Mustafa Mehyar1, Mohammad Mosallam1, Abdelghani Tbakhi2, Ala Saab1, Iyad Sultan3, Rasha Deebajah3, Imad Jaradat4, Reem AlJabari1, Mona Mohammad1, Ibrahim AlNawaiseh1, Maysa Al-Hussaini5, Yacoub A Yousef6. 1. Department of Surgery, King Hussein Cancer Center, Amman, Jordan. 2. Department of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman, Jordan. 3. Department of Pediatric Oncology, King Hussein Cancer Center, Amman, Jordan. 4. Department of Radiotherapy, King Hussein Cancer Center, Amman, Jordan. 5. Department of Pathology, King Hussein Cancer Center, Amman, Jordan. 6. Department of Surgery, King Hussein Cancer Center, Amman, Jordan. Electronic address: yyousef@khcc.jo.
Abstract
OBJECTIVE/ BACKGROUND: Retinoblastoma (RB), the most common intraocular malignancy in children, is caused by biallelic inactivation of the human retinoblastoma susceptibility gene (RB1). We are evaluating the impact of the type of RB1 gene mutation on clinical presentation and management outcome. METHODS: A retrospective case series of 50 patients with RB. Main outcomes were clinical and pathologic features and types of RB1 gene mutations detected using quantitative multiplex polymerase chain reaction (PCR), allele-specific PCR, next-generation sequencing analysis, and Sanger sequencing. RESULTS: Twenty (40%) patients had unilateral RB and 30 (60%) had bilateral RB. Overall, 36 (72%) patients had germline disease, 17 (47%) of whom inherited the disease. Of these 17 inherited cases, paternal origin of the RB1 mutation was seen in 15 (88%). The overall eye salvage rate was 74% (n = 49/66; 100% for Groups A + B + C, and 79% for Group D eyes). The most frequent type of mutation was a nonsense mutation generating a stop codon (15/36, 42%). Other mutations that result in a premature stop codon due to deletions or insertions with donor splice site or receptor splice site mutations were detected in 7/36 (19%), 10/36 (28%), and 2/26 (6%) patients, respectively. The remaining two (6%) patients had frameshift mutation. Patients with deletion, acceptor splice site, and frameshift mutations presented with more advanced ICRB (International Classification of Retinoblastoma) stage (75% diagnosed with Group D or E), even though there was no significant difference in eye salvage rate or tumor invasiveness between patients with different types of mutations. CONCLUSION: Despite the heterogeneous nature of RB1 gene mutations, tumor stage remains the most important predictive factor for clinical presentation and outcome. Furthermore, acceptor splice site and frameshift mutations are associated with more advanced tumor stage at diagnosis.
OBJECTIVE/ BACKGROUND:Retinoblastoma (RB), the most common intraocular malignancy in children, is caused by biallelic inactivation of the humanretinoblastoma susceptibility gene (RB1). We are evaluating the impact of the type of RB1 gene mutation on clinical presentation and management outcome. METHODS: A retrospective case series of 50 patients with RB. Main outcomes were clinical and pathologic features and types of RB1 gene mutations detected using quantitative multiplex polymerase chain reaction (PCR), allele-specific PCR, next-generation sequencing analysis, and Sanger sequencing. RESULTS: Twenty (40%) patients had unilateral RB and 30 (60%) had bilateral RB. Overall, 36 (72%) patients had germline disease, 17 (47%) of whom inherited the disease. Of these 17 inherited cases, paternal origin of the RB1 mutation was seen in 15 (88%). The overall eye salvage rate was 74% (n = 49/66; 100% for Groups A + B + C, and 79% for Group D eyes). The most frequent type of mutation was a nonsense mutation generating a stop codon (15/36, 42%). Other mutations that result in a premature stop codon due to deletions or insertions with donor splice site or receptor splice site mutations were detected in 7/36 (19%), 10/36 (28%), and 2/26 (6%) patients, respectively. The remaining two (6%) patients had frameshift mutation. Patients with deletion, acceptor splice site, and frameshift mutations presented with more advanced ICRB (International Classification of Retinoblastoma) stage (75% diagnosed with Group D or E), even though there was no significant difference in eye salvage rate or tumor invasiveness between patients with different types of mutations. CONCLUSION: Despite the heterogeneous nature of RB1 gene mutations, tumor stage remains the most important predictive factor for clinical presentation and outcome. Furthermore, acceptor splice site and frameshift mutations are associated with more advanced tumor stage at diagnosis.
Authors: Liya Xu; Lishuang Shen; Ashley Polski; Rishvanth K Prabakar; Rachana Shah; Rima Jubran; Jonathan W Kim; Jacklyn Biegel; Peter Kuhn; David Cobrinik; James Hicks; Xiaowu Gai; Jesse L Berry Journal: Ophthalmic Genet Date: 2020-08-17 Impact factor: 1.803