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Sci Rep ; 11(1): 23429, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873180

RESUMO

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.


Assuntos
Instabilidade Cromossômica , Cromossomos/ultraestrutura , Replicação do DNA , Algoritmos , Antineoplásicos/administração & dosagem , DNA/análise , Dano ao DNA , Análise Mutacional de DNA , Reparo do DNA , Elementos Facilitadores Genéticos , Redes Reguladoras de Genes , Genoma Humano , Humanos , Estimativa de Kaplan-Meier , Metástase Neoplásica , Neoplasias/genética , Regiões Promotoras Genéticas , Risco , Sarcoma/patologia , Análise de Sequência de DNA , Transcrição Gênica , Resultado do Tratamento
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