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Clinical Studies

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

Abstract

Background

Post-colonoscopy colorectal cancers (PCCRCs) pose challenges in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. In a nested case–control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs).

Methods

Whole-genome chromosomal copy number changes and mutation status of genes commonly affected in CRC were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status was also determined.

Results

In total, 122 PCCRCs and 98 DCRCs with high-quality DNA were examined. PCCRCs were more often located proximally (P < 0.001), non-polypoid appearing (P = 0.004), early stage (P = 0.009) and poorly differentiated (P = 0.006). PCCRCs showed significantly less 18q loss (FDR < 0.2), compared to DCRCs. No significant differences in mutations were observed. PCCRCs were more commonly CIMP high (P = 0.014) and MSI (P = 0.029). After correction for tumour location, only less 18q loss remained significant (P = 0.005).

Conclusion

Molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. These together with the clinical features observed support the hypothesis that SSLs and non-polypoid CRNs are contributors to the development of PCCRCs. The future focus should be directed at improving the detection and endoscopic removal of these non-polypoid CRN and SSLs.

Clinical trial registration

NTR3093 in the Dutch trial register (www.trialregister.nl).

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Fig. 1: Flowchart of the process of selection of CRC cases for molecular analysis.
Fig. 2: Comparison of molecular features between post-colonoscopy colorectal cancers (PCCRCs) and detected colorectal cancers (DCRCs).
Fig. 3: Unsupervised hierarchal cluster analysis based on the molecular features of all CRCs analysed.

Data availability

The sequencing data used in this study are available in the European Genomes and phenomes Archive (ega-archive.org), with provisory number EGAS00001004686.

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Acknowledgements

We thank the technicians of the pathology laboratory at the Netherlands Cancer Institute in Amsterdam for their help with the DNA isolations. We thank the Tumour Genome Analysis Core at Amsterdam UMC for low-coverage WGS and cancer-related gene panel-targeted sequencing. We thank the Genomics Core Facility at the Netherlands Cancer Institute for cancer-related gene panel-targeted sequencing. We thank the technicians of the pathology laboratory at the Maastricht University Medical Centre for their help with the CIMP analysis. We thank Dr. Silvia Sanduleanu for her contribution to the origin of this study. We acknowledge that a part of this work has been presented at the UEGW 2016 in Vienna [57]. This work was performed within the frame of the COST Action [CA17118], supported by COST (European Cooperation in Science and Technology).

Funding

RB and CLC received an unrestricted educational grant from Pentax Medical BV. BY contributed to the manuscript with the support of the Dutch Cancer Society (Grant No. KWF 2015-7882).

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Contributions

RB, CC, ME, GM and BC conceived the study concept and design; RB, CC, QV, MC, DS, CR, EB, SV, NG, RR, PS, ES, BY and BC contributed to the acquisition of the data; RB, CC, QV, MC, DS, CR, EB, SV, NG, RV, BW, ME, BY, GM, AM and BC participated in analysis and interpretation of the data; RB, CC, QV, CR, BW, AM and BC drafted the manuscript; all authors did a critical revision of the manuscript for important intellectual content; RB, CR, RV and BW performed the statistical analysis; AM and BC had the study supervision. AM is the guarantor of the article. All authors approved the final version.

Corresponding author

Correspondence to Ad A. M. Masclee.

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Competing interests

AM received funding from the Dutch Cancer Society, from the Dutch Organization for Health Research and Development, from Pentax Europe GmBH. AM has given scientific advice to Kyowa Kirin, Bayer, and Takeda. BC has several patents pending. The remaining authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Medical Ethical Committee of the Maastricht University Medical Centre, which waived the need for informed consent. The study is registered as study NTR3093 in the Dutch trial register (www.trialregister.nl). The study was performed in accordance with the Declaration of Helsinki.

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Bogie, R.M.M., le Clercq, C.M.C., Voorham, Q.J.M. et al. Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case–control study. Br J Cancer 126, 865–873 (2022). https://doi.org/10.1038/s41416-021-01619-z

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