Molecular diagnosis of retinoblastoma by circulating tumor DNA analysis.

Marion Gauthier-Villars, Gudrun Schleiermacher, Olivier Delattre, Lisa Golmard, François Doz, Victor Renault, Isabelle Aerts, Alexandre Matet, Livia Lumbroso, Nathalie Cassoux, Sylvain Baulande, Dominique Stoppa-Lyonnet, Irene Jiménez, Hervé J Brisse, Virginie Bernard, François Radvanyi, Claude Houdayer, Eve Lapouble, Arnaud Gauthier, Camille Benoist, Jessica Le Gall, Catherine Dehainault, Mathieu Chicard, Éléonore Frouin

Journal: European journal of cancer (Oxford, England : 1990) 2021;154():277-287

PMID: 34298378

Full Text on Elsevier Science View on PubMed

Abstract

PURPOSE

The analysis of circulating tumor DNA (ctDNA), a fraction of total cell-free DNA (cfDNA), might be of special interest in retinoblastoma patients. Because the accessibility to tumor tissue is very limited in these patients, either for histopathological diagnosis of suspicious intraocular masses (biopsies are proscribed) or for somatic RB1 studies and genetic counseling (due to current successful conservative approaches), we aim to validate the detection of ctDNA in plasma of non-hereditary retinoblastoma patients by molecular analysis of RB1 gene.

EXPERIMENTAL DESIGN

In a cohort of 19 intraocular unilateral non-hereditary retinoblastoma patients for whom a plasma sample was available at diagnosis, we performed high-deep next-generation sequencing (NGS) of RB1 in cfDNA. Two different bioinformatics/statistics approaches were applied depending on whether the somatic RB1 status was available or not.

RESULTS

Median plasma sample volume was 600 μL [100-1000]; median cfDNA plasma concentration was 119 [38-1980] and 27 [11-653] ng/mL at diagnosis and after complete remission, respectively. In the subgroup of patients with known somatic RB1 alterations (n = 11), seven of nine somatic mutations were detected (median allele fraction: 6.7%). In patients without identified somatic RB1 alterations (n = 8), six candidate variants were identified for seven patients.

CONCLUSIONS

Despite small tumor size, blood-ocular barrier, poor ctDNA blood release and limited plasma sample volumes, we confirm that it is possible to detect ctDNA with high-deep NGS in plasma from patients with intraocular non-hereditary retinoblastoma. This may aid in diagnosis of suspicious cases, family genetic counseling or follow-up of residual intraocular disease.

Address: SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique », Translational Research Department, PSL Research University, Institut Curie Research Center, Paris, France; INSERM U830, Equipe Labellisée Ligue Contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, Institut Curie Research Center, Paris, France; SIREDO Center: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France.; Clinical Bioinformatics, PSL Research University, Institut Curie, Paris, France.; Department of Genetics, PSL Research University, Institut Curie, Paris, France.; Pathology Department, PSL Research University, Institut Curie, Paris, France.; Somatic Genetics Unit, PSL Research University, Institut Curie, Paris, France.; INSERM U1245, Normandie University, UNIROUEN, Normandy Centre for Genomic and Personalized Medicine and Rouen University Hospital, Department of Genetics, Rouen, France.; CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, Institut Curie, PSL Research University, Paris, France.; Centre Hospitalier Universitaire Grenoble-Alpes, Grenoble, France.; Imaging Department, PSL Research University, Institut Curie, Paris, France.; Institut Curie Genomics of Excellence (ICGex) Platform, PSL Research University, Research Center, Institut Curie, Paris, France.; SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique », Translational Research Department, PSL Research University, Institut Curie Research Center, Paris, France; SIREDO Center: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France; Université de Paris, Paris, France.; Ocular Oncology Service, Institut Curie, Paris, France.; Ocular Oncology Service, Institut Curie, Paris, France; Université de Paris, Paris, France.; SIREDO Center: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France.; SIREDO Center: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France; Université de Paris, Paris, France.; INSERM U830, Equipe Labellisée Ligue Contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France; SIREDO Center: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France.; SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique », Translational Research Department, PSL Research University, Institut Curie Research Center, Paris, France; INSERM U830, Equipe Labellisée Ligue Contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, Institut Curie Research Center, Paris, France; SIREDO Center: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France. Electronic address: [email protected].

DOI: 10.1016/j.ejca.2021.05.039

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MeSH Terms: Child, Child, Preschool, Circulating Tumor DNA, Computational Biology, Female, Humans, Infant, Male, Mutation, Retinoblastoma, Retinoblastoma Binding Proteins, Retrospective Studies, Ubiquitin-Protein Ligases