Leveraging Tissue-Specific Enhancer-Target Gene Regulatory Networks Identifies Enhancer Somatic Mutations That Functionally Impact Lung Cancer.

Autor:	Hariprakash JM; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Salviato E; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., La Mastra F; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Sebestyén E; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Tagliaferri I; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Silva RS; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Lucini F; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Farina L; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Cinquanta M; Cogentech Società Benefit srl, Milan, Italy., Rancati I; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Riboni M; Cogentech Società Benefit srl, Milan, Italy., Minardi SP; Cogentech Società Benefit srl, Milan, Italy., Roz L; Fondazione IRCCS-Istituto Nazionale Tumori, Milan, Italy., Gorini F; INGM, National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi,' Milan, Italy., Lanzuolo C; INGM, National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi,' Milan, Italy.; Institute of Biomedical Technologies, National Research Council (ITB-CNR), Segrate, Italy., Casola S; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy., Ferrari F; IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy.; Institute of Molecular Genetics 'Luigi Luca Cavalli-Sforza,' National Research Council (IGM-CNR), Pavia, Italy.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Jan 02; Vol. 84 (1), pp. 133-153.
DOI:	10.1158/0008-5472.CAN-23-1129
Abstrakt:	Enhancers are noncoding regulatory DNA regions that modulate the transcription of target genes, often over large distances along with the genomic sequence. Enhancer alterations have been associated with various pathological conditions, including cancer. However, the identification and characterization of somatic mutations in noncoding regulatory regions with a functional effect on tumorigenesis and prognosis remain a major challenge. Here, we present a strategy for detecting and characterizing enhancer mutations in a genome-wide analysis of patient cohorts, across three lung cancer subtypes. Lung tissue-specific enhancers were defined by integrating experimental data and public epigenomic profiles, and the genome-wide enhancer-target gene regulatory network of lung cells was constructed by integrating chromatin three-dimensional architecture data. Lung cancers possessed a similar mutation burden at tissue-specific enhancers and exons but with differences in their mutation signatures. Functionally relevant alterations were prioritized on the basis of the pathway-level integration of the effect of a mutation and the frequency of mutations on individual enhancers. The genes enriched for mutated enhancers converged on the regulation of key biological processes and pathways relevant to tumor biology. Recurrent mutations in individual enhancers also affected the expression of target genes, with potential relevance for patient prognosis. Together, these findings show that noncoding regulatory mutations have a potential relevance for cancer pathogenesis and can be exploited for patient classification. Significance: Mapping enhancer-target gene regulatory interactions and analyzing enhancer mutations at the level of their target genes and pathways reveal convergence of recurrent enhancer mutations on biological processes involved in tumorigenesis and prognosis. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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