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The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2

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The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2. / Hinić, Snežana; Cybulski, Cezary; Van der Post, Rachel S; Vos, Janet R; Schuurs-Hoeijmakers, Janneke; Brugnoletti, Fulvia; Koene, Saskia; Vreede, Lilian; van Zelst-Stams, Wendy A G; Kets, C Marleen; Haadsma, Maaike; Spruijt, Liesbeth; Wevers, Marijke R; Evans, D Gareth; Wimmer, Katharina; Schnaiter, Simon; Volk, Alexander E; Möllring, Anna; de Putter, Robin; Soikkonen, Leila; Kahre, Tiina; Tooming, Mikk; de Jong, Mirjam M; Vaz, Fátima; Mensenkamp, Arjen R; Genuardi, Maurizio; Lubinski, Jan; Ligtenberg, Marjolijn; Hoogerbrugge, Nicoline; de Voer, Richarda M.

In: GENET MED, Vol. 26, No. 5, 101101, 05.2024.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Hinić, S, Cybulski, C, Van der Post, RS, Vos, JR, Schuurs-Hoeijmakers, J, Brugnoletti, F, Koene, S, Vreede, L, van Zelst-Stams, WAG, Kets, CM, Haadsma, M, Spruijt, L, Wevers, MR, Evans, DG, Wimmer, K, Schnaiter, S, Volk, AE, Möllring, A, de Putter, R, Soikkonen, L, Kahre, T, Tooming, M, de Jong, MM, Vaz, F, Mensenkamp, AR, Genuardi, M, Lubinski, J, Ligtenberg, M, Hoogerbrugge, N & de Voer, RM 2024, 'The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2', GENET MED, vol. 26, no. 5, 101101. https://doi.org/10.1016/j.gim.2024.101101

APA

Hinić, S., Cybulski, C., Van der Post, R. S., Vos, J. R., Schuurs-Hoeijmakers, J., Brugnoletti, F., Koene, S., Vreede, L., van Zelst-Stams, W. A. G., Kets, C. M., Haadsma, M., Spruijt, L., Wevers, M. R., Evans, D. G., Wimmer, K., Schnaiter, S., Volk, A. E., Möllring, A., de Putter, R., ... de Voer, R. M. (2024). The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2. GENET MED, 26(5), [101101]. https://doi.org/10.1016/j.gim.2024.101101

Vancouver

Hinić S, Cybulski C, Van der Post RS, Vos JR, Schuurs-Hoeijmakers J, Brugnoletti F et al. The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2. GENET MED. 2024 May;26(5). 101101. https://doi.org/10.1016/j.gim.2024.101101

Bibtex

@article{7f8fc2915284454f8565a7ccd2a86862,
title = "The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2",
abstract = "PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291).RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins.CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.",
keywords = "Adult, Female, Humans, Male, Middle Aged, Alleles, Breast Neoplasms/genetics, Checkpoint Kinase 2/genetics, Colorectal Neoplasms/genetics, Exome Sequencing/methods, Genetic Predisposition to Disease, Germ-Line Mutation/genetics, Neoplasms/genetics, Phenotype, Prostatic Neoplasms/genetics",
author = "Sne{\v z}ana Hini{\'c} and Cezary Cybulski and {Van der Post}, {Rachel S} and Vos, {Janet R} and Janneke Schuurs-Hoeijmakers and Fulvia Brugnoletti and Saskia Koene and Lilian Vreede and {van Zelst-Stams}, {Wendy A G} and Kets, {C Marleen} and Maaike Haadsma and Liesbeth Spruijt and Wevers, {Marijke R} and Evans, {D Gareth} and Katharina Wimmer and Simon Schnaiter and Volk, {Alexander E} and Anna M{\"o}llring and {de Putter}, Robin and Leila Soikkonen and Tiina Kahre and Mikk Tooming and {de Jong}, {Mirjam M} and F{\'a}tima Vaz and Mensenkamp, {Arjen R} and Maurizio Genuardi and Jan Lubinski and Marjolijn Ligtenberg and Nicoline Hoogerbrugge and {de Voer}, {Richarda M}",
note = "Copyright {\textcopyright} 2024 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2024",
month = may,
doi = "10.1016/j.gim.2024.101101",
language = "English",
volume = "26",
journal = "GENET MED",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

RIS

TY - JOUR

T1 - The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2

AU - Hinić, Snežana

AU - Cybulski, Cezary

AU - Van der Post, Rachel S

AU - Vos, Janet R

AU - Schuurs-Hoeijmakers, Janneke

AU - Brugnoletti, Fulvia

AU - Koene, Saskia

AU - Vreede, Lilian

AU - van Zelst-Stams, Wendy A G

AU - Kets, C Marleen

AU - Haadsma, Maaike

AU - Spruijt, Liesbeth

AU - Wevers, Marijke R

AU - Evans, D Gareth

AU - Wimmer, Katharina

AU - Schnaiter, Simon

AU - Volk, Alexander E

AU - Möllring, Anna

AU - de Putter, Robin

AU - Soikkonen, Leila

AU - Kahre, Tiina

AU - Tooming, Mikk

AU - de Jong, Mirjam M

AU - Vaz, Fátima

AU - Mensenkamp, Arjen R

AU - Genuardi, Maurizio

AU - Lubinski, Jan

AU - Ligtenberg, Marjolijn

AU - Hoogerbrugge, Nicoline

AU - de Voer, Richarda M

N1 - Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2024/5

Y1 - 2024/5

N2 - PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291).RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins.CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.

AB - PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291).RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins.CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.

KW - Adult

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Alleles

KW - Breast Neoplasms/genetics

KW - Checkpoint Kinase 2/genetics

KW - Colorectal Neoplasms/genetics

KW - Exome Sequencing/methods

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation/genetics

KW - Neoplasms/genetics

KW - Phenotype

KW - Prostatic Neoplasms/genetics

U2 - 10.1016/j.gim.2024.101101

DO - 10.1016/j.gim.2024.101101

M3 - SCORING: Journal article

C2 - 38362852

VL - 26

JO - GENET MED

JF - GENET MED

SN - 1098-3600

IS - 5

M1 - 101101

ER -