Whole-genome sequencing facilitates patient-specific quantitative PCR-based minimal residual disease monitoring in acute lymphoblastic leukaemia, neuroblastoma and Ewing sarcoma

Subhash, VV; Huang, L; Kamili, A; Wong, M; Chen, D; Venn, NC; Atkinson, C; Mayoh, C; Venkat, P; Tyrrell, V; Marshall, GM; Cowley, MJ; Ekert, PG; Norris, MD; Haber, M; Henderson, MJ; Sutton, R; Fletcher, JI; Trahair, TN

Author(s): Subhash, VV; Huang, L; Kamili, A; Wong, M; Chen, D; Venn, NC; Atkinson, C; Mayoh, C; Venkat, P; Tyrrell, V; Marshall, GM; Cowley, MJ; Ekert, PG; Norris, MD; Haber, M; Henderson, MJ; Sutton, R; Fletcher, JI; Trahair, TN;
Details: Publication Year 2022-02,Volume 126,Issue #3,Page 482-491
Journal Title: British Journal of Cancer
Publication Type: Research article
Abstract: BACKGROUND: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA. METHODS: We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) (n = 6 each). RESULTS: Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10(-4) (0.01%)-10(-5) (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical samples, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays. CONCLUSIONS: WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours.
Keywords: Adolescent; Biomarkers, Tumor/*genetics; Bone Neoplasms/blood/genetics/pathology; Child; Child, Preschool; Female; *Gene Rearrangement; Humans; Infant; Male; N-Myc Proto-Oncogene Protein/genetics; Neoplasm, Residual/genetics/*pathology; Neuroblastoma/blood/genetics/*pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood/genetics/*pathology; Proto-Oncogene Protein c-fli-1/genetics; Receptors, Antigen, T-Cell/genetics; Sarcoma, Ewing/blood/genetics/*pathology; Transcriptional Regulator ERG/genetics; Whole Genome Sequencing/*methods
Department(s): Laboratory Research
PubMed ID: 34471258
Publisher's Version: https://doi.org/10.1038/s41416-021-01538-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41416-021-01538-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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