Possible reasons why colonoscopy does not substantially prevent colon cancer in carriers of pathogenic MMR variants

Pål Møller1, Aysel Ahadova2, Mev Dominguez-Valentin1, Toni Seppälä3, Julian Sampson4, Rodney Scott5, Lone Sunde6, Finlay Macrae7, Gabriela Möslein8, Noralane Lindor9, D. Gareth Evans10, Elke Holinski-Feder11, Gabriel Capella12, Eivind Hovig1, Magnus v Knebel Doeberitz13, Matthias Kloor2

1Norwegian Radium Hospital, part of Oslo University Hospital, Oslo, Norway. 2University Hospital and DKFZ , Heidelberg, Germany. 3Helsinki University Central Hospital, Helsinki, Finland. 4Medical Genetics, Cardiff University, Cardiff, United Kingdom. 5University of Newcastle and the Hunter Medical Research Institute, Newcastle, Australia. 6Aarhus University Hospital, Aarhus, Denmark. 7The Royal Melbourne Hospital, Melbourne, Australia. 8: University Witten-Herdecke, Wuppertal, Germany. 9Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA. 10University of Manchester, Manchester, United Kingdom. 11Universität München, München, Germany. 12Hereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain. 13Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

Abstract

Objectives

Reducing colon cancer incidence in carriers of pathogenic MMR variants.

Methods

Colonoscopy surveillance with removal of adenomas.

Results

The Prospective Lynch Syndrome Database (PLSD) has reported that colon cancer continues to occur despite colonoscopy with removal of adenomas, and that shorter interval between colonoscopies were not associated with decreased colon cancer incidence while overall survival was good. Several theories might provide explanations for these observations:

  • Colonoscopy as applied may have been insufficient to prevent colorectal cancer because of technical and skill limitations.
  • Cancers may develop without an intermediary polyp amenable to removal at a pre-cancerous stage.
  • The host immune system which may kill cancer precursor cells, may also eradicate invasive cancers, to the effect that invasive colorectal cancer may spontaneously disappear, diluting the comparative effect of colonoscopy versus spontaneously resolving invasive CRC in control cohorts.
  • Colonoscopy may disturb the colon surface potentially influencing the homeostasis of mismatch repair-deficient cells.
  • Bowel cleansing may affect the gut microbiome and possibly modulate a carcinogenic process.
  • General increase in use of antibiotics and changes in dietary habits may affect the gut microbiome.
  • Cancers in LS may grow faster and arise through polyps between colonoscopy intervals

 

Conclusions

All the theories mentioned may simultaneously be true. In particular, being carrier of a pathogenic MMR variant does not exclude developing colorectal cancer initiated by other mechanism(s). Our intention is to promote discussion of how to design new studies assessing the probabilities of each of the theories being true.

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