dataset
posted on 2024-09-04, 07:41 authored by Iros Barozzi, Neil Slaven, Eleonora Canale, Rui Lopes, Inês Amorim Monteiro Barbosa, Melusine Bleu, Diana Ivanoiu, Claudia Pacini, Emanuela Mensa’, Alfie Chambers, Sara Bravaccini, Sara Ravaioli, Balázs Győrffy, Maria Vittoria Dieci, Giancarlo Pruneri, Giorgio Giacomo Galli, Luca Magnani Supplementary Table S13: Computational predictions of the functional impact of the SNVs and short INDELs identified through SIDV. S13.1: for each variant, the type (SNV or INDEL_short) and its hg38 coordinates are listed, along with the symbol of the nearest gene, and the distance to its TSS in bp (positive or negative values indicate the region is either downstream or upstream the TSS, respectively). Reference and alternative alleles are also provided, along with whether the variant is computationally predicted to alter the molecular function of the genomic element bearing it (indicated as different “pathogenic” classes; column mutation_class) or not (“benign”). The table is then indicating, for each one of the models considered, whether the variant is predicted to significantly affect the indicated molecular function. S13.2: extract of S12.1, for three regions of interest.
Funding
Cancer Research UK (CRUK)
History
ARTICLE ABSTRACT
Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process.Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters.
