Medium levels of transcription and replication related chromosomal instability are associated with poor clinical outcome

Ataaillah Benhaddou, Laetitia Gaston, Gaëlle Pérot, Nelly Desplat, Laura Leroy, Sophie Le Guellec, Mohamed Ben Haddou, Philippe Rochaix, Thibaud Valentin, Gwenaël Ferron, Christine Chevreau, Binh Bui, Eberhard Stoeckle, Axel Le Cesne, Sophie Piperno-Neumann, Françoise Collin, Nelly Firmin, Gonzague De Pinieux, Jean Michel Coindre, Jean Yves BlayFrédéric Chibon

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

1 Citation (Scopus)

Résumé

Genomic instability (GI) influences treatment efficacy and resistance, and an accurate measure of it is lacking. Current measures of GI are based on counts of specific structural variation (SV) and mutational signatures. Here, we present a holistic approach to measuring GI based on the quantification of the steady-state equilibrium between DNA damage and repair as assessed by the residual breakpoints (BP) remaining after repair, irrespective of SV type. We use the notion of Hscore, a BP “hotspotness” magnitude scale, to measure the propensity of genomic structural or functional DNA elements to break more than expected by chance. We then derived new measures of transcription- and replication-associated GI that we call iTRAC (transcription-associated chromosomal instability index) and iRACIN (replication-associated chromosomal instability index). We show that iTRAC and iRACIN are predictive of metastatic relapse in Leiomyosarcoma (LMS) and that they may be combined to form a new classifier called MAGIC (mixed transcription- and replication-associated genomic instability classifier). MAGIC outperforms the gold standards FNCLCC and CINSARC in stratifying metastatic risk in LMS. Furthermore, iTRAC stratifies chemotherapeutic response in LMS. We finally show that this approach is applicable to other cancers.

langue originaleAnglais
Numéro d'article23429
journalScientific Reports
Volume11
Numéro de publication1
Les DOIs
étatPublié - 1 déc. 2021
Modification externeOui

Contient cette citation