Tumour break load is a biologically relevant feature of genomic instability with prognostic value in colorectal cancer
We are pleased to share our recent publication by Soufyan Lakbir and Sanne Abeln in collaboration with Remond Fijneman, showing that the Tumor Break Load (TBL) is a distinct feature of genomic instability with prognostic value for patients with resected stage II and III microsatellite stable colorectal cancer.
Highlights
- Tumour break load (TBL) is a distinct feature of genomic instability.
- TBL status (high or low) has a large impact on tumour biology.
- TBL is a prognostic biomarker for patients with resected stage II and III microsatellite stable colorectal cancer.
- TBL has the potential to be implemented in routine molecular diagnostics.
Abstract
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.