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It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT. [ABSTRACT FROM AUTHOR]

Background Structural variants in DNA such as translocations are increasingly found as key oncogenic events in tumors, and detection is clinically relevant for therapy choice in many conditions. Despite developments in targeted and whole genome gene sequencing, the robust detection of structural variants remains a challenge, especially in FFPE specimens. Methods Targeted proximity ligation assays selectively amplify and sequence entire genes based on the crosslinking of physically proximal sequences, and thereby enable complete sequencing of genes of interest, including single nucleotide and structural variants. Because these assays are based on the crosslinking and fragmenting of DNA, they have particular advantages in the analysis of FFPE samples, in which DNA is inherently crosslinked and fragmented. Results We will show that we have successfully developed targeted proximity ligation assays on representative clinical FFPE samples with considerably fragmented DNA. By making use of the DNA crosslinks in these samples, we can generate very broad sequence information over 100's of kb's, where other targeted NGS technologies are limited by the fragment size. We will show that we can detect NTRK fusions at DNA level, including determination of the fusion partner and the exact translocation breakpoint sequence. The latter can be used as a very sensitive and cancer-specific marker for minimal residual disease (MRD) testing and ctDNA monitoring with PCR. Conclusions Our newly developed targeted proximity ligation assays enable robust detection of structural variation in FFPE samples and the development of personalized MRD/ctDNA tests. Legal entity responsible for the study Cergentis. Funding Cergentis via Horizon2020 SME funding. Disclosure H. Feitsma: Full / Part-time employment: Cergentis. M. Yilmaz: Full / Part-time employment: Cergentis. J. Swennenhuis: Full / Part-time employment: Cergentis. A. Rakszewska: Full / Part-time employment: Cergentis. K. Hajo: Full / Part-time employment: Cergentis. E. Splinter: Full / Part-time employment: Cergentis. M. Simonis: Full / Part-time employment: Cergentis. M. Van Min: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cergentis. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]