Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9

Background: MCM8 and MCM9 are 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 germline MCM8 / MCM9 variants. Methods: Population 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. Results: Predicted loss of function and missense variants in MCM8 (1.4 per 100,000 individuals) and MCM9 (2.5 per 100,000 individuals) were found to be rare in gnomAD. However, biallelic MCM9 variants 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 biallelic MCM8 variant carriers or in the 200K UK Biobank. In our case series, which included 26 biallelic MCM8 and 28 biallelic MCM9 variant carriers, we documented polyposis, gastric cancer, and early–onset colorectal cancer in 6, 1, and 6 biallelic MCM9 variant carriers, respectively, while these phenotypes were not observed in biallelic MCM8 variant carriers. Additionally, our case series indicates that, beyond hypogonadism—which was present in 23 and 26 of the carriers, respectively—biallelic MCM8 and MCM9 variants are associated with early–onset germ cell tumors (occurring before age 15) in 2 MCM8 and 1 MCM9 variant carriers. Tumors from MCM8 / MCM9 variant 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. Discussion: Our data indicates 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.