Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients

G. Wieme; J. Kral; T. Rosseel; P. Zemankova; B. Parton; M. Vocka; M. Van Heetvelde; P. Kleiblova; B. Blaumeiser; J. Soukupova; J. van den Ende; P. Nehasil; S. Tejpar; M. Borecka; E.B.G. Garcia; M.J. Blok; M. Safarikova; M. Kalousova; K. Geboes; R. De Putter; B. Poppe; K. De Leeneer; Z. Kleibl; M. Janatova; K.B.M. Claes

doi:10.3390/cancers13174430

Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients

G. Wieme, J. Kral, T. Rosseel, P. Zemankova, B. Parton, M. Vocka, M. Van Heetvelde, P. Kleiblova, B. Blaumeiser, J. Soukupova, J. van den Ende, P. Nehasil, S. Tejpar, M. Borecka, E.B.G. Garcia, M.J. Blok, M. Safarikova, M. Kalousova, K. Geboes, R. De PutterB. Poppe, K. De Leeneer, Z. Kleibl, M. Janatova^*, K.B.M. Claes^*

^*Corresponding author for this work

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

Abstract

Simple Summary We performed genetic analysis of 53 cancer predisposing genes in Belgian and Czech pancreatic cancer patients. In known pancreatic cancer predisposing genes, a high mutation detection ratio was observed in patients with multiple primary tumors and/or a family history of pancreatic or breast, ovarian or colon cancer or melanoma. BRCA1, BRCA2, and ATM were most frequently affected. Pathogenic variants in cancer predisposition genes for which the association with pancreatic cancer has not been firmly established, were less frequent, except for CHEK2. This observation warrants further analyses in other populations. To accurately determine risk associations our study highlights the importance of using a geographically-matched control population. (1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34-0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.

Original language	English
Article number	4430
Number of pages	15
Journal	Cancers
Volume	13
Issue number	17
DOIs	https://doi.org/10.3390/cancers13174430
Publication status	Published - 1 Sept 2021

Keywords

pancreatic ductal adenocarcinoma
overall survival
multigene panel testing
family history
germline
MUTATION PREVALENCE
BRCA1
RISK
ASSOCIATION
SURVIVAL

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Wieme, G., Kral, J., Rosseel, T., Zemankova, P., Parton, B., Vocka, M., Van Heetvelde, M., Kleiblova, P., Blaumeiser, B., Soukupova, J., van den Ende, J., Nehasil, P., Tejpar, S., Borecka, M., Garcia, E. B. G., Blok, M. J., Safarikova, M., Kalousova, M., Geboes, K., ... Claes, K. B. M. (2021). Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients. Cancers, 13(17), Article 4430. https://doi.org/10.3390/cancers13174430

@article{94d9236fac524c27a9850a5c03c4be8e,

title = "Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients",

abstract = "Simple Summary We performed genetic analysis of 53 cancer predisposing genes in Belgian and Czech pancreatic cancer patients. In known pancreatic cancer predisposing genes, a high mutation detection ratio was observed in patients with multiple primary tumors and/or a family history of pancreatic or breast, ovarian or colon cancer or melanoma. BRCA1, BRCA2, and ATM were most frequently affected. Pathogenic variants in cancer predisposition genes for which the association with pancreatic cancer has not been firmly established, were less frequent, except for CHEK2. This observation warrants further analyses in other populations. To accurately determine risk associations our study highlights the importance of using a geographically-matched control population. (1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34-0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.",

keywords = "pancreatic ductal adenocarcinoma, overall survival, multigene panel testing, family history, germline, MUTATION PREVALENCE, BRCA1, RISK, ASSOCIATION, SURVIVAL",

author = "G. Wieme and J. Kral and T. Rosseel and P. Zemankova and B. Parton and M. Vocka and {Van Heetvelde}, M. and P. Kleiblova and B. Blaumeiser and J. Soukupova and {van den Ende}, J. and P. Nehasil and S. Tejpar and M. Borecka and E.B.G. Garcia and M.J. Blok and M. Safarikova and M. Kalousova and K. Geboes and {De Putter}, R. and B. Poppe and {De Leeneer}, K. and Z. Kleibl and M. Janatova and K.B.M. Claes",

note = "Funding Information: Funding: This work was supported by The King Baudouin foundation (2017-J1140800-207846) and Kom op tegen Kanker (STI.VLK.2017.0007.01), grant projects by Ministry of Health of the Czech Republic (NU20-03-00285 and RVO-VFN 64165), Charles University research projects SVV 260516, PROGRES Q28/LF1. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = sep,

day = "1",

doi = "10.3390/cancers13174430",

language = "English",

volume = "13",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "17",

}

Wieme, G, Kral, J, Rosseel, T, Zemankova, P, Parton, B, Vocka, M, Van Heetvelde, M, Kleiblova, P, Blaumeiser, B, Soukupova, J, van den Ende, J, Nehasil, P, Tejpar, S, Borecka, M, Garcia, EBG , Blok, MJ, Safarikova, M, Kalousova, M, Geboes, K, De Putter, R, Poppe, B, De Leeneer, K, Kleibl, Z, Janatova, M & Claes, KBM 2021, 'Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients', Cancers, vol. 13, no. 17, 4430. https://doi.org/10.3390/cancers13174430

TY - JOUR

T1 - Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients

AU - Wieme, G.

AU - Kral, J.

AU - Rosseel, T.

AU - Zemankova, P.

AU - Parton, B.

AU - Vocka, M.

AU - Van Heetvelde, M.

AU - Kleiblova, P.

AU - Blaumeiser, B.

AU - Soukupova, J.

AU - van den Ende, J.

AU - Nehasil, P.

AU - Tejpar, S.

AU - Borecka, M.

AU - Garcia, E.B.G.

AU - Blok, M.J.

AU - Safarikova, M.

AU - Kalousova, M.

AU - Geboes, K.

AU - De Putter, R.

AU - Poppe, B.

AU - De Leeneer, K.

AU - Kleibl, Z.

AU - Janatova, M.

AU - Claes, K.B.M.

N1 - Funding Information: Funding: This work was supported by The King Baudouin foundation (2017-J1140800-207846) and Kom op tegen Kanker (STI.VLK.2017.0007.01), grant projects by Ministry of Health of the Czech Republic (NU20-03-00285 and RVO-VFN 64165), Charles University research projects SVV 260516, PROGRES Q28/LF1. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/9/1

Y1 - 2021/9/1

N2 - Simple Summary We performed genetic analysis of 53 cancer predisposing genes in Belgian and Czech pancreatic cancer patients. In known pancreatic cancer predisposing genes, a high mutation detection ratio was observed in patients with multiple primary tumors and/or a family history of pancreatic or breast, ovarian or colon cancer or melanoma. BRCA1, BRCA2, and ATM were most frequently affected. Pathogenic variants in cancer predisposition genes for which the association with pancreatic cancer has not been firmly established, were less frequent, except for CHEK2. This observation warrants further analyses in other populations. To accurately determine risk associations our study highlights the importance of using a geographically-matched control population. (1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34-0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.

AB - Simple Summary We performed genetic analysis of 53 cancer predisposing genes in Belgian and Czech pancreatic cancer patients. In known pancreatic cancer predisposing genes, a high mutation detection ratio was observed in patients with multiple primary tumors and/or a family history of pancreatic or breast, ovarian or colon cancer or melanoma. BRCA1, BRCA2, and ATM were most frequently affected. Pathogenic variants in cancer predisposition genes for which the association with pancreatic cancer has not been firmly established, were less frequent, except for CHEK2. This observation warrants further analyses in other populations. To accurately determine risk associations our study highlights the importance of using a geographically-matched control population. (1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34-0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.

KW - pancreatic ductal adenocarcinoma

KW - overall survival

KW - multigene panel testing

KW - family history

KW - germline

KW - MUTATION PREVALENCE

KW - BRCA1

KW - RISK

KW - ASSOCIATION

KW - SURVIVAL

U2 - 10.3390/cancers13174430

DO - 10.3390/cancers13174430

M3 - Article

C2 - 34503238

SN - 2072-6694

VL - 13

JO - Cancers

JF - Cancers

IS - 17

M1 - 4430

ER -