domingo, 29 de septiembre de 2019

A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations. - PubMed - NCBI

2019 Sep 11. pii: S0959-8049(19)30446-0. doi: 10.1016/j.ejca.2019.07.027. [Epub ahead of print]

A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations.

George SL1, Izquierdo E2, Campbell J3, Koutroumanidou E4, Proszek P4, Jamal S4, Hughes D4, Yuan L4, Marshall LV5, Carceller F5, Chisholm JC5, Vaidya S5, Mandeville H6, Angelini P6, Wasti A6, Bexelius T6, Thway K7, Gatz SA8, Clarke M9, Al-Lazikani B3, Barone G10, Anderson J11, Tweddle DA12, Gonzalez D13, Walker BA14, Barton J15, Depani S10, Eze J16, Ahmed SW16, Moreno L17, Pearson A6, Shipley J18, Jones C9, Hargrave D19, Jacques TS16, Hubank M4, Chesler L5.

Author information

1: Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, London, UK; Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, UK. Electronic address: sally.george@icr.ac.uk.
2: Molecular Diagnostics Department, The Institute of Cancer Research and Clinical Genomics, The Royal Marsden NHS Foundation, London, UK; Glioma Team, Division of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, UK.
3: Bioinformatics Core Facility, The Institute of Cancer Research, London, UK.
4: Molecular Diagnostics Department, The Institute of Cancer Research and Clinical Genomics, The Royal Marsden NHS Foundation, London, UK.
5: Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, London, UK; Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, UK.
6: Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, UK.
7: Pathology Department, Royal Marsden NHS Foundation Trust, London, UK.
8: Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, UK; Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, UK; Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
9: Glioma Team, Division of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, UK.
10: Department of Haematology and Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
11: Department of Haematology and Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; Developmental Biology and Cancer Programme, UCL GOS Institute of Child Health, London, UK.
12: Northern Institute for Cancer Research, Newcastle University, Newcastle, UK.
13: Molecular Diagnostics Department, The Institute of Cancer Research and Clinical Genomics, The Royal Marsden NHS Foundation, London, UK; Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.
14: Molecular Diagnostics Department, The Institute of Cancer Research and Clinical Genomics, The Royal Marsden NHS Foundation, London, UK; Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
15: Developmental Biology and Cancer Programme, UCL GOS Institute of Child Health, London, UK.
16: Department of Haematology and Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; Department of Histology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
17: Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, UK; HNJ-CNIO Clinical Research Unit, Hospital Universitario Nino Jesus, Madrid, Spain; Paediatric Oncology & Haematology, Vall d'Hebron University Hospital, Barcelona, Spain.
18: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, UK.
19: Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; Department of Haematology and Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Abstract

BACKGROUND:

For children with cancer, the clinical integration of precision medicine to enable predictive biomarker-based therapeutic stratification is urgently needed.

METHODS:

We have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)-specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings.

RESULTS:

A total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma.

CONCLUSION:

We demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel-based approach can identify actionable genetic alterations in a high proportion of patients.