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

Toni T. Seppälä, Aysel Ahadova, Mev Dominguez-Valentin, Finlay Macrae, D. Gareth Evans, Christina Therkildsen, Julian Sampson, Rodney Scott, John Burn, Gabriela Möslein, Inge Bernstein, Elke Holinski-Feder, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepistö, Charlotte Kvist Lautrup, Annika Lindblom, John Paul Plazzer, Ingrid Winship, Douglas Tjandra & 37 others Lior H. Katz, Stefan Aretz, Robert Hüneburg, Stefanie Holzapfel, Karl Heinimann, Adriana Della Valle, Florencia Neffa, Nathan Gluck, Wouter H. De Vos Tot Nederveen Cappel, Hans Vasen, Monika Morak, Verena Steinke-Lange, Christoph Engel, Nils Rahner, Wolff Schmiegel, Deepak Vangala, Huw Thomas, Kate Green, Fiona Lalloo, Emma J. Crosbie, James Hill, Gabriel Capella, Marta Pineda, Matilde Navarro, Ignacio Blanco, Sanne Ten Broeke, Maartje Nielsen, Ken Ljungmann, Sigve Nakken, Noralane Morey Lindor, Ian Frayling, Eivind Hovig, Lone Sunde, Matthias Kloor, Jukka Pekka Mecklin, Mette Kalager, Pål Møller

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number8
JournalHereditary Cancer in Clinical Practice
Volume17
Issue number1
DOIs
StatePublished - Feb 28 2019

Fingerprint

Hereditary Nonpolyposis Colorectal Neoplasms
Colonoscopy
Early Detection of Cancer
DNA Mismatch Repair
Databases
Colorectal Neoplasms
Neoplasms
Incidence
Polyps
Adenoma
Breast Neoplasms
Carcinoma

Keywords

  • Colonoscopy
  • Colorectal cancer
  • Endoscopy
  • Hereditary cancer
  • Hereditary nonpolyposis colorectal cancer
  • Lynch syndrome
  • Microsatellite instability
  • Mismatch repair
  • Over-diagnosis
  • Screening
  • Surveillance

ASJC Scopus subject areas

  • Oncology
  • Genetics(clinical)

Cite this

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. / 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; Valle, Adriana Della; 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 Morey; Frayling, Ian; Hovig, Eivind; Sunde, Lone; Kloor, Matthias; Mecklin, Jukka Pekka; Kalager, Mette; Møller, Pål.

In: Hereditary Cancer in Clinical Practice, Vol. 17, No. 1, 8, 28.02.2019.

Research output: Contribution to journalArticle

Seppälä, TT, Ahadova, A, Dominguez-Valentin, M, Macrae, F, Evans, DG, Therkildsen, C, Sampson, J, Scott, R, Burn, J, Möslein, G, Bernstein, I, Holinski-Feder, E, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Lautrup, CK, Lindblom, A, Plazzer, JP, Winship, I, Tjandra, D, Katz, LH, Aretz, S, Hüneburg, R, Holzapfel, S, Heinimann, K, Valle, AD, Neffa, F, Gluck, N, De Vos Tot Nederveen Cappel, WH, Vasen, H, Morak, M, Steinke-Lange, V, Engel, C, Rahner, N, Schmiegel, W, Vangala, D, Thomas, H, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Capella, G, Pineda, M, Navarro, M, Blanco, I, Ten Broeke, S, Nielsen, M, Ljungmann, K, Nakken, S, Lindor, NM, Frayling, I, Hovig, E, Sunde, L, Kloor, M, Mecklin, JP, Kalager, M & Møller, P 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, vol. 17, no. 1, 8. https://doi.org/10.1186/s13053-019-0106-8
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 ; Valle, Adriana Della ; 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 Morey ; Frayling, Ian ; Hovig, Eivind ; Sunde, Lone ; Kloor, Matthias ; Mecklin, Jukka Pekka ; Kalager, Mette ; Møller, Pål. / 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. In: Hereditary Cancer in Clinical Practice. 2019 ; Vol. 17, No. 1.
@article{507ccdf3142a4a20b9a58c3d8f03acd2,
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",
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.",
keywords = "Colonoscopy, Colorectal cancer, Endoscopy, Hereditary cancer, Hereditary nonpolyposis colorectal cancer, Lynch syndrome, Microsatellite instability, Mismatch repair, Over-diagnosis, Screening, Surveillance",
author = "Sepp{\"a}l{\"a}, {Toni T.} and Aysel Ahadova and Mev Dominguez-Valentin and Finlay Macrae and Evans, {D. Gareth} and Christina Therkildsen and Julian Sampson and Rodney Scott and John Burn and Gabriela M{\"o}slein and Inge Bernstein and Elke Holinski-Feder and Kirsi Pylv{\"a}n{\"a}inen and Laura Renkonen-Sinisalo and Anna Lepist{\"o} and Lautrup, {Charlotte Kvist} and Annika Lindblom and Plazzer, {John Paul} and Ingrid Winship and Douglas Tjandra and Katz, {Lior H.} and Stefan Aretz and Robert H{\"u}neburg and Stefanie Holzapfel and Karl Heinimann and Valle, {Adriana Della} and Florencia Neffa and Nathan Gluck and {De Vos Tot Nederveen Cappel}, {Wouter H.} and Hans Vasen and Monika Morak and Verena Steinke-Lange and Christoph Engel and Nils Rahner and Wolff Schmiegel and Deepak Vangala and Huw Thomas and Kate Green and Fiona Lalloo and Crosbie, {Emma J.} and James Hill and Gabriel Capella and Marta Pineda and Matilde Navarro and Ignacio Blanco and {Ten Broeke}, Sanne and Maartje Nielsen and Ken Ljungmann and Sigve Nakken and Lindor, {Noralane Morey} and Ian Frayling and Eivind Hovig and Lone Sunde and Matthias Kloor and Mecklin, {Jukka Pekka} and Mette Kalager and P{\aa}l M{\o}ller",
year = "2019",
month = "2",
day = "28",
doi = "10.1186/s13053-019-0106-8",
language = "English (US)",
volume = "17",
journal = "Hereditary Cancer in Clinical Practice",
issn = "1731-2302",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - 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

AU - Seppälä, Toni T.

AU - Ahadova, Aysel

AU - Dominguez-Valentin, Mev

AU - Macrae, Finlay

AU - Evans, D. Gareth

AU - Therkildsen, Christina

AU - Sampson, Julian

AU - Scott, Rodney

AU - Burn, John

AU - Möslein, Gabriela

AU - Bernstein, Inge

AU - Holinski-Feder, Elke

AU - Pylvänäinen, Kirsi

AU - Renkonen-Sinisalo, Laura

AU - Lepistö, Anna

AU - Lautrup, Charlotte Kvist

AU - Lindblom, Annika

AU - Plazzer, John Paul

AU - Winship, Ingrid

AU - Tjandra, Douglas

AU - Katz, Lior H.

AU - Aretz, Stefan

AU - Hüneburg, Robert

AU - Holzapfel, Stefanie

AU - Heinimann, Karl

AU - Valle, Adriana Della

AU - Neffa, Florencia

AU - Gluck, Nathan

AU - De Vos Tot Nederveen Cappel, Wouter H.

AU - Vasen, Hans

AU - Morak, Monika

AU - Steinke-Lange, Verena

AU - Engel, Christoph

AU - Rahner, Nils

AU - Schmiegel, Wolff

AU - Vangala, Deepak

AU - Thomas, Huw

AU - Green, Kate

AU - Lalloo, Fiona

AU - Crosbie, Emma J.

AU - Hill, James

AU - Capella, Gabriel

AU - Pineda, Marta

AU - Navarro, Matilde

AU - Blanco, Ignacio

AU - Ten Broeke, Sanne

AU - Nielsen, Maartje

AU - Ljungmann, Ken

AU - Nakken, Sigve

AU - Lindor, Noralane Morey

AU - Frayling, Ian

AU - Hovig, Eivind

AU - Sunde, Lone

AU - Kloor, Matthias

AU - Mecklin, Jukka Pekka

AU - Kalager, Mette

AU - Møller, Pål

PY - 2019/2/28

Y1 - 2019/2/28

N2 - 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.

AB - 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.

KW - Colonoscopy

KW - Colorectal cancer

KW - Endoscopy

KW - Hereditary cancer

KW - Hereditary nonpolyposis colorectal cancer

KW - Lynch syndrome

KW - Microsatellite instability

KW - Mismatch repair

KW - Over-diagnosis

KW - Screening

KW - Surveillance

UR - http://www.scopus.com/inward/record.url?scp=85062324759&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062324759&partnerID=8YFLogxK

U2 - 10.1186/s13053-019-0106-8

DO - 10.1186/s13053-019-0106-8

M3 - Article

VL - 17

JO - Hereditary Cancer in Clinical Practice

JF - Hereditary Cancer in Clinical Practice

SN - 1731-2302

IS - 1

M1 - 8

ER -