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. 2024 Dec;26(12):1065-1080.
doi: 10.1016/j.jmoldx.2024.08.004. Epub 2024 Sep 26.

High Prevalence of Chromosomal Rearrangements and LINE Retrotranspositions Detected in Formalin-Fixed, Paraffin-Embedded Colorectal Cancer Tissue

Carmen Rubio-Alarcón  1 , Ellen Stelloo  2 , Daan C L Vessies  3 , Iris van 't Erve  1 , Nienke J Mekkes  4 , Joost Swennenhuis  2 , Soufyan Lakbir  5 , Elisabeth J van Bree  1 , Marianne Tijssen  1 , Pien Delis-van Diemen  1 , Mirthe Lanfermeijer  3 , Theodora Linders  3 , Daan van den Broek  3 , Cornelis J A Punt  6 , Jaap Heringa  4 , Gerrit A Meijer  1 , Sanne Abeln  7 , Harma Feitsma  2 , Remond J A Fijneman  8
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Free article

High Prevalence of Chromosomal Rearrangements and LINE Retrotranspositions Detected in Formalin-Fixed, Paraffin-Embedded Colorectal Cancer Tissue

Carmen Rubio-Alarcón et al. J Mol Diagn. 2024 Dec.
Free article

Abstract

Structural variants (SVs) caused by chromosomal rearrangements in common fragile sites or long interspersed nuclear element (LINE) retrotranspositions are highly prevalent in colorectal cancer. However, methodology for the targeted detection of these SVs is lacking. This article reports the use of formalin-fixed, paraffin-embedded targeted-locus capture (FFPE-TLC) sequencing as a novel technology for the targeted detection of tumor-specific SVs. Analysis of 29 FFPE colorectal tumor samples and 8 matched normal samples revealed tumor-specific SVs in 24 patients (83%), with a median of 2 SVs per patient (range, 1 to 21). A total of 104 SVs were found in the common fragile site-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. FFPE-TLC sequencing enabled 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 effects of SVs using FFPE material from (retrospective) cohorts of cancer patients and has potential clinical applicability in the detection of SV biomarkers in the routine molecular diagnostics setting.

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Conflict of interest statement

Disclosure Statement C.R.-A. declares nonfinancial support from Personal Genome Diagnostics and Cergentis BV. E.S., J.S., and H.F. are employees of Cergentis BV (a Solvias company), the inventor and owner of the patents on FFPE-TLC technology. S.L. reports nonfinancial support from Cergentis BV and a patent pending. E.J.v.B. reports nonfinancial support from Cergentis BV. D.v.d.B. has provided lectures, expert testimony, and advisory board presence to Roche Diagnostics, all outside the submitted work and all financial supports transferred to institute. G.A.M. is co-founder and board member (CSO) of CRCbioscreen BV; has had research collaboration with CZ Health Insurances (cash matching to ZonMW grant); has had research collaborations with Exact Sciences, Sysmex, Sentinel Ch SpA, Personal Genome Diagnostics, DELFi, and HMF (these companies provide materials, equipment and/or sample/genomic analyses); and has several patents pending/issued. S.A. reports public–private partnership consortia grants in collaboration with Cergentis BV, Olink Proteomics AB, and Quanterix Corporation and has a patent pending. R.J.A.F. reports public–private partnership consortia grants in collaboration with Cergentis BV; reports public–private partnership consortia grants and nonfinancial support in collaboration with Personal Genome Diagnostics, Delfi, Natera, and Merck BV outside the submitted work; and has several patents pending.

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