Proteomic and genomic signatures of repeat instability in cancer and adjacent normal tissues.

Persi, Erez; Prandi, Davide; Wolf, Yuri I; Pozniak, Yair; Barnabas, Georgina D; Levanon, Keren; Barshack, Iris; Barbieri, Christopher; Gasperini, Paola; Beltran, Himisha; Faltas, Bishoy M; Rubin, Mark A.; Geiger, Tamar; Koonin, Eugene V; Demichelis, Francesca; Horn, David (2019). Proteomic and genomic signatures of repeat instability in cancer and adjacent normal tissues. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 116(34), pp. 16987-16996. National Academy of Sciences NAS 10.1073/pnas.1908790116

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Repetitive sequences are hotspots of evolution at multiple levels. However, due to difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content, beyond microsatellites, in proteomes and genomes directly from proteomic and genomic raw data. This method was applied to a wide range of tumors and normal tissues. We identify high similarity between repeat instability patterns in tumors and their patient-matched adjacent normal tissues. Nonetheless, tumor-specific signatures both in protein expression and in the genome strongly correlate with cancer progression and robustly predict the tumorigenic state. In a patient, the hierarchy of genomic repeat instability signatures accurately reconstructs tumor evolution, with primary tumors differentiated from metastases. We observe an inverse relationship between repeat instability and point mutation load within and across patients independent of other somatic aberrations. Thus, repeat instability is a distinct, transient, and compensatory adaptive mechanism in tumor evolution and a potential signal for early detection.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

UniBE Contributor:

Rubin, Mark Andrew

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0027-8424

Publisher:

National Academy of Sciences NAS

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

19 Dec 2019 15:14

Last Modified:

19 Dec 2019 15:14

Publisher DOI:

10.1073/pnas.1908790116

PubMed ID:

31387980

Uncontrolled Keywords:

cancer evolution diagnosis genome instability prognosis repeats

BORIS DOI:

10.7892/boris.136294

URI:

https://boris.unibe.ch/id/eprint/136294

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