Abstract 3118
Background
Retinoblastoma (RB) is the most common pediatric intraocular neoplasm caused by the biallelic inactivation of the RB1 tumor suppressor gene. In 40% of cases, the development of RB is mediated by a germline mutation in one of the alleles of RB1. Patients with germline mutation develop bilateral tumor with penetrance of more than 90%. However, some families demonstrate cases of RB with low penetrance (unaffected carries) and variable expressivity (carries develop either bi- or uni- RB).
It is believed that the phenotypic manifestation of hereditary retinoblastoma depends on the functional type of the germinal mutation in the RB1. The molecular mechanisms underlying the variable phenotypic manifestation of the same mutation in different family members are currently explained by the parent-of-origin effect of RB1 mutation.
Methods
Using NGS of the RB1 we have analyzed DNA from blood of 331 unrelated patients with RB (226 patients with uni- RB and 105 with bi- RB). DNA samples of available family members were also examined for the presence of an identified mutation using Sanger sequencing.
Results
We identified 11 germline mutations in the RB1 that led to the RB with low penetrance and/or variable expressivity in 12 families. Among the identified mutations:, 25.0% - are missense mutations, 58.3% - are splice mutations and 16.7% - are frame shift mutations. In 91,7% of cases, probands inherited the mutant allele from their fathers, who were either clinically healthy carriers (7 families) or had the uni-/bilateral form of RB (3 families).Table: 1170P
Mutations | Carrier (Proband, P) | Form (uni, U; bi-lateral, B; no symptoms, -) |
---|---|---|
c.1364G>C; c.1573G>A; c.1981C>T; с.607 + 1G-T (2 families); c.45_76del; с.83del | P ♂ | U - |
c.861G>C | P ♀ | U - |
c.939G>A | P ♂ Grandfather Uncle | U - - U |
c.380 + 1G-A; с.1695 + 5G-T; c.1696-2A-G | P ♂ | B U |
Conclusions
The identification of mutations in the RB1 leading to the development of RB with low penetrance and variable expressivity, is necessary for adequate treatment and competent determination of the risk of developing the disease in other family members.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
State assignment of Ministry of Science and Higher Education of the Russian Federation.
Funding
The state assignment of Ministry of Science and Higher Education of the Russian Federation.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4370 - Continental differences in pathologic response with neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO) in patients with macroscopic stage III melanoma in the phase 2 OpACIN-neo trial.
Presenter: Irene Reijers
Session: Poster Display session 3
Resources:
Abstract
3230 - Comparable responses of melanoma at primary site and synchronous lymph node metastases upon neoadjuvant ipilimumab (IPI) and nivolumab (NIVO)
Presenter: Judith Versluis
Session: Poster Display session 3
Resources:
Abstract
3171 - Adjuvant Therapies for Stage III Melanoma: Benchmarks for Bringing Clinical Trials to Clinical Practice
Presenter: Tina HIEKEN
Session: Poster Display session 3
Resources:
Abstract
3493 - Mixture-cure modeling for resected stage III/IV melanoma in the phase 3 CheckMate 238 trial
Presenter: Jeffrey Weber
Session: Poster Display session 3
Resources:
Abstract
3036 - An open-label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib for patients with unresectable advanced BRAFV600-mutant melanoma: a subgroup analysis of patients with brain metastasis
Presenter: Caroline Dutriaux
Session: Poster Display session 3
Resources:
Abstract
2233 - Adverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting
Presenter: Jean Jacques Grob
Session: Poster Display session 3
Resources:
Abstract
2435 - A Single Arm, Open Label, Phase II, Multicenter Study to Assess the Detection of the BRAF V600 Mutation on cfDNA from Plasma in Patients with Advanced Melanoma
Presenter: Piotr Rutkowski
Session: Poster Display session 3
Resources:
Abstract
1766 - Efficacy and Safety of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600 Mutation-positive Melanoma in the Real-World Setting – Interim results of the non-interventional COMBI-r study
Presenter: Carola Berking
Session: Poster Display session 3
Resources:
Abstract
2131 - Trial update: A randomized Phase Ib/II study of the selective small molecule Axl inhibitor Bemcentinib (BGB324) in combination with either dabrafenib/trametinib (D/T) or pembrolizumab in patients with metastatic melanoma
Presenter: Oddbjørn Straume
Session: Poster Display session 3
Resources:
Abstract
4074 - Analysis of pyrexia in patients (pts) treated with dabrafenib (D) and/or trametinib (T) across clinical trials
Presenter: Caroline Robert
Session: Poster Display session 3
Resources:
Abstract