Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9

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...

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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-10-01
Series:HGG Advances
Subjects:
MCM8
MCM9
Polyposis
adenomatous polyps
inheritable tumor syndrome
early-onset colorectal cancer
Online Access:http://www.sciencedirect.com/science/article/pii/S2666247725000831
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Summary: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.
ISSN:2666-2477

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