Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9
Summary: MCM8 and MCM9 are newly proposed cancer predisposition genes, linked to polyposis and early-onset cancer, in addition to their previously established association with hypogonadism. Given the uncertain range of phenotypic manifestations and unclear cancer risk estimates, this study aimed to...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-10-01
|
| Series: | HGG Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247725000831 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849239578930577408 |
|---|---|
| author | Noah C. Helderman Ting Yang Claire Palles Diantha Terlouw Hailiang Mei Ruben H.P. Vorderman Davy Cats Marcos Díaz-Gay Marjolijn C.J. Jongmans Ashwin Ramdien Irma van de Beek Thomas F. Eleveld Andrew Green Frederik J. Hes Marry M. van den Heuvel-Eibrink Annelore Van Der Kelen Sabine Kliesch Roland P. Kuiper Inge M.M. Lakeman Lisa E.E.L.O. Lashley Leendert H.J. Looijenga Manon S. Oud Johanna Steingröver Yardena Tenenbaum-Rakover Carli M. Tops Frank Tüttelmann Richarda M. de Voer Dineke Westra Margot J. Wyrwoll Mariano Golubicki Marina Antelo Laia Bonjoch Mariona Terradas Laura Valle Ludmil B. Alexandrov Hans Morreau Tom van Wezel Sergi Castellví-Bel Yael Goldberg Maartje Nielsen |
| author_facet | Noah C. Helderman Ting Yang Claire Palles Diantha Terlouw Hailiang Mei Ruben H.P. Vorderman Davy Cats Marcos Díaz-Gay Marjolijn C.J. Jongmans Ashwin Ramdien Irma van de Beek Thomas F. Eleveld Andrew Green Frederik J. Hes Marry M. van den Heuvel-Eibrink Annelore Van Der Kelen Sabine Kliesch Roland P. Kuiper Inge M.M. Lakeman Lisa E.E.L.O. Lashley Leendert H.J. Looijenga Manon S. Oud Johanna Steingröver Yardena Tenenbaum-Rakover Carli M. Tops Frank Tüttelmann Richarda M. de Voer Dineke Westra Margot J. Wyrwoll Mariano Golubicki Marina Antelo Laia Bonjoch Mariona Terradas Laura Valle Ludmil B. Alexandrov Hans Morreau Tom van Wezel Sergi Castellví-Bel Yael Goldberg Maartje Nielsen |
| author_sort | Noah C. Helderman |
| collection | DOAJ |
| description | Summary: MCM8 and MCM9 are newly proposed cancer predisposition genes, linked to polyposis and early-onset cancer, in addition to their previously established association with hypogonadism. Given the uncertain range of phenotypic manifestations and unclear cancer risk estimates, this study aimed to delineate the molecular and clinical characteristics of biallelic germline MCM8/MCM9 variant carriers. We found significant enrichment of biallelic MCM9 variants in individuals with colonic polyps (odds ratio [OR] 6.51, 95% confidence interval [CI] 1.24–34.11, p = 0.03), rectal polyps (OR 8.40, 95% CI 1.28–55.35, p = 0.03), and gastric cancer (OR 27.03, 95% CI 2.93–248.5; p = 0.004) in data from the 100000 Genomes Project, compared to controls. No similar enrichment was found for biallelic MCM8 variants or in the 200000 UK Biobank. Likewise, in our case series, which included 26 MCM8 and 28 MCM9 variant carriers, we documented polyposis, gastric cancer, and early-onset colorectal cancer (CRC) in MCM9 carriers but not in MCM8 carriers. Moreover, our case series indicates that beyond hypogonadism, biallelic MCM8 and MCM9 variants are associated with early-onset germ cell tumors (occurring before age 15). Tumors from MCM8/MCM9 variant carriers predominantly displayed clock-like mutational processes, without evidence of DNA repair deficiency-associated signatures. Collectively, our data indicate that biallelic MCM9 variants are associated with polyposis, gastric cancer, and early-onset CRC, while both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the early development of germ cell tumors. These findings underscore the importance of including MCM8/MCM9 in diagnostic gene panels for certain clinical contexts and suggest that biallelic carriers may benefit from cancer surveillance. |
| format | Article |
| id | doaj-art-3d2ca6dd8e7b422cba827f54cd193015 |
| institution | Kabale University |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj-art-3d2ca6dd8e7b422cba827f54cd1930152025-08-20T04:00:55ZengElsevierHGG Advances2666-24772025-10-016410048010.1016/j.xhgg.2025.100480Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9Noah C. Helderman0Ting Yang1Claire Palles2Diantha Terlouw3Hailiang Mei4Ruben H.P. Vorderman5Davy Cats6Marcos Díaz-Gay7Marjolijn C.J. Jongmans8Ashwin Ramdien9Irma van de Beek10Thomas F. Eleveld11Andrew Green12Frederik J. Hes13Marry M. van den Heuvel-Eibrink14Annelore Van Der Kelen15Sabine Kliesch16Roland P. Kuiper17Inge M.M. Lakeman18Lisa E.E.L.O. Lashley19Leendert H.J. Looijenga20Manon S. Oud21Johanna Steingröver22Yardena Tenenbaum-Rakover23Carli M. Tops24Frank Tüttelmann25Richarda M. de Voer26Dineke Westra27Margot J. Wyrwoll28Mariano Golubicki29Marina Antelo30Laia Bonjoch31Mariona Terradas32Laura Valle33Ludmil B. Alexandrov34Hans Morreau35Tom van Wezel36Sergi Castellví-Bel37Yael Goldberg38Maartje Nielsen39Department of Clinical Genetics, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USAInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UKDepartment of Pathology, Leiden University Medical Center, Leiden, the NetherlandsSequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the NetherlandsSequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the NetherlandsSequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA; Digital Genomics Group, Structural Biology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, SpainPrincess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, the NetherlandsDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Clinical Genetics, The Netherlands Cancer Institute, Amsterdam, the NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, the NetherlandsDepartment of Clinical Genetics, Children’s Health Ireland (CHI) at Crumlin, Dublin, IrelandVrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Clinical Sciences, Research Group Genetics, Reproduction, and Development, Centre for Medical Genetics, Brussels, BelgiumPrincess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands; Division of Childhealth, University Medical Center Utrecht, Utrecht, the NetherlandsVrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Clinical Sciences, Research Group Genetics, Reproduction, and Development, Centre for Medical Genetics, Brussels, BelgiumCentre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster, GermanyPrincess Maxima Center for Pediatric Oncology, Utrecht, the NetherlandsDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Obstetrics and Gynecology, Leiden University Medical Center, Leiden, the NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, the NetherlandsDepartment of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the NetherlandsCentre of Medical Genetics, Institute of Reproductive Genetics, University and University Hospital of Münster, Münster, GermanyPediatric Endocrinology, Clalit Health Services, Afula, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, IsraelDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, the NetherlandsCentre of Medical Genetics, Institute of Reproductive Genetics, University and University Hospital of Münster, Münster, GermanyDepartment of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the NetherlandsDepartment of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the NetherlandsCentre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UKOncology Section and Molecular Biology Laboratory, Hospital of Gastroenterology “Dr. C.B. Udaondo”, Buenos Aires, ArgentinaOncology Section and Molecular Biology Laboratory, Hospital of Gastroenterology “Dr. C.B. Udaondo”, Buenos Aires, ArgentinaGastroenterology, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Clínic Barcelona, Barcelona, SpainHereditary Cancer Program, Catalan Institute of Oncology, Oncobell Program, IDIBELL, CIBERONC, Hospitalet de Llobregat, Barcelona, SpainHereditary Cancer Program, Catalan Institute of Oncology, Oncobell Program, IDIBELL, CIBERONC, Hospitalet de Llobregat, Barcelona, SpainDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USADepartment of Pathology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Pathology, Leiden University Medical Center, Leiden, the NetherlandsGastroenterology, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Clínic Barcelona, Barcelona, SpainRaphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petah Tikva, IsraelDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands; Corresponding authorSummary: MCM8 and MCM9 are newly proposed cancer predisposition genes, linked to polyposis and early-onset cancer, in addition to their previously established association with hypogonadism. Given the uncertain range of phenotypic manifestations and unclear cancer risk estimates, this study aimed to delineate the molecular and clinical characteristics of biallelic germline MCM8/MCM9 variant carriers. We found significant enrichment of biallelic MCM9 variants in individuals with colonic polyps (odds ratio [OR] 6.51, 95% confidence interval [CI] 1.24–34.11, p = 0.03), rectal polyps (OR 8.40, 95% CI 1.28–55.35, p = 0.03), and gastric cancer (OR 27.03, 95% CI 2.93–248.5; p = 0.004) in data from the 100000 Genomes Project, compared to controls. No similar enrichment was found for biallelic MCM8 variants or in the 200000 UK Biobank. Likewise, in our case series, which included 26 MCM8 and 28 MCM9 variant carriers, we documented polyposis, gastric cancer, and early-onset colorectal cancer (CRC) in MCM9 carriers but not in MCM8 carriers. Moreover, our case series indicates that beyond hypogonadism, biallelic MCM8 and MCM9 variants are associated with early-onset germ cell tumors (occurring before age 15). Tumors from MCM8/MCM9 variant carriers predominantly displayed clock-like mutational processes, without evidence of DNA repair deficiency-associated signatures. Collectively, our data indicate that biallelic MCM9 variants are associated with polyposis, gastric cancer, and early-onset CRC, while both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the early development of germ cell tumors. These findings underscore the importance of including MCM8/MCM9 in diagnostic gene panels for certain clinical contexts and suggest that biallelic carriers may benefit from cancer surveillance.http://www.sciencedirect.com/science/article/pii/S2666247725000831MCM8MCM9Polyposisadenomatous polypsinheritable tumor syndromeearly-onset colorectal cancer |
| spellingShingle | Noah C. Helderman Ting Yang Claire Palles Diantha Terlouw Hailiang Mei Ruben H.P. Vorderman Davy Cats Marcos Díaz-Gay Marjolijn C.J. Jongmans Ashwin Ramdien Irma van de Beek Thomas F. Eleveld Andrew Green Frederik J. Hes Marry M. van den Heuvel-Eibrink Annelore Van Der Kelen Sabine Kliesch Roland P. Kuiper Inge M.M. Lakeman Lisa E.E.L.O. Lashley Leendert H.J. Looijenga Manon S. Oud Johanna Steingröver Yardena Tenenbaum-Rakover Carli M. Tops Frank Tüttelmann Richarda M. de Voer Dineke Westra Margot J. Wyrwoll Mariano Golubicki Marina Antelo Laia Bonjoch Mariona Terradas Laura Valle Ludmil B. Alexandrov Hans Morreau Tom van Wezel Sergi Castellví-Bel Yael Goldberg Maartje Nielsen Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9 HGG Advances MCM8 MCM9 Polyposis adenomatous polyps inheritable tumor syndrome early-onset colorectal cancer |
| title | Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9 |
| title_full | Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9 |
| title_fullStr | Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9 |
| title_full_unstemmed | Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9 |
| title_short | Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9 |
| title_sort | clinical syndromes linked to biallelic germline variants in mcm8 and mcm9 |
| topic | MCM8 MCM9 Polyposis adenomatous polyps inheritable tumor syndrome early-onset colorectal cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2666247725000831 |
| work_keys_str_mv | AT noahchelderman clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT tingyang clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT clairepalles clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT dianthaterlouw clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT hailiangmei clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT rubenhpvorderman clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT davycats clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT marcosdiazgay clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT marjolijncjjongmans clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT ashwinramdien clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT irmavandebeek clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT thomasfeleveld clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT andrewgreen clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT frederikjhes clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT marrymvandenheuveleibrink clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT annelorevanderkelen clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT sabinekliesch clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT rolandpkuiper clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT ingemmlakeman clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT lisaeelolashley clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT leenderthjlooijenga clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT manonsoud clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT johannasteingrover clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT yardenatenenbaumrakover clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT carlimtops clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT franktuttelmann clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT richardamdevoer clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT dinekewestra clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT margotjwyrwoll clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT marianogolubicki clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT marinaantelo clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT laiabonjoch clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT marionaterradas clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT lauravalle clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT ludmilbalexandrov clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT hansmorreau clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT tomvanwezel clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT sergicastellvibel clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT yaelgoldberg clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 AT maartjenielsen clinicalsyndromeslinkedtobiallelicgermlinevariantsinmcm8andmcm9 |