American Association for Cancer Research
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Supplementary Table 2 from Whole-Exome Sequencing of Cell-Free DNA Reveals Temporo-spatial Heterogeneity and Identifies Treatment-Resistant Clones in Neuroblastoma

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posted on 2023-03-31, 19:41 authored by Mathieu Chicard, Leo Colmet-Daage, Nathalie Clement, Adrien Danzon, Mylène Bohec, Virginie Bernard, Sylvain Baulande, Angela Bellini, Paul Deveau, Gaëlle Pierron, Eve Lapouble, Isabelle Janoueix-Lerosey, Michel Peuchmaur, Nadège Corradini, Anne Sophie Defachelles, Dominique Valteau-Couanet, Jean Michon, Valérie Combaret, Olivier Delattre, Gudrun Schleiermacher

Table S2 : detailed description of time points for plasma sampling.

Funding

Annenberg Foundation

Nelia and Amadeo Barletta Foundation

Association Hubert Gouin Enfance et Cancer

Associations Enfants et Santé

SiRIC/INCa

CEST of Institute Curie

PHRC

Agence Nationale de la Recherche

Canceropole Ile-de-France

SiRIC-Curie program

History

ARTICLE ABSTRACT

Purpose: Neuroblastoma displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression.Experimental Design: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole-exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 neuroblastoma patients.Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of single-nucleotide variants (SNV) and copy number alterations, with 41% and 93% of all detected alterations common to the primary neuroblastoma and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate time points during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2.Conclusions: Modelization of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating toward tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies. Clin Cancer Res; 24(4); 939–49. ©2017 AACR.

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