Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes

Pål Møller; Saskia Haupt; Aysel Ahadova; Matthias Kloor; Julian R Sampson; Lone Sunde; Toni Seppälä; John Burn; Inge Bernstein; Gabriel Capella; D Gareth Evans; Annika Lindblom; Ingrid Winship; Finlay Macrae; Lior Katz; Ido Laish; Elez Vainer; Kevin Monahan; Elizabeth Half; Karoline Horisberger; Leandro Apolinário da Silva; Vincent Heuveline; Christina Therkildsen; Charlotte Lautrup; Louise L Klarskov; Giulia Martina Cavestro; Gabriela Möslein; Eivind Hovig; Mev Dominguez-Valentin

doi:10.1186/s13053-024-00279-3

Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes

Hered Cancer Clin Pract. 2024 May 13;22(1):6. doi: 10.1186/s13053-024-00279-3.

Authors

Pål Møller^#¹, Saskia Haupt^#^{2

3}, Aysel Ahadova^#^{4

5}, Matthias Kloor^#^{4

5}, Julian R Sampson^#⁶, Lone Sunde^#^{7

8

9}, Toni Seppälä^{10

11

12}, John Burn¹³, Inge Bernstein^{14

15}, Gabriel Capella¹⁶, D Gareth Evans¹⁷, Annika Lindblom^{18

19}, Ingrid Winship^{20

21}, Finlay Macrae²¹, Lior Katz²², Ido Laish²³, Elez Vainer²², Kevin Monahan²⁴, Elizabeth Half²⁵, Karoline Horisberger²⁶, Leandro Apolinário da Silva²⁷, Vincent Heuveline^{2

3}, Christina Therkildsen²⁸, Charlotte Lautrup²⁹, Louise L Klarskov^{30

31}, Giulia Martina Cavestro³², Gabriela Möslein³³, Eivind Hovig^{34

35}, Mev Dominguez-Valentin³⁴

Affiliations

¹ Department of Tumour Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo, 0379, Norway. moller.pal@gmail.com.
² Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
³ Data Mining and Uncertainty Quantification (DMQ), Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany.
⁴ Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁵ Clinical Cooperation Unit Applied Tumour Biology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
⁶ Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
⁷ Department of Clinical Genetics, Aalborg University Hospital, Aalborg, 9000, Denmark.
⁸ Department of Biomedicine, Aarhus University, Aarhus, DK-8000, Denmark.
⁹ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
¹⁰ Faculty of Medicine and Health Technology, Tays Cancer Center, Tampere University, Tampere University Hospital, Tampere, Finland.
¹¹ Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
¹² Applied Tumour Genomics, Research Program Unit, University of Helsinki, Helsinki, Finland.
¹³ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
¹⁴ Dept. of Quality and Coherence, Aalborg University Hospital, Aalborg, 9000, Denmark.
¹⁵ Department of Clinical Medicine, Aalborg University Hospital, Aalborg University, Aalborg, 9100, Denmark.
¹⁶ Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L; Hospitalet de Llobregat, Barcelona, 08908, Spain.
¹⁷ Manchester Centre for Genomic Medicine, Division of Evolution, Infection and Genomic Sciences, University of Manchester, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK.
¹⁸ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, 171 76, Sweden.
¹⁹ Dept Clinical Genetics, Karolinska University Hospital, Solna, Sweden.
²⁰ Genomic Medicine, The Royal Melbourne Hospital, Melbourne, Australia.
²¹ Department of Medicine, University of Melbourne, Melbourne, Australia.
²² Department of Gastroenterology, Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah, Israel.
²³ Gastroenerolgy institute, Sheba medical center and Faculty of medicine Tel Aviv university, Tel Aviv, Israel.
²⁴ Lynch Syndrome & Family Cancer Clinic, Centre for Familial Intestinal Caner, St Mark's Hospital, London, UK.
²⁵ Gastrointestinal Cancer Prevention Unit, Gastroenterology Department, Rambam Health Care Campus, Haifa, Israel.
²⁶ Department of Surgery, Universitätsmedizin Mainz, Mainz, Germany.
²⁷ Hospital Universitário Oswaldo Cruz, Universidade de Pernambuco, Recife, Brazil & SEQUIPE, Recife, Brazil.
²⁸ Gastro Unit, The Danish HNPCC Register, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark.
²⁹ Department of Clinical Genetics, Aarhus University Hospital, DK 8000, Aarhus, Denmark.
³⁰ Dept of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.
³¹ Dept of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³² Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy.
³³ Surgical Center for Hereditary Tumors, University Düsseldorf, Ev. Bethesda Khs, Duisburg, Germany.
³⁴ Department of Tumour Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo, 0379, Norway.
³⁵ Centre for bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.

^# Contributed equally.

Abstract

Background: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes.

Materials and methods: We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms.

Results: Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers.

Conclusions: Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.

Keywords: MLH1; MSH2; MSH6; PMS2; Adenoma; Colonoscopy; Colorectal; Lynch syndromes; MSI; Sojourn time; cancer; dMMR.

Abstract

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