Pancreatic cancer risk and survival in patients with Lynch syndrome: a nationwide Dutch cohort study

Aleksander M Bogdanski; Derk C F Klatte; Bert A Bonsing; Lodewijk A A Brosens; Evelien Dekker; Lydia G van der Geest; Joep E G Ijspeert; Jan J Koornstra; Mariëtte C A van Kouwen; Alexandra M J Langers; Maartje Nielsen; Dewkoemar Ramsoekh; Manon C Spaander; Wouter H de Vos Tot Nederveen Cappel; Jeanin E Van Hooft; Monique E van Leerdam

doi:10.1016/j.eclinm.2026.103755

Pancreatic cancer risk and survival in patients with Lynch syndrome: a nationwide Dutch cohort study

Aleksander M Bogdanski
, Derk C F Klatte
, Bert A Bonsing
, Lodewijk A A Brosens
, Evelien Dekker
, Lydia G van der Geest
, Joep E G Ijspeert
, Jan J Koornstra
, Mariëtte C A van Kouwen
, Alexandra M J Langers
, Maartje Nielsen
, Dewkoemar Ramsoekh
, Manon C Spaander
, Wouter H de Vos Tot Nederveen Cappel
, Jeanin E Van Hooft
, Monique E van Leerdam^*
,

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Individuals with Lynch syndrome (LS) are advised to undergo pancreatic ductal adenocarcinoma (PDAC) surveillance if their lifetime risk is ≥5%, however, evidence is limited. This study quantifies lifetime risk and survival of three cancers relevant to PDAC surveillance, including PDAC, ampullary carcinoma (AC) and distal cholangiocarcinoma (dCC), to evaluate whether surveillance is justified.

METHODS: This retrospective nationwide Dutch cohort study included individuals with LS pathogenic variants (PVs) in MLH1, MSH2, MSH6, PMS2 or EpCAM (identified between 1985 and 2024) and compared them to sporadic cases from the general population (diagnosed between 2000 and 2022). Cumulative incidence (CI) of PDAC, AC and dCC was estimated using Fine-and-Gray models for LS and a CI formula for sporadic cases. Relative risks (RRs) were calculated by comparing CIs. Survival of the cancers was compared between both cohorts using 1:10 matched analyses by age at diagnosis, sex, stage, and year of diagnosis.

FINDINGS: In total, 2605 individuals with LS were included (median age 63.9 years; IQR 53.7-74.0), of whom 1515 (58.2%) were female. PVs were identified in MLH1 (723, 27.8%), MSH2 (895, 34.4%), MSH6 (731, 28.1%), PMS2 (233, 8.9%) and EpCAM (23, 0.9%). By age 75, the combined CI of PDAC, AC and dCC was 3.0% (95% CIs, 1.5-5.8) in MLH1, 3.4% (95% CIs, 2.0-5.8) in MSH2/EpCAM, 1.0% (95% CIs, 0.3-2.7) in MSH6 and 0% in PMS2. No familial-clustering of cancers was observed. Matched survival did not differ between PDACs in LS and sporadic cases. In contrast, survival was better for AC in LS (34.3 months; 95% CIs, 3.2-Inf) compared to sporadic cases (15.5 months; 95% CIs, 9.9-19.3).

INTERPRETATION: In LS, the combined lifetime risk of PDAC, AC and dCC ranged from 0 to 3.4% across different genes, remaining below the 5% risk threshold for PDAC surveillance. Additionally, having an affected relative did not appear to increase risk. These findings suggest that current surveillance recommendations for individuals with LS should be re-evaluated.

FUNDING: Lynch-Polyposis.

Original language	English
Article number	103755
Journal	EClinicalMedicine
Volume	91
DOIs	https://doi.org/10.1016/j.eclinm.2026.103755
Publication status	Published - Jan 2026

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Pancreatic cancer risk and survival in patients with Lynch syndrome: a nationwide Dutch cohort studyFinal published version, 632 KBLicence: CC BY

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Bogdanski, A. M., Klatte, D. C. F., Bonsing, B. A., Brosens, L. A. A., Dekker, E., van der Geest, L. G., Ijspeert, J. E. G., Koornstra, J. J., van Kouwen, M. C. A., Langers, A. M. J., Nielsen, M., Ramsoekh, D., Spaander, M. C., de Vos Tot Nederveen Cappel, W. H., Van Hooft, J. E., van Leerdam, M. E. (2026). Pancreatic cancer risk and survival in patients with Lynch syndrome: a nationwide Dutch cohort study. EClinicalMedicine, 91, Article 103755. https://doi.org/10.1016/j.eclinm.2026.103755

@article{17a2b84aff934e2799d3e7eaaf797768,

title = "Pancreatic cancer risk and survival in patients with Lynch syndrome: a nationwide Dutch cohort study",

abstract = "BACKGROUND: Individuals with Lynch syndrome (LS) are advised to undergo pancreatic ductal adenocarcinoma (PDAC) surveillance if their lifetime risk is ≥5\%, however, evidence is limited. This study quantifies lifetime risk and survival of three cancers relevant to PDAC surveillance, including PDAC, ampullary carcinoma (AC) and distal cholangiocarcinoma (dCC), to evaluate whether surveillance is justified.METHODS: This retrospective nationwide Dutch cohort study included individuals with LS pathogenic variants (PVs) in MLH1, MSH2, MSH6, PMS2 or EpCAM (identified between 1985 and 2024) and compared them to sporadic cases from the general population (diagnosed between 2000 and 2022). Cumulative incidence (CI) of PDAC, AC and dCC was estimated using Fine-and-Gray models for LS and a CI formula for sporadic cases. Relative risks (RRs) were calculated by comparing CIs. Survival of the cancers was compared between both cohorts using 1:10 matched analyses by age at diagnosis, sex, stage, and year of diagnosis. FINDINGS: In total, 2605 individuals with LS were included (median age 63.9 years; IQR 53.7-74.0), of whom 1515 (58.2\%) were female. PVs were identified in MLH1 (723, 27.8\%), MSH2 (895, 34.4\%), MSH6 (731, 28.1\%), PMS2 (233, 8.9\%) and EpCAM (23, 0.9\%). By age 75, the combined CI of PDAC, AC and dCC was 3.0\% (95\% CIs, 1.5-5.8) in MLH1, 3.4\% (95\% CIs, 2.0-5.8) in MSH2/EpCAM, 1.0\% (95\% CIs, 0.3-2.7) in MSH6 and 0\% in PMS2. No familial-clustering of cancers was observed. Matched survival did not differ between PDACs in LS and sporadic cases. In contrast, survival was better for AC in LS (34.3 months; 95\% CIs, 3.2-Inf) compared to sporadic cases (15.5 months; 95\% CIs, 9.9-19.3). INTERPRETATION: In LS, the combined lifetime risk of PDAC, AC and dCC ranged from 0 to 3.4\% across different genes, remaining below the 5\% risk threshold for PDAC surveillance. Additionally, having an affected relative did not appear to increase risk. These findings suggest that current surveillance recommendations for individuals with LS should be re-evaluated.FUNDING: Lynch-Polyposis.",

author = "Bogdanski, \{Aleksander M\} and Klatte, \{Derk C F\} and Bonsing, \{Bert A\} and Brosens, \{Lodewijk A A\} and Evelien Dekker and \{van der Geest\}, \{Lydia G\} and Ijspeert, \{Joep E G\} and Koornstra, \{Jan J\} and \{van Kouwen\}, \{Mari{\"e}tte C A\} and Langers, \{Alexandra M J\} and Maartje Nielsen and Dewkoemar Ramsoekh and Spaander, \{Manon C\} and \{de Vos Tot Nederveen Cappel\}, \{Wouter H\} and \{Van Hooft\}, \{Jeanin E\} and \{van Leerdam\}, \{Monique E\}",

note = "{\textcopyright} 2026 The Author(s).",

year = "2026",

month = jan,

doi = "10.1016/j.eclinm.2026.103755",

language = "English",

volume = "91",

journal = "EClinicalMedicine",

issn = "2589-5370",

publisher = "Elsevier Limited",

}

Bogdanski, AM, Klatte, DCF, Bonsing, BA, Brosens, LAA, Dekker, E, van der Geest, LG, Ijspeert, JEG, Koornstra, JJ, van Kouwen, MCA, Langers, AMJ, Nielsen, M, Ramsoekh, D, Spaander, MC, de Vos Tot Nederveen Cappel, WH, Van Hooft, JE, van Leerdam, ME 2026, 'Pancreatic cancer risk and survival in patients with Lynch syndrome: a nationwide Dutch cohort study', EClinicalMedicine, vol. 91, 103755. https://doi.org/10.1016/j.eclinm.2026.103755

TY - JOUR

T1 - Pancreatic cancer risk and survival in patients with Lynch syndrome

T2 - a nationwide Dutch cohort study

AU - Bogdanski, Aleksander M

AU - Klatte, Derk C F

AU - Bonsing, Bert A

AU - Brosens, Lodewijk A A

AU - Dekker, Evelien

AU - van der Geest, Lydia G

AU - Ijspeert, Joep E G

AU - Koornstra, Jan J

AU - van Kouwen, Mariëtte C A

AU - Langers, Alexandra M J

AU - Nielsen, Maartje

AU - Ramsoekh, Dewkoemar

AU - Spaander, Manon C

AU - de Vos Tot Nederveen Cappel, Wouter H

AU - Van Hooft, Jeanin E

AU - van Leerdam, Monique E

PY - 2026/1

Y1 - 2026/1

N2 - BACKGROUND: Individuals with Lynch syndrome (LS) are advised to undergo pancreatic ductal adenocarcinoma (PDAC) surveillance if their lifetime risk is ≥5%, however, evidence is limited. This study quantifies lifetime risk and survival of three cancers relevant to PDAC surveillance, including PDAC, ampullary carcinoma (AC) and distal cholangiocarcinoma (dCC), to evaluate whether surveillance is justified.METHODS: This retrospective nationwide Dutch cohort study included individuals with LS pathogenic variants (PVs) in MLH1, MSH2, MSH6, PMS2 or EpCAM (identified between 1985 and 2024) and compared them to sporadic cases from the general population (diagnosed between 2000 and 2022). Cumulative incidence (CI) of PDAC, AC and dCC was estimated using Fine-and-Gray models for LS and a CI formula for sporadic cases. Relative risks (RRs) were calculated by comparing CIs. Survival of the cancers was compared between both cohorts using 1:10 matched analyses by age at diagnosis, sex, stage, and year of diagnosis. FINDINGS: In total, 2605 individuals with LS were included (median age 63.9 years; IQR 53.7-74.0), of whom 1515 (58.2%) were female. PVs were identified in MLH1 (723, 27.8%), MSH2 (895, 34.4%), MSH6 (731, 28.1%), PMS2 (233, 8.9%) and EpCAM (23, 0.9%). By age 75, the combined CI of PDAC, AC and dCC was 3.0% (95% CIs, 1.5-5.8) in MLH1, 3.4% (95% CIs, 2.0-5.8) in MSH2/EpCAM, 1.0% (95% CIs, 0.3-2.7) in MSH6 and 0% in PMS2. No familial-clustering of cancers was observed. Matched survival did not differ between PDACs in LS and sporadic cases. In contrast, survival was better for AC in LS (34.3 months; 95% CIs, 3.2-Inf) compared to sporadic cases (15.5 months; 95% CIs, 9.9-19.3). INTERPRETATION: In LS, the combined lifetime risk of PDAC, AC and dCC ranged from 0 to 3.4% across different genes, remaining below the 5% risk threshold for PDAC surveillance. Additionally, having an affected relative did not appear to increase risk. These findings suggest that current surveillance recommendations for individuals with LS should be re-evaluated.FUNDING: Lynch-Polyposis.

AB - BACKGROUND: Individuals with Lynch syndrome (LS) are advised to undergo pancreatic ductal adenocarcinoma (PDAC) surveillance if their lifetime risk is ≥5%, however, evidence is limited. This study quantifies lifetime risk and survival of three cancers relevant to PDAC surveillance, including PDAC, ampullary carcinoma (AC) and distal cholangiocarcinoma (dCC), to evaluate whether surveillance is justified.METHODS: This retrospective nationwide Dutch cohort study included individuals with LS pathogenic variants (PVs) in MLH1, MSH2, MSH6, PMS2 or EpCAM (identified between 1985 and 2024) and compared them to sporadic cases from the general population (diagnosed between 2000 and 2022). Cumulative incidence (CI) of PDAC, AC and dCC was estimated using Fine-and-Gray models for LS and a CI formula for sporadic cases. Relative risks (RRs) were calculated by comparing CIs. Survival of the cancers was compared between both cohorts using 1:10 matched analyses by age at diagnosis, sex, stage, and year of diagnosis. FINDINGS: In total, 2605 individuals with LS were included (median age 63.9 years; IQR 53.7-74.0), of whom 1515 (58.2%) were female. PVs were identified in MLH1 (723, 27.8%), MSH2 (895, 34.4%), MSH6 (731, 28.1%), PMS2 (233, 8.9%) and EpCAM (23, 0.9%). By age 75, the combined CI of PDAC, AC and dCC was 3.0% (95% CIs, 1.5-5.8) in MLH1, 3.4% (95% CIs, 2.0-5.8) in MSH2/EpCAM, 1.0% (95% CIs, 0.3-2.7) in MSH6 and 0% in PMS2. No familial-clustering of cancers was observed. Matched survival did not differ between PDACs in LS and sporadic cases. In contrast, survival was better for AC in LS (34.3 months; 95% CIs, 3.2-Inf) compared to sporadic cases (15.5 months; 95% CIs, 9.9-19.3). INTERPRETATION: In LS, the combined lifetime risk of PDAC, AC and dCC ranged from 0 to 3.4% across different genes, remaining below the 5% risk threshold for PDAC surveillance. Additionally, having an affected relative did not appear to increase risk. These findings suggest that current surveillance recommendations for individuals with LS should be re-evaluated.FUNDING: Lynch-Polyposis.

U2 - 10.1016/j.eclinm.2026.103755

DO - 10.1016/j.eclinm.2026.103755

M3 - Article

C2 - 41583364

SN - 2589-5370

VL - 91

JO - EClinicalMedicine

JF - EClinicalMedicine

M1 - 103755

ER -

Pancreatic cancer risk and survival in patients with Lynch syndrome: a nationwide Dutch cohort study

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