Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals

I J M Levink; D C F Klatte; R G Hanna-Sawires; G C M Vreeker; I S Ibrahim; Y E M van der Burgt; K A Overbeek; B D M Koopmann; D L Cahen; G M Fuhler; M Wuhrer; B A Bonsing; R A E M Tollenaar; F P Vleggaar; H F A Vasen; M E van Leerdam; M J Bruno; W E Mesker

doi:10.1016/j.pan.2022.03.021

Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals

I J M Levink, D C F Klatte, R G Hanna-Sawires, G C M Vreeker, I S Ibrahim, Y E M van der Burgt, K A Overbeek, B D M Koopmann, D L Cahen, G M Fuhler, M Wuhrer, B A Bonsing, R A E M Tollenaar, F P Vleggaar, H F A Vasen, M E van Leerdam, M J Bruno, W E Mesker

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Abstract

BACKGROUND: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals.

METHODS: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature.

RESULTS: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%.

CONCLUSION: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.

Original language	English
Pages (from-to)	497-506
Number of pages	10
Journal	Pancreatology
Volume	22
Issue number	4
Early online date	4 Apr 2022
DOIs	https://doi.org/10.1016/j.pan.2022.03.021
Publication status	Published - May 2022

Keywords

Early detection
Glycan biomarker
Glycosylation
Pancreatic cancer
Protein

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Levink, I. J. M., Klatte, D. C. F., Hanna-Sawires, R. G., Vreeker, G. C. M., Ibrahim, I. S., van der Burgt, Y. E. M., Overbeek, K. A., Koopmann, B. D. M., Cahen, D. L., Fuhler, G. M., Wuhrer, M., Bonsing, B. A., Tollenaar, R. A. E. M., Vleggaar, F. P., Vasen, H. F. A., van Leerdam, M. E., Bruno, M. J., & Mesker, W. E. (2022). Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals. Pancreatology, 22(4), 497-506. https://doi.org/10.1016/j.pan.2022.03.021

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abstract = "BACKGROUND: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals.METHODS: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature.RESULTS: 165 individuals ({"}FPC-cohort{"} N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%.CONCLUSION: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.",

keywords = "Early detection, Glycan biomarker, Glycosylation, Pancreatic cancer, Protein",

author = "Levink, {I J M} and Klatte, {D C F} and Hanna-Sawires, {R G} and Vreeker, {G C M} and Ibrahim, {I S} and {van der Burgt}, {Y E M} and Overbeek, {K A} and Koopmann, {B D M} and Cahen, {D L} and Fuhler, {G M} and M Wuhrer and Bonsing, {B A} and Tollenaar, {R A E M} and Vleggaar, {F P} and Vasen, {H F A} and {van Leerdam}, {M E} and Bruno, {M J} and Mesker, {W E}",

note = "Funding Information: We would like to acknowledge R.L.P van Vlierberghe. He does not fulfill the requirements for authorship, yet substantially attributed to the project. The current study was supported by ZonNW project number 531002011 and Genootschap Bollenstreek – Bollenstreekfonds, Lisse-Hillegom, The Netherlands. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = may,

doi = "10.1016/j.pan.2022.03.021",

language = "English",

volume = "22",

pages = "497--506",

journal = "Pancreatology",

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Levink, IJM, Klatte, DCF, Hanna-Sawires, RG, Vreeker, GCM, Ibrahim, IS, van der Burgt, YEM, Overbeek, KA, Koopmann, BDM, Cahen, DL, Fuhler, GM, Wuhrer, M, Bonsing, BA, Tollenaar, RAEM, Vleggaar, FP, Vasen, HFA, van Leerdam, ME, Bruno, MJ & Mesker, WE 2022, 'Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals', Pancreatology, vol. 22, no. 4, pp. 497-506. https://doi.org/10.1016/j.pan.2022.03.021

TY - JOUR

T1 - Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals

AU - Levink, I J M

AU - Klatte, D C F

AU - Hanna-Sawires, R G

AU - Vreeker, G C M

AU - Ibrahim, I S

AU - van der Burgt, Y E M

AU - Overbeek, K A

AU - Koopmann, B D M

AU - Cahen, D L

AU - Fuhler, G M

AU - Wuhrer, M

AU - Bonsing, B A

AU - Tollenaar, R A E M

AU - Vleggaar, F P

AU - Vasen, H F A

AU - van Leerdam, M E

AU - Bruno, M J

AU - Mesker, W E

N1 - Funding Information: We would like to acknowledge R.L.P van Vlierberghe. He does not fulfill the requirements for authorship, yet substantially attributed to the project. The current study was supported by ZonNW project number 531002011 and Genootschap Bollenstreek – Bollenstreekfonds, Lisse-Hillegom, The Netherlands. Publisher Copyright: © 2022 The Authors

PY - 2022/5

Y1 - 2022/5

N2 - BACKGROUND: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals.METHODS: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature.RESULTS: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%.CONCLUSION: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.

AB - BACKGROUND: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals.METHODS: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature.RESULTS: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%.CONCLUSION: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.

KW - Early detection

KW - Glycan biomarker

KW - Glycosylation

KW - Pancreatic cancer

KW - Protein

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DO - 10.1016/j.pan.2022.03.021

M3 - Article

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SN - 1424-3903

VL - 22

SP - 497

EP - 506

JO - Pancreatology

JF - Pancreatology

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ER -

Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals

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