Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case-control study

Abstract

Background: Post-colonoscopy colorectal cancers (PCCRCs) pose a challenge in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. Specific features of lesions may contribute for this. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). Methods: PCCRCs were defined according to the WEO 2018 classification, as cancers occurring after a complete index colonoscopy, which excluded CRC. CRCs in patients without colonoscopy or with colonoscopy >10 years before were defined as DCRCs. Whole genome chromosomal copy number changes and mutation status of genes commonly affected in CRC (including APC, KRAS, BRAF, FBXW7, PIK3CA, NRAS, SMAD4 and TP53) were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status were also determined. Results: In total, 122 PCCRCs and 98 DCRCs with high quality DNA were examined. PCCRCs were more often located proximally in the colon (p<0.001), non-polypoid appearing (p=0.004), early stage (p=0.009), and poorly differentiated (p=0.006). PCCRCs showed similar patterns of DNA copy number changes typical of CRC, although significantly less 18q loss (FDR <0.2), compared to DCRCs. No significant differences in mutations were detected between PCCRCs and DCRCs. PCCRCs were more commonly CIMP-high (p=0.014) and MSI (p=0.029). After correction for tumour location, the only molecular difference between PCCRCs and DCRCs that remained significant was less frequent loss of 18q chromosome in PCCRCs (p=0.005). Conclusion: Although PCCRCs show molecular characteristics that are common to the canonical CIN, MSI and hypermethylation pathways, molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. This and the clinical features observed in PCCRCs support the hypothesis that sessile serrated lesions and non-polypoid CRNs are contributors to the development of these cancers. In order to further reduce the occurrence of PCCRCs, the focus should be directed at improving the detection, determination and endoscopic removal of these non-polypoid CRN and SSLs. Clinical Trial Registration: NTR3093 in the Dutch trial register (www.trialregister.nl)