Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9

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

doi:10.1016/j.xhgg.2025.100480

Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9

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^*

^*Corresponding author for this work

CCA - Cancer biology and immunology

Leiden University
University of California at San Diego
University of Birmingham
Spanish National Cancer Research Centre (CNIO), Structural Biology and Biocomputing Programme
Princess Máxima Center for Pediatric Oncology
Utrecht University
Netherlands Cancer Institute
Children’s Health Ireland
Vrije Universiteit Brussel
University of Münster
Radboud University Nijmegen
Technion-Israel Institute of Technology
University of Edinburgh
Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo
University of Barcelona
L'Hospitalet de Llobregat
Rabin Medical Center Israel

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

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Abstract

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.

Original language	English
Article number	100480
Journal	Human Genetics and Genomics Advances
Volume	6
Issue number	4
DOIs	https://doi.org/10.1016/j.xhgg.2025.100480
Publication status	Published - 9 Oct 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

MCM8
MCM9
Polyposis
adenomatous polyps
early-onset colorectal cancer
gastric cancer
hypogonadism
infertility
inheritable tumor syndrome
primary ovarian insufficiency

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Helderman, N. C., Yang, T., Palles, C., Terlouw, D., Mei, H., Vorderman, R. H. P., Cats, D., Díaz-Gay, M., Jongmans, M. C. J., Ramdien, A., van de Beek, I., Eleveld, T. F., Green, A., Hes, F. J., van den Heuvel-Eibrink, M. M., van der Kelen, A., Kliesch, S., Kuiper, R. P., Lakeman, I. M. M., ... Nielsen, M. (2025). Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9. Human Genetics and Genomics Advances, 6(4), Article 100480. https://doi.org/10.1016/j.xhgg.2025.100480

@article{3c8ab1fd376a411a98d7d0f0ac380774,

title = "Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9",

abstract = "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.",

keywords = "MCM8, MCM9, Polyposis, adenomatous polyps, early-onset colorectal cancer, gastric cancer, hypogonadism, infertility, inheritable tumor syndrome, primary ovarian insufficiency",

author = "Helderman, \{Noah C.\} and Ting Yang and Claire Palles and Diantha Terlouw and Hailiang Mei and Vorderman, \{Ruben H. P.\} and Davy Cats and Marcos D{\'i}az-Gay and Jongmans, \{Marjolijn C. J.\} and Ashwin Ramdien and \{van de Beek\}, Irma and Eleveld, \{Thomas F.\} and Andrew Green and Hes, \{Frederik J.\} and \{van den Heuvel-Eibrink\}, \{Marry M.\} and \{van der Kelen\}, Annelore and Sabine Kliesch and Kuiper, \{Roland P.\} and Lakeman, \{Inge M. M.\} and Lashley, \{Lisa E. E. L. O.\} and Looijenga, \{Leendert H. J.\} and Oud, \{Manon S.\} and Johanna Steingr{\"o}ver and Yardena Tenenbaum-Rakover and Tops, \{Carli M.\} and Frank t{\"u}ttelmann and \{de Voer\}, \{Richarda M.\} and Dineke Westra and Wyrwoll, \{Margot J.\} and Mariano Golubicki and Marina Antelo and Laia Bonjoch and Mariona Terradas and Laura Valle and Alexandrov, \{Ludmil B.\} and Hans Morreau and \{van Wezel\}, Tom and Sergi Castellv{\'i}-Bel and Yael Goldberg and Maartje Nielsen",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = oct,

day = "9",

doi = "10.1016/j.xhgg.2025.100480",

language = "English",

volume = "6",

journal = "Human Genetics and Genomics Advances",

issn = "2666-2477",

publisher = "Cell Press",

number = "4",

}

Helderman, NC, Yang, T, Palles, C, Terlouw, D, Mei, H, Vorderman, RHP, Cats, D, Díaz-Gay, M, Jongmans, MCJ, Ramdien, A, van de Beek, I, Eleveld, TF, Green, A, Hes, FJ, van den Heuvel-Eibrink, MM, van der Kelen, A, Kliesch, S, Kuiper, RP, Lakeman, IMM, Lashley, LEELO, Looijenga, LHJ, Oud, MS, Steingröver, J, Tenenbaum-Rakover, Y, Tops, CM, tüttelmann, F, de Voer, RM, Westra, D, Wyrwoll, MJ, Golubicki, M, Antelo, M, Bonjoch, L, Terradas, M, Valle, L, Alexandrov, LB, Morreau, H, van Wezel, T, Castellví-Bel, S, Goldberg, Y & Nielsen, M 2025, 'Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9', Human Genetics and Genomics Advances, vol. 6, no. 4, 100480. https://doi.org/10.1016/j.xhgg.2025.100480

TY - JOUR

T1 - Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9

AU - Helderman, Noah C.

AU - Yang, Ting

AU - Palles, Claire

AU - Terlouw, Diantha

AU - Mei, Hailiang

AU - Vorderman, Ruben H. P.

AU - Cats, Davy

AU - Díaz-Gay, Marcos

AU - Jongmans, Marjolijn C. J.

AU - Ramdien, Ashwin

AU - van de Beek, Irma

AU - Eleveld, Thomas F.

AU - Green, Andrew

AU - Hes, Frederik J.

AU - van den Heuvel-Eibrink, Marry M.

AU - van der Kelen, Annelore

AU - Kliesch, Sabine

AU - Kuiper, Roland P.

AU - Lakeman, Inge M. M.

AU - Lashley, Lisa E. E. L. O.

AU - Looijenga, Leendert H. J.

AU - Oud, Manon S.

AU - Steingröver, Johanna

AU - Tenenbaum-Rakover, Yardena

AU - Tops, Carli M.

AU - tüttelmann, Frank

AU - de Voer, Richarda M.

AU - Westra, Dineke

AU - Wyrwoll, Margot J.

AU - Golubicki, Mariano

AU - Antelo, Marina

AU - Bonjoch, Laia

AU - Terradas, Mariona

AU - Valle, Laura

AU - Alexandrov, Ludmil B.

AU - Morreau, Hans

AU - van Wezel, Tom

AU - Castellví-Bel, Sergi

AU - Goldberg, Yael

AU - Nielsen, Maartje

PY - 2025/10/9

Y1 - 2025/10/9

N2 - 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.

AB - 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.

KW - MCM8

KW - MCM9

KW - Polyposis

KW - adenomatous polyps

KW - early-onset colorectal cancer

KW - gastric cancer

KW - hypogonadism

KW - infertility

KW - inheritable tumor syndrome

KW - primary ovarian insufficiency

UR - https://www.scopus.com/pages/publications/105012831663

U2 - 10.1016/j.xhgg.2025.100480

DO - 10.1016/j.xhgg.2025.100480

M3 - Article

C2 - 40684266

SN - 2666-2477

VL - 6

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

IS - 4

M1 - 100480

ER -

Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9

Abstract

UN SDGs

Keywords

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