TY - JOUR
T1 - Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes
AU - Møller, Pål
AU - Haupt, Saskia
AU - Ahadova, Aysel
AU - Kloor, Matthias
AU - Sampson, Julian R
AU - Sunde, Lone
AU - Seppälä, Toni
AU - Burn, John
AU - Bernstein, Inge
AU - Capella, Gabriel
AU - Evans, D Gareth
AU - Lindblom, Annika
AU - Winship, Ingrid
AU - Macrae, Finlay
AU - Katz, Lior
AU - Laish, Ido
AU - Vainer, Elez
AU - Monahan, Kevin
AU - Half, Elizabeth
AU - Horisberger, Karoline
AU - da Silva, Leandro Apolinário
AU - Heuveline, Vincent
AU - Therkildsen, Christina
AU - Lautrup, Charlotte
AU - Klarskov, Louise L
AU - Cavestro, Giulia Martina
AU - Möslein, Gabriela
AU - Hovig, Eivind
AU - Dominguez-Valentin, Mev
N1 - © 2024. The Author(s).
PY - 2024/5
Y1 - 2024/5
N2 - 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.
AB - 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.
KW - Adenoma
KW - Colonoscopy
KW - Colorectal
KW - Lynch syndromes
KW - MLH1
KW - MSH2
KW - MSH6
KW - MSI
KW - PMS2
KW - Sojourn time
KW - cancer
KW - dMMR
UR - http://www.scopus.com/inward/record.url?scp=85192889861&partnerID=8YFLogxK
U2 - 10.1186/s13053-024-00279-3
DO - 10.1186/s13053-024-00279-3
M3 - Journal article
C2 - 38741120
SN - 1731-2302
VL - 22
SP - 6
JO - Hereditary Cancer in Clinical Practice
JF - Hereditary Cancer in Clinical Practice
IS - 1
M1 - 6
ER -