2/8), D19S220 (2/14), D20S117 (2/12) and D21S1914 (2/14). The interval between markers D19S902 and D19S571 at the long arm of chromosome 19 (19q) had the highest frequency of LOH (20%, 3/15). Peak LOH frequency (25.0%, 2/8) was observed in 8 informative allele loci at D19S571 on 19q13.

Interestingly, two retinoblastoma patients were genetically unstable when compared to the others. Patient RB-2 exhibited a much higher frequency of allelic loss (LOH) on chromosome 19, with LOH in 5 out of 10 (50.0%) informative loci throughout this chromosome, especially on the long arm. Patient RB-3 displayed LOH at more than one allelic loci among the 4 autosomal chromosomes examined. Of the 18 markers used in chromosome X, the average heterozygosity was only 28%. The low frequency of chromosome X was likely attributed to the sex distribution in this study with 10 males and only 5 females (Table 1).

Presence of MSI (microsatellite instability) in a subset of retinoblastoma tumors

MSI status was designated positive if one or both alleles in the tumor exhibited size variation due to expansion or contraction of the repeat sequences when compared with paired normal tissue from the same individual obtained by microdissection. Two retinoblastoma specimens (RB-2 and RB-5), showed MSI of more than 4 markers among the 37 autosomal markers investigated (Figure 2). In addition, our results indicate that a subset of retinoblastoma patients (RB-2, RB-5, RB-10, RB-11, RB-13 and RB-15) showed microsatellite instability in at least one of the 55 markers.

Pathology and clinical features of retinoblastoma with genome instability

Among the 15 patients, 11 had bilateral retinoblastoma, and 4 had unilateral tumor (Table 1). It is notable that 4 of the 5 female patients had bilateral tumor and among the 8 cases with LOH, 3 were female. The frequency of LOH was not significantly different between bilateral (6/11) and unilateral (2/4) retinoblastoma (Fisher's exact 2-tailed test). The frequency of MSI was also not significantly different between age at presentation and laterality. However, all of the 3 cases (RB-2, RB-3, RB-5) showing moderate frequency of LOH and/or MSI (at least 6 markers having genome instability in the 55 tested markers) were bilateral cases (Table 1).


In this study, we investigated the possible involvement of genetic alteration at chromosomes 19, 20, 21, 22, and X in the RB genome and their possible link to the pathogenesis and tumorigenesis of retinoblastoma. As far as we know, this is the first report on LOH analysis of these 5 chromosomes in retinoblastoma. We show a low to moderate frequency of LOH (0-9 allelic loci) per tumor (Table 1). Our results demonstrate that in retinoblastoma the loss of a single allele is more frequent in chromosomes 19 (33%) and 20 (27%) than chromosomes 21, 22, and X, (13% in each). Meanwhile, the presence of allelic loss and unbalanced translocation on chromosome 20 have been detected in multiple myeloid and prostate malignancies, and may contribute to the pathogenesis of cancer [27,28]. LOH at chromosomes 21 and 22 have also been reported in gastric adenocarcinoma and colorectal carcinoma respectively [31,32]. MSI commonly occurs in some cancers including colorectal and gastric carcinomas. But for retinoblastoma, this is the first report on MSI investigation among chromosomes 19, 20, 21, 22, and X. In previous studies, chromosome karyotype abnormalities had been discovered on chromosomes 19, 21, 22, and X in retinoblastoma tumor cells [7,8,17-26,33]. Such cytogenetic abnormalities detected on these chromosomes had been considered as late chromosome rearrangements that might facilitate neoplastic behavior, such as an undifferentiated state and optic nerve invasion in retinoblastoma [7]. However, in our study, no significant clinical correlation was identified (Table 1).

Translocation of 13qXp has been reported in 10 retinoblastoma patients [17-20,22-26,34]. It has been suggested that the 13qXp translocation might contribute to retinoblastoma development. Of the 15 patients in this study, 2 of the 5 female cases (40%) showed LOH at chromosome X. Our results provide further evidence of the involvement of LOH at chromosome X in retinoblastoma. However, whether genome instability on chromosome X is associated with the rearrangement between chromosomes 13 and X is still not clear and needs further investigation. Presence of the LOH indicates that particular allelic loci are more commonly subjected to allelic loss in retinoblastoma. The frequent occurrence of LOH in 20% of our patients (3/15) between the miscrosatellite markers D19S902 and D19S571 at the long arm of chromosome 19 (19q) suggests that genes at or near 19q13 might be involved in the development of RB. D19S902 and D19S571 flank the 19q13.2-13.3 minimal deleted regions, spanning 11.02 cM on the genetic map. We searched for potential tumor suppressor genes in this region at the NCBI Human Genome Resources website. Genes of interest include a candidate tumor suppressor gene, HPCQTL19 (Prostate Cancer Aggressiveness Quantitative Trait Locus on chromosome 19). The cone-rod homeobox protein (CRX) is a photoreceptor-specific transcription factor, which plays a role in the differentiation of photoreceptor cells.

Our study indicates a subset of retinoblastoma to be genetically unstable. When compared with other subjects, three retinoblastoma cases, RB-2, Rb-3 and RB-5, showed higher genome instability. They had LOH and/or MSI throughout chromosomes 19, 20, 21 and 22. The comparatively high proportion of LOH and/or MSI in these 3 bilateral retinoblastoma cases indicates that the DNA protection system may be defective during cancer development. And such somatic instability is observed as either a substantial change in repeat length or lost heterozygosity at particular loci in retinoblastoma. Although functions of the genes (loci) examined in this study remain unknown, our results provide new evidence that retinoblastoma may indeed be genetically unstable.

Our unpublished data indicated that genome instability in retinoblastoma might arise through a mechanism that involves somatic instability and promoter methylation of DNA repair genes. An example is hMLH-1, which is involved in mismatch repair (MMR) of DNA. The function of the MMR system is to repair DNA replication errors during DNA replication. Deficiencies of this system can result in mutation rates at least 100-fold greater than those observed in normal cells [35,36]. These mutations are particularly frequent in microsatellite sequences. MSI is therefore regarded as an important mutation phenotype of cells deficient in MMR. Consequently, it can be a marker for human cancers [37]. In the present study, there is a subset of retinoblastoma, 6 out of 15 cases that showed microsatellite instability in one or more loci throughout the 5 tested chromosomes. Based on previous studies, genomic instability is directly associated with the genetic and/or epigenetic deficiency of MMR genes. In this study, we identified different degrees of genome instability as shown by LOH or MSI on chromosomes 19, 20, 21, 22, and X in the 15 retinoblastoma patients. There is no significant correlation between LOH/MSI and pathology and clinical features of retinoblastoma due to the small number of cases. A large study is required to affirm the lack of association. But our results provide new evidence that genome instability is a distinctive trait of retinoblastoma and this is in concordance with the genome-wide instability recently reported in a mouse retinoblastoma model [38]. We further propose that while genomic instability might contribute to the development or progression of retinoblastoma, it could still be a secondary phenomenon in malignancy and not necessarily be playing a critical role in the pathogeneses or progression of disease.


The work described in this paper was partially supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. CUHK 4091/01M) and by the Mrs Annie Wong Eye Foundation, Hong Kong.


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