eprintid: 26147
rev_number: 13
eprint_status: archive
userid: 1589
dir: disk0/00/02/61/47
datestamp: 2019-05-09 12:56:45
lastmod: 2024-03-30 19:30:48
status_changed: 2019-05-09 12:56:45
type: article
metadata_visibility: show
creators_name: Seppälä, Toni T.
creators_name: Ahadova, Aysel
creators_name: Dominguez-Valentin, Mev
creators_name: Macrae, Finlay
creators_name: Evans, D. Gareth
creators_name: Therkildsen, Christina
creators_name: Sampson, Julian
creators_name: Scott, Rodney
creators_name: Burn, John
creators_name: Möslein, Gabriela
creators_name: Bernstein, Inge
creators_name: Holinski-Feder, Elke
creators_name: Pylvänäinen, Kirsi
creators_name: Renkonen-Sinisalo, Laura
creators_name: Lepistö, Anna
creators_name: Lautrup, Charlotte Kvist
creators_name: Lindblom, Annika
creators_name: Plazzer, John-Paul
creators_name: Winship, Ingrid
creators_name: Tjandra, Douglas
creators_name: Katz, Lior H.
creators_name: Aretz, Stefan
creators_name: Hüneburg, Robert
creators_name: Holzapfel, Stefanie
creators_name: Heinimann, Karl
creators_name: Della Valle, Adriana
creators_name: Neffa, Florencia
creators_name: Gluck, Nathan
creators_name: de Vos tot Nederveen Cappel, Wouter H.
creators_name: Vasen, Hans
creators_name: Morak, Monika
creators_name: Steinke-Lange, Verena
creators_name: Engel, Christoph
creators_name: Rahner, Nils
creators_name: Schmiegel, Wolff
creators_name: Vangala, Deepak
creators_name: Thomas, Huw
creators_name: Green, Kate
creators_name: Lalloo, Fiona
creators_name: Crosbie, Emma J.
creators_name: Hill, James
creators_name: Capella, Gabriel
creators_name: Pineda, Marta
creators_name: Navarro, Matilde
creators_name: Blanco, Ignacio
creators_name: ten Broeke, Sanne
creators_name: Nielsen, Maartje
creators_name: Ljungmann, Ken
creators_name: Nakken, Sigve
creators_name: Lindor, Noralane
creators_name: Frayling, Ian
creators_name: Hovig, Eivind
creators_name: Sunde, Lone
creators_name: Kloor, Matthias
creators_name: Mecklin, Jukka-Pekka
creators_name: Kalager, Mette
creators_name: Møller, Pål
title: Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report
subjects: 610
divisions: 850300
keywords: Mismatch repair, Microsatellite instability, Lynch syndrome, Hereditary cancer, Colorectal cancer, Hereditary nonpolyposis colorectal cancer, Colonoscopy, Endoscopy, Surveillance, Screening, Over-diagnosis
abstract: Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal.

Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers.

Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5–2.5, 2.5–3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III–IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14).   

Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.
date: 2019
publisher: BioMed Central ; Springer
id_scheme: DOI
ppn_swb: 1666226548
own_urn: urn:nbn:de:bsz:16-heidok-261472
language: eng
bibsort: SEPPALATONLACKOFASSO2019
full_text_status: public
publication: Hereditary Cancer in Clinical Practice
volume: 17
number: 8
place_of_pub: London ; Berlin, Heidelberg
pagerange: 1-8
issn: 1897-4287
citation:   Seppälä, Toni T. ; Ahadova, Aysel ; Dominguez-Valentin, Mev ; Macrae, Finlay ; Evans, D. Gareth ; Therkildsen, Christina ; Sampson, Julian ; Scott, Rodney ; Burn, John ; Möslein, Gabriela ; Bernstein, Inge ; Holinski-Feder, Elke ; Pylvänäinen, Kirsi ; Renkonen-Sinisalo, Laura ; Lepistö, Anna ; Lautrup, Charlotte Kvist ; Lindblom, Annika ; Plazzer, John-Paul ; Winship, Ingrid ; Tjandra, Douglas ; Katz, Lior H. ; Aretz, Stefan ; Hüneburg, Robert ; Holzapfel, Stefanie ; Heinimann, Karl ; Della Valle, Adriana ; Neffa, Florencia ; Gluck, Nathan ; de Vos tot Nederveen Cappel, Wouter H. ; Vasen, Hans ; Morak, Monika ; Steinke-Lange, Verena ; Engel, Christoph ; Rahner, Nils ; Schmiegel, Wolff ; Vangala, Deepak ; Thomas, Huw ; Green, Kate ; Lalloo, Fiona ; Crosbie, Emma J. ; Hill, James ; Capella, Gabriel ; Pineda, Marta ; Navarro, Matilde ; Blanco, Ignacio ; ten Broeke, Sanne ; Nielsen, Maartje ; Ljungmann, Ken ; Nakken, Sigve ; Lindor, Noralane ; Frayling, Ian ; Hovig, Eivind ; Sunde, Lone ; Kloor, Matthias ; Mecklin, Jukka-Pekka ; Kalager, Mette ; Møller, Pål  (2019) Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report.  Hereditary Cancer in Clinical Practice, 17 (8).  pp. 1-8.  ISSN 1897-4287     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/26147/1/13053_2019_Article_106.pdf