Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

AB109. Novel constitutional and somatic RB1 mutations underlying retinal cancers in addition to TNFα, KIF13A and MGMT alterations

10.21037/atm.2017.s1095S2AB109-AB10

Parental origin of allelic loss.

<p>Parental origin of allelic loss.</p

Clinicopathological distribution of heritable and non-heritable retinoblastoma patients by laterality, age at diagnosis and family history.

<p>Clinicopathological distribution of heritable and non-heritable retinoblastoma patients by laterality, age at diagnosis and family history.</p

Novel <i>RB1</i> point mutations.

<p>Novel <i>RB1</i> point mutations.</p

Recurrent <i>RB1</i> point mutations.

<p>Recurrent <i>RB1</i> point mutations.</p

Mutation spectrum of <i>RB1</i> mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

<div><p>Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of <i>RB1</i> gene. Early diagnosis and identification of carriers of heritable <i>RB1</i> mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic <i>RB1</i> mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic family members carrying low-penetrance, germline mosaicism or heritable unilateral mutational phenotypes.</p></div

Incidence of germline and somatic <i>RB1</i> point mutations in 50 RB cases.

<p>A total of 61 <i>RB1</i> point mutations were identified in 50 RB probands. The distribution of mutations by type of tumor (unilateral and bilateral) and whether they were detected in blood (germline) or only tumor (somatic) is shown.</p

Age distribution of heritable and non-heritable RB cases.

<p>The age distribution between Heritable-familial, Heritable-non familial and Non-Heritable RB cases was significant by Welch’s t test of unpaired groups (p = 0.001351; 95% CI [-22.4729, -5.7665]). Three cases had unknown age at diagnosis and hence not reflected.</p

Schematic representation of sequence mutations across <i>RB1</i> gene.

<p>(GenBank Accession Number: L11910.1). The pocket domains are highlighted in orange (Pocket A) and purple (Pocket B) and exons are numbered respectively. Exons known to be mutational hotspots are highlighted with yellow boxes (Valverde et al 2005). Novel mutations are shown in callout boxes. Gross <i>RB1</i> deletions are shown in blue for paternal loss of allele and pink for maternal loss of allele. Grey indicates unknown inheritance. The respective frequencies of gross <i>RB1</i> deletions are given in brackets.</p