A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Medicine in Ophthalmology Johannesburg, 2014 / Retinoblastoma is the most frequent malignant intraocular tumour of childhood, and in Africa it is the commonest and most important life threatening ocular neoplasm. In resource-rich countries such as the United States and Canada, survival rates for patients with retinoblastoma approach 100%. This is in stark contrast to developing countries where survival rates may be less that 20%. Despite the vast majority of affected patients living in less developed countries, there is little attention and published literature on disease characteristics in these populations. OBJECTIVES: To characterise retinoblastoma in the South African population through a 20-year retrospective analysis of patient records at two tertiary academic hospitals in Johannesburg. DESIGN AND METHOD: Retrospective clinical case series analysis of medical records of patients with retinoblastoma presenting to Charlotte Maxeke Johannesburg Academic Hospital and Chris Hani Baragwanath Academic Hospital between 01 January 1992 and 31 December 2011. RESULTS: The total number of retinoblastoma cases identified was 282, with 245 of these meeting the study inclusion criteria. Retinoblastoma comprised 6.9% of total paediatric oncology presentations. 65.3% were unilateral, 34.3% bilateral and 0.4% trilateral. The overall male to female ratio was 1.08. Mean age at presentation overall was 32.6 months (median 28.0 months), for unilateral 39.4 months (median 33.0 months) and for bilateral 19.7 months (median 17.0 months). The mean delay to presentation overall was 7.0 months (median 4.0 months), for unilateral 8.5 months (median 5.0 months) and for bilateral 4.4 months (median 3.0 months). The most frequent presenting symptoms were leukocoria (37.1%) and proptosis (34.7%). Distribution of disease stage at presentation (using the International Retinoblastoma Staging System) was 1.6% with Stage 0, 24.1% with Stage I, 27.8% Stage II, 16.3% Stage III and 25.3% Stage IV (data not available in 4.9%). 26.5% of patients defaulted care. The five-year survival rate was 57.7% in the overall study population, and according to disease stage at presentation: 95.3% - Stage I, 84.8% - Stage II, 49.7% - Stage III and 5.7% - Stage IV. CONCLUSION: The five-year survival rate for Stage I disease is similar to the overall five-year survival rates reported in the developed world. This suggests that treatment standards at the study hospitals are comparable with those of developed countries and that similar overall survival rates may be achieved if patients were to present as early. Delay to presentation, disease stage at presentation and defaulting care were identified as key factors contributing to the poor overall survival rate. This study provides information regarding patient demographics, social challenges in management, and patient outcomes in comparison to developed countries and to reports from other African populations. It also highlights the need for educational campaigns and screening initiatives to address poor survival outcomes as a result of late presentation and high rates of patients defaulting care. Finally, this report serves as a platform for comparison with future research in this area.

Retinoblastoma is the second most common childhood intraocular malignancy and development of the tumour is initiated by bi-allelic loss of the RB1 gene. Bi-allelic RB1 loss may not always directly lead to malignant retinoblastoma. Subsequent mutational events, specifically gain and loss of chromosomal regions harbouring key oncogenes and tumour suppressor genes, appear to underlie the progression of precursor lesions such as retinoma to retinoblastoma. Research thus far has implicated several cytogenetic aberrations in this sequence of molecular events, the two most recurrent and notable being the augmented copy number status of KIF14 and MDM4 on 1q and of DEK and E2F3 on 6p. A small subset of retinoblastoma exhibits high-level amplification of the MYCN gene on chromosome 2p and is characterized by pRb expression and aggressive histology. 1p36 deletion is also associated with MYCN amplification in neuroblastoma. Our project is testing the hypothesis that 1q and 6p gain and 2p amplification – defined by extra copies of KIF14 and MDM4, DEK and E2F3 and MYCN respectively, and 1p36 deletion – are biomarkers of retinoblastoma progression. This study reports the results of formalin-fixed paraffin-embedded fluorescence in situ hybridization (FFPE-FISH) analysis of the aforementioned genes in two pre-constructed tissue microarrays (TMAs) comprising 270 retinoblastoma patient tumours. Results show 1q gain (3-10 copies) in 136/262 (52%), 6p gain in 127/262 (48.7%), MYCN gain in 18/265 (6.8%) and MYCN amplification (>10 copies) in 20/265 (7.5%) patient tumours. MYCN amplification was also observed in a sample which retained pRb protein expression. Additionally we have demonstrated statistically significant associations between 1q and 6p gain and MYCN amplification and 1p36 deletion. The large cohort and consequent statistical power of our results has enabled a better understanding of the M3 to Mn sequence of genomic aberrations in the progression from retinoma to retinoblastoma. Statistically significant associations between 1q and 6p, indicates synergy within these two regions of gain that would be particularly beneficial to tumours. Owing to the biological interactions among the proteins encoded by DEK, E2F3, KIF14 and MDM4, tumour cells manifesting both 1q and 6p aberrations would have a selective survival and proliferative advantage. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2010-10-18 16:59:40.965

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

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Retinoblastoma is the prototype genetic cancer caused by mutations disrupting the RB1 tumor suppressor gene. Following loss of RB1, retinoblastoma acquires further genetic changes in a characteristic set of oncogenes and tumor suppressors including gains of the oncogenes KIF14, DEK, E2F3, and MYCN and loss of the tumor suppressor CDH11. The constellation of genetic changes is the postulated genetic pathway leading to retinoblastoma. However, advances in molecular diagnostic testing for RB1 gene mutations allows detection of at least one RB1 mutation in 98% of unilateral retinoblastomas leaving 2% of cases with undetectable RB1 mutations (RB1+/+ retinoblastoma). RB1+/+ retinoblastomas have high-level MYCN gene amplification (>30 copies) and few other genetic changes. In addition, RB1+/+ retinoblastoma present earlier than conventional RB1-/- retinoblastoma and show histologic features similar to MYCN-amplified neuroblastoma. Altogether, this study describes a distinct genetic subset of retinoblastoma characterized by wild-type RB1 gene and high-level MYCN gene amplification.

Retinoblastoma is the prototype genetic cancer caused by mutations disrupting the RB1 tumor suppressor gene. Following loss of RB1, retinoblastoma acquires further genetic changes in a characteristic set of oncogenes and tumor suppressors including gains of the oncogenes KIF14, DEK, E2F3, and MYCN and loss of the tumor suppressor CDH11. The constellation of genetic changes is the postulated genetic pathway leading to retinoblastoma. However, advances in molecular diagnostic testing for RB1 gene mutations allows detection of at least one RB1 mutation in 98% of unilateral retinoblastomas leaving 2% of cases with undetectable RB1 mutations (RB1+/+ retinoblastoma). RB1+/+ retinoblastomas have high-level MYCN gene amplification (>30 copies) and few other genetic changes. In addition, RB1+/+ retinoblastoma present earlier than conventional RB1-/- retinoblastoma and show histologic features similar to MYCN-amplified neuroblastoma. Altogether, this study describes a distinct genetic subset of retinoblastoma characterized by wild-type RB1 gene and high-level MYCN gene amplification.

Thesis (Ph. D.)--University of Hong Kong, 1994. / Includes list of author's publication (leaves viii-xiv). Includes bibliographical references (leaves 253-281).

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