Danish retinoblastoma patients 1943–2013 – genetic testing and clinical implications

Abstract

Background: In heritable retinoblastoma there is a 50% risk of transmitting the RB1 mutation, and offspring carriers have more than 90% risk of developing retinoblastoma. Today, all newly diagnosed retinoblastoma patients in Denmark are screened for mutations in RB1, as opposed to only a minority of patients diagnosed before DNA testing was offered. Knowledge of heredity increases the chance of early diagnosis in offspring, leading to improved prognosis. We present data from the Danish retinoblastoma patients that emphasize the need for genetic counseling and RB1 screening in all untested retinoblastoma survivors. Material and methods: Data are extracted from The Danish Ocular Oncology Group Database, a national population database containing data on all Danish retinoblastoma patients since 1943. Results: In total 323 retinoblastoma patients have been diagnosed between 1943 and 2013. Since 1963, the rate has been stable around 1 per 14 000 live births with 95% of the patients surviving their retinoblastoma. Stratifying data on the time of diagnosis and status of genetic testing, the number of screened patients gradually increased from 5% in the beginning of the period to 96% in the last five-year period. A cohort of 181 retinoblastoma survivors with sporadic disease (15% heritable) did not receive genetic testing. Since the introduction of routine testing, one of 14 sporadic unilateral patients tested (7%) has been identified with a germline mutation. Before routine testing, five additional sporadic unilateral patients have been identified as heritable. Conclusion: Only a minority of Danish retinoblastoma patients diagnosed before routine genetic testing was offered have been RB1 screened. To counsel the remaining untested patients and their families sufficiently regarding the risk to offspring and elevated risk of second primary cancers, we recommend information and access to genetic counseling and RB1 screening. This has ethical, psychological and possible economic consequences, and should be handled with caution.

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

“…Despite annual variation in crude incidences, especially in small populations and over short observation periods, the incidence of retinoblastoma has remained stable over the last fifty years wherever reliable records exist (Broaddus et al, 2009;Gatta et al, 2012;Gregersen et al, 2016;Li et al, 2016;MacCarthy et al, 2009;Moreno et al, 2014), especially when the analysis is based on birth cohorts rather than on live births or on children of specified age in a given year (Park et al, 2014;Seregard et al, 2004).…”

“…Unilateral retinoblastoma represents 61-75% of all cases, with 25-39% bilateral according to recent population-based series (Andreoli et al, 2017;Azar et al, 2006;Gregersen et al, 2016;Khandekar et al, 2004;MacCarthy et al, 2009;Moreno et al, 2014). Part of this variation is explained by the fact that some initially unilateral hereditary retinoblastomas will progress to bilateral disease (Moreno et al, 2014), while the contribution from familial cases also varies between countries (Usmanov and Kivela, 2014).…”

Incidence and Mortality of Second Primary Cancers in Danish Patients With Retinoblastoma, 1943-2013

“…The risk of death from retinoblastoma decreased significantly since 1943. 29 The risk of death from SPC was studied in the 290 patients surviving retinoblastoma: among the 116 with heritable retinoblastoma, 13 patients (11%) died of SPC and 3 patients (3%) died of other known causes; among 174 patients with nonheritable retinoblastoma, 9 patients (5%) died of SPC and 3 patients (2%) died of other known causes. The overall cumulative mortality rate was 48% for patients with heritable retinoblastoma and 23% for patients with nonheritable retinoblastoma.…”

“…The proportion of patients with heritable retinoblastoma was lower for patients diagnosed in 1966 (35%) vs after 1966 (44%). This difference could reflect the lower frequency of genetic tests in patients diagnosed early in the period, 29 resulting in a higher risk of misclassifying sporadic unilateral heritable cases as nonheritable. Also, the proportion of familial cases increased over time, probably reflecting improved survival rates following changes in treatment guidelines.…”

“…For the past decade, most patients with newly diagnosed retinoblastoma have undergone RB1 testing, and many older patients have been tested as a result of implementing genetic testing or another reason. 29 Because the study cohort contains both genetically tested and untested patients, heritable retinoblastoma was defined by bilateral or multifocal disease, familial presentation, and/or identification of an RB1 variant. Nonheritable retinoblastoma was defined by unilateral, unifocal, and sporadic disease.…”