Tumour break load is a biologically relevant feature of genomic instability with prognostic value in colorectal cancer.

Autor: Lakbir S; Bioinformatics Group, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam 1081HV, the Netherlands; Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, the Netherlands., Lahoz S; Translational Colorectal Cancer Genomics, Gastrointestinal and Pancreatic Oncology Team, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, 08036, Spain., Cuatrecasas M; Pathology Department, Biomedical Diagnostic Center (CDB), Hospital Clínic de Barcelona, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universitat de Barcelona (UB), Barcelona, 08036, Spain., Camps J; Translational Colorectal Cancer Genomics, Gastrointestinal and Pancreatic Oncology Team, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, 08036, Spain; Department of Cell Biology, Physiology and Immunology, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, 08193, Spain., Glas RA; Bioinformatics Group, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam 1081HV, the Netherlands; Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, the Netherlands., Heringa J; Bioinformatics Group, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam 1081HV, the Netherlands; AIMMS - Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam 1081HV, the Netherlands., Meijer GA; Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, the Netherlands., Abeln S; Bioinformatics Group, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam 1081HV, the Netherlands; Life Sciences and Health Research Group, Centrum Wiskunde & Informatica (CWI), Science Park 123, Amsterdam 1098 XG, the Netherlands. Electronic address: s.abeln@vu.nl., Fijneman RJA; Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, the Netherlands. Electronic address: r.fijneman@nki.nl.
Jazyk: angličtina
Zdroj: European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2022 Dec; Vol. 177, pp. 94-102. Date of Electronic Publication: 2022 Oct 08.
DOI: 10.1016/j.ejca.2022.09.034
Abstrakt: Background: Clinically implemented prognostic biomarkers are lacking for the 80% of colorectal cancers (CRCs) that exhibit chromosomal instability (CIN). CIN is characterised by chromosome segregation errors and double-strand break repair defects that lead to somatic copy number aberrations (SCNAs) and chromosomal rearrangement-associated structural variants (SVs), respectively. We hypothesise that the number of SVs is a distinct feature of genomic instability and defined a new measure to quantify SVs: the tumour break load (TBL). The present study aimed to characterise the biological impact and clinical relevance of TBL in CRC.
Methods: Disease-free survival and SCNA data were obtained from The Cancer Genome Atlas and two independent CRC studies. TBL was defined as the sum of SCNA-associated SVs. RNA gene expression data of microsatellite stable (MSS) CRC samples were used to train an RNA-based TBL classifier. Dichotomised DNA-based TBL data were used for survival analysis.
Results: TBL shows large variation in CRC with poor correlation to tumour mutational burden and fraction of genome altered. TBL impact on tumour biology was illustrated by the high accuracy of classifying cancers in TBL-high and TBL-low (area under the receiver operating characteristic curve [AUC]: 0.88; p < 0.01). High TBL was associated with disease recurrence in 85 stages II-III MSS CRCs from The Cancer Genome Atlas (hazard ratio [HR]: 6.1; p = 0.007) and in two independent validation series of 57 untreated stages II-III (HR: 4.1; p = 0.012) and 74 untreated stage II MSS CRCs (HR: 2.4; p = 0.01).
Conclusion: TBL is a prognostic biomarker in patients with non-metastatic MSS CRC with great potential to be implemented in routine molecular diagnostics.
Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. R.J.A.F. reports grants and non-financial support from Personal Genome Diagnostics, non-financial support from Delfi Diagnostics, grants from MERCK BV, grants and non-financial support from Cergentis BV, outside the submitted work; In addition, R.J.A.F. has several patents pending. S.A. reports grants and non-financial support from Cergentis BV and a patent pending outside the submitted work. S.Lakbir. reports non-financial support from Cergentis BV and a patent pending outside the submitted work. J.H. reports a patent pending outside the submitted work. G.A.M. reports non-financial support from Exact Sciences, non-financial support from Sysmex, non-financial support from Sentinel CH. SpA, non-financial support from Personal Genome Diagnostics (PGDX), other from Hartwig Medical Foundation, grants from CZ (OWM Centrale Zorgverzekeraars groep Zorgverzekeraar u.a), other from Royal Philips, other from GlaxoSmithKline, other from Keosys SARL, other from OpenClinica LLC, other from Roche Diagnostics Nederland BV, other from The Hyve BV, other from Open Text, other from SURFSara BV, other from Vancis BV, other from CSC Computer Sciences BV, outside the submitted work; In addition, G.A.M. has several patents pending. The other authors declare no potential conflicts of interest.
(Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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