Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

Mariano Golubicki; Laia Bonjoch; José G. Acuña-Ochoa; Marcos Díaz-Gay; Jenifer Muñoz; Miriam Cuatrecasas; Teresa Ocaña; Soledad Iseas; Guillermo Mendez; Daniel Cisterna; Stephanie A. Schubert; Maartje Nielsen; Tom van Wezel; Yael Goldberg; Eli Pikarsky; Juan Robbio; Enrique Roca; Antoni Castells; Francesc Balaguer; Marina Antelo; Sergi Castellví-Bel

doi:10.1172/JCI.INSIGHT.140698

Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

Mariano Golubicki, Laia Bonjoch, José G. Acuña-Ochoa, Marcos Díaz-Gay, Jenifer Muñoz, Miriam Cuatrecasas, Teresa Ocaña, Soledad Iseas, Guillermo Mendez, Daniel Cisterna, Stephanie A. Schubert, Maartje Nielsen, Tom van Wezel, Yael Goldberg, Eli Pikarsky, Juan Robbio, Enrique Roca, Antoni Castells, Francesc Balaguer, Marina Antelo^*Sergi Castellví-Bel^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

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

17 Scopus citations

Abstract

Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/ Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8^KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8^KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.

Original language	American English
Article number	e140698
Journal	JCI insight
Volume	5
Issue number	18
DOIs	https://doi.org/10.1172/JCI.INSIGHT.140698
State	Published - Aug 2020

Bibliographical note

Funding Information:
MG and MA were supported by Foundation Nelia et Amadeo Barletta contract. LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). JM was supported by a contract from CIBEREHD. MD-G was supported by a contract from Agència de Gestió d'Ajuts Universitaris i de Recerca -AGAUR(Generalitat de Catalunya, 2019FI_B2_00203). CIBEREHD is funded by the Instituto de Salud Carlos III. This research was supported by grants from Foundation Nelia et Amadeo Barletta FNAB and the Argentinian National Cancer Institute. This research was supported by grants from Fondo de Investigación Sanitaria/ FEDER (16/00766, 17/00878, 17/01304, 19/01867), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Program (Generalitat de Catalunya), and Agència de Gestió d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). This research was funded by a research grant from the Dutch Digestive Foundation (MLDS FP13-13), awarded to TVW. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology, https://www.cost.eu). We are sincerely grateful to the patients, Celia Badenas, Esteban Cvitkovic, CNAG, and the Biobank of Hospital Clínic-IDIBAPS. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona.

Funding Information:
MG and MA were supported by Foundation Nelia et Amadeo Barletta contract. LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). JM was supported by a contract from CIBEREHD. MD-G was supported by a contract from Agència de Gestió d’Ajuts Universitaris i de Recerca -AGAUR-(Generalitat de Catalunya, 2019FI_B2_00203). CIBEREHD is funded by the Instituto de Salud Carlos III. This research was supported by grants from Foundation Nelia et Amadeo Barletta FNAB and the Argentinian National Cancer Institute. This research was supported by grants from Fondo de Investigación Sanitaria/ FEDER (16/00766, 17/00878, 17/01304, 19/01867), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Program (Generalitat de Catalunya), and Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalun-ya, GRPRE 2017SGR21, GRC 2017SGR653). This research was funded by a research grant from the Dutch Digestive Foundation (MLDS FP13-13), awarded to TVW. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology, https://www.cost.eu). We are sincerely grateful to the patients, Celia Badenas, Esteban Cvitkovic, CNAG, and the Biobank of Hospital Clínic–IDIBAPS. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona.

Publisher Copyright:
Copyright: © 2020, Golubicki et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

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10.1172/JCI.INSIGHT.140698

Cite this

Golubicki, M., Bonjoch, L., Acuña-Ochoa, J. G., Díaz-Gay, M., Muñoz, J., Cuatrecasas, M., Ocaña, T., Iseas, S., Mendez, G., Cisterna, D., Schubert, S. A., Nielsen, M., van Wezel, T., Goldberg, Y., Pikarsky, E., Robbio, J., Roca, E., Castells, A., Balaguer, F., ... Castellví-Bel, S. (2020). Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome. JCI insight, 5(18), Article e140698. https://doi.org/10.1172/JCI.INSIGHT.140698

@article{4789792a77a24cbf9d722950ab85e433,

title = "Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome",

abstract = "Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/ Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.",

author = "Mariano Golubicki and Laia Bonjoch and Acu{\~n}a-Ochoa, {Jos{\'e} G.} and Marcos D{\'i}az-Gay and Jenifer Mu{\~n}oz and Miriam Cuatrecasas and Teresa Oca{\~n}a and Soledad Iseas and Guillermo Mendez and Daniel Cisterna and Schubert, {Stephanie A.} and Maartje Nielsen and {van Wezel}, Tom and Yael Goldberg and Eli Pikarsky and Juan Robbio and Enrique Roca and Antoni Castells and Francesc Balaguer and Marina Antelo and Sergi Castellv{\'i}-Bel",

note = "Funding Information: MG and MA were supported by Foundation Nelia et Amadeo Barletta contract. LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). JM was supported by a contract from CIBEREHD. MD-G was supported by a contract from Ag{\`e}ncia de Gesti{\'o} d'Ajuts Universitaris i de Recerca -AGAUR(Generalitat de Catalunya, 2019FI_B2_00203). CIBEREHD is funded by the Instituto de Salud Carlos III. This research was supported by grants from Foundation Nelia et Amadeo Barletta FNAB and the Argentinian National Cancer Institute. This research was supported by grants from Fondo de Investigaci{\'o}n Sanitaria/ FEDER (16/00766, 17/00878, 17/01304, 19/01867), Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola contra el C{\'a}ncer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Program (Generalitat de Catalunya), and Ag{\`e}ncia de Gesti{\'o} d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). This research was funded by a research grant from the Dutch Digestive Foundation (MLDS FP13-13), awarded to TVW. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology, https://www.cost.eu). We are sincerely grateful to the patients, Celia Badenas, Esteban Cvitkovic, CNAG, and the Biobank of Hospital Cl{\'i}nic-IDIBAPS. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona. Funding Information: MG and MA were supported by Foundation Nelia et Amadeo Barletta contract. LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). JM was supported by a contract from CIBEREHD. MD-G was supported by a contract from Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca -AGAUR-(Generalitat de Catalunya, 2019FI_B2_00203). CIBEREHD is funded by the Instituto de Salud Carlos III. This research was supported by grants from Foundation Nelia et Amadeo Barletta FNAB and the Argentinian National Cancer Institute. This research was supported by grants from Fondo de Investigaci{\'o}n Sanitaria/ FEDER (16/00766, 17/00878, 17/01304, 19/01867), Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola contra el C{\'a}ncer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Program (Generalitat de Catalunya), and Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca (Generalitat de Catalun-ya, GRPRE 2017SGR21, GRC 2017SGR653). This research was funded by a research grant from the Dutch Digestive Foundation (MLDS FP13-13), awarded to TVW. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology, https://www.cost.eu). We are sincerely grateful to the patients, Celia Badenas, Esteban Cvitkovic, CNAG, and the Biobank of Hospital Cl{\'i}nic–IDIBAPS. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona. Publisher Copyright: Copyright: {\textcopyright} 2020, Golubicki et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2020",

month = aug,

doi = "10.1172/JCI.INSIGHT.140698",

language = "American English",

volume = "5",

journal = "JCI insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "18",

}

Golubicki, M, Bonjoch, L, Acuña-Ochoa, JG, Díaz-Gay, M, Muñoz, J, Cuatrecasas, M, Ocaña, T, Iseas, S, Mendez, G, Cisterna, D, Schubert, SA, Nielsen, M, van Wezel, T, Goldberg, Y, Pikarsky, E, Robbio, J, Roca, E, Castells, A, Balaguer, F, Antelo, M & Castellví-Bel, S 2020, 'Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome', JCI insight, vol. 5, no. 18, e140698. https://doi.org/10.1172/JCI.INSIGHT.140698

TY - JOUR

T1 - Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

AU - Golubicki, Mariano

AU - Bonjoch, Laia

AU - Acuña-Ochoa, José G.

AU - Díaz-Gay, Marcos

AU - Muñoz, Jenifer

AU - Cuatrecasas, Miriam

AU - Ocaña, Teresa

AU - Iseas, Soledad

AU - Mendez, Guillermo

AU - Cisterna, Daniel

AU - Schubert, Stephanie A.

AU - Nielsen, Maartje

AU - van Wezel, Tom

AU - Goldberg, Yael

AU - Pikarsky, Eli

AU - Robbio, Juan

AU - Roca, Enrique

AU - Castells, Antoni

AU - Balaguer, Francesc

AU - Antelo, Marina

AU - Castellví-Bel, Sergi

N1 - Funding Information: MG and MA were supported by Foundation Nelia et Amadeo Barletta contract. LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). JM was supported by a contract from CIBEREHD. MD-G was supported by a contract from Agència de Gestió d'Ajuts Universitaris i de Recerca -AGAUR(Generalitat de Catalunya, 2019FI_B2_00203). CIBEREHD is funded by the Instituto de Salud Carlos III. This research was supported by grants from Foundation Nelia et Amadeo Barletta FNAB and the Argentinian National Cancer Institute. This research was supported by grants from Fondo de Investigación Sanitaria/ FEDER (16/00766, 17/00878, 17/01304, 19/01867), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Program (Generalitat de Catalunya), and Agència de Gestió d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). This research was funded by a research grant from the Dutch Digestive Foundation (MLDS FP13-13), awarded to TVW. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology, https://www.cost.eu). We are sincerely grateful to the patients, Celia Badenas, Esteban Cvitkovic, CNAG, and the Biobank of Hospital Clínic-IDIBAPS. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona. Funding Information: MG and MA were supported by Foundation Nelia et Amadeo Barletta contract. LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). JM was supported by a contract from CIBEREHD. MD-G was supported by a contract from Agència de Gestió d’Ajuts Universitaris i de Recerca -AGAUR-(Generalitat de Catalunya, 2019FI_B2_00203). CIBEREHD is funded by the Instituto de Salud Carlos III. This research was supported by grants from Foundation Nelia et Amadeo Barletta FNAB and the Argentinian National Cancer Institute. This research was supported by grants from Fondo de Investigación Sanitaria/ FEDER (16/00766, 17/00878, 17/01304, 19/01867), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Program (Generalitat de Catalunya), and Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalun-ya, GRPRE 2017SGR21, GRC 2017SGR653). This research was funded by a research grant from the Dutch Digestive Foundation (MLDS FP13-13), awarded to TVW. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology, https://www.cost.eu). We are sincerely grateful to the patients, Celia Badenas, Esteban Cvitkovic, CNAG, and the Biobank of Hospital Clínic–IDIBAPS. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona. Publisher Copyright: Copyright: © 2020, Golubicki et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

PY - 2020/8

Y1 - 2020/8

N2 - Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/ Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.

AB - Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/ Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.

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DO - 10.1172/JCI.INSIGHT.140698

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VL - 5

JO - JCI insight

JF - JCI insight

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Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

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