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

Background: Clinically implemented prognostic biomarkers are lacking for the 80% of colorectal cancers (CRCs) that exhibit chromosomal instability (CIN). CIN is charac-terised 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 breakload (TBL). The present study aimed to characterise the biological impact and clinical rele-vance 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 sur-vival 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. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

The study demonstrates that tumor breakload (TBL) is an important prognostic biomarker in colorectal cancer, impacting tumor biology and predicting disease recurrence.