Abstract
Structural variants (SVs) caused by chromosomal rearrangements in common fragile sites (CFS) or LINE retrotranspositions are highly prevalent in colorectal cancer (CRC). However, methodology for targeted detection of these SVs is lacking. We here report the use of formalin-fixed paraffin-embedded targeted locus capture (FFPE-TLC) sequencing as a novel technology for targeted detection of tumor-specific SVs. Analysis of 29 FFPE colorectal tumor and 8 matched normal samples revealed tumor-specific SVs in 24 patients (83%) with a median of 2 SVs per patient (range 1-21). 104 SVs were found in the CFS-associated genes MACROD2, PRKN, FHIT and WWOX in 18 patients (62%) and 39 SVs caused by three LINE transposable elements were found in 15 patients (52%). Tumor-specificity of SVs was independently verified by droplet digital PCR of tumor tissue DNA and their applicability as plasma circulating tumor DNA biomarkers was demonstrated. We conclude that FFPE-TLC sequencing enables the detection of tumor-specific SVs caused by chromosomal rearrangements and LINE retrotranspositions in FFPE tissue. Therefore, FFPE-TLC sequencing facilitates the investigation of the biological and clinical impact of SVs using FFPE material from (retrospective) cohorts of cancer patients and has potential clinical applicability to detect SV biomarkers in the routine molecular diagnostics setting.
Published Version
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