Clinical syndromes linked to biallelic germline variants inMCM8andMCM9
Authors: Helderman Noah C. , Yang Ting , Palles Claire , Terlouw Diantha , Mei Hailiang , Vorderman Ruben H.P. , Cats Davy , Gay Marcos Díaz , Jongmans Marjolijn C.J. , Ramdien Ashwin ,   MCM8-MCM9 study group, Golubicki Mariano , Antelo Marina , Bonjoch Laia , Terradas Mariona , Valle Laura , Alexandrov Ludmil B. , Morreau Hans , van Wezel Tom , Castellví-Bel Sergi , Goldberg Yael , Nielsen Maartje , van de Beek Irma , Eleveld Thomas F. , Green Andrew , Hes Frederik J. , van den Heuvel-Eibrink Marry M. , Van Der Kelen Annelore , Kliesch Sabine , Kuiper Roland P. , Lakeman Inge M.M. , Lashley Lisa E.E.L.O. , Looijenga Leendert H.J. , Oud Manon S. , Steingröver Johanna , Tenenbaum-Rakover Yardena , Tops Carli M. , Tüttelmann Frank , de Voer Richarda M. , Westra Dineke , Wyrwoll Margot J. 
Published: November 2024

AbstractBackgroundMCM8andMCM9are newly proposed cancer predisposition genes, linked to polyposis and early-onset cancer, in addition to their 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 individuals with biallelic germlineMCM8/MCM9variants.MethodsPopulation allele frequencies and biallelic variant carrier frequencies were calculated using data from gnomAD, and a variant enrichment analysis was conducted across multiple cancer and non-cancer phenotypes using data from the 100K Genomes Project and the 200K exome release of the UK Biobank. A case series was conducted, including previously reported variant carriers with and without updated clinical data and newly identified carriers through the European Reference Network (ERN) initiative for rare genetic tumor risk syndromes (GENTURIS). Additionally, mutational signature analysis was performed on tumor data from our case series and publicly available datasets from the Hartwig Medical Foundation and TCGA Pan-Cancer Atlas to identify mutational signatures potentially associated with MCM8/MCM9 deficiency.ResultsPredicted loss of function and missense variants inMCM8(1.4 per 100,000 individuals) andMCM9(2.5 per 100,000 individuals) were found to be rare in gnomAD. However, biallelicMCM9variants showed significant enrichment in cases from the 100K Genomes Project compared to controls for 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). No significant enrichment was found for biallelicMCM8variant carriers or in the 200K UK Biobank. In our case series, which included 26 biallelicMCM8and 28 biallelicMCM9variant carriers, we documented polyposis, gastric cancer, and early-onset colorectal cancer in 6, 1, and 6 biallelicMCM9variant carriers, respectively, while these phenotypes were not observed in biallelicMCM8variant carriers. Additionally, our case series indicates that, beyond hypogonadism—which was present in 23 and 26 of the carriers, respectively—biallelicMCM8andMCM9variants are associated with early-onset germ cell tumors (occurring before age 15) in 2MCM8and 1MCM9variant carriers. Tumors fromMCM8/MCM9variant carriers with available germline sequencing data predominantly displayed clock-like mutational processes (single base substitution signatures 1 and 5), with no evidence of signatures associated with DNA repair deficiencies.DiscussionOur data indicates that biallelicMCM9variants are associated with polyposis, gastric cancer, and early-onset CRC, while both biallelicMCM8andMCM9variants are linked to hypogonadism and the early development of germ cell tumors. These findings underscore the importance of includingMCM8/MCM9in diagnostic gene panels for certain clinical contexts and suggest that biallelic carriers may benefit from cancer surveillance.