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.

Figure 1

Flowchart of study approach Pathogenicity-based filtering of (A) population-based cohorts, (B) our case series and cancer-specific cohorts, and (C) TCGA Pan-Cancer atlas dataset. ^afCRCX cohort comprised 24 CRC-affected members of 16 Amsterdam-positive non-polyposis CRC families; ^bSPS cohort comprised 44 unrelated serrated polyposis families; ^cHMF cohort comprised 632 metastasized CRCs and 25 metastasized ECs. Tumors from TCGA Pan-Cancer Atlas were selected based on the presence of somatic MCM8/MCM9 variants and are not related to germline variant carriers. ACMG/AMP, American College of Medical Genetics and Genomics; AF, allele frequency; CADD, Combined Annotation-Dependent Depletion; CRC, colorectal cancer; EC, endometrial cancer; pLoF, predicted loss of function; VUS, variant of uncertain significance.

Figure 2

Phenotype of biallelic MCM8/MCM9 variant carriers The phenotype is presented for all (A) biallelic MCM8 and (B) biallelic MCM9 variant carriers from our case series. Each column represents an individual, while each row corresponds to one of the four primary observed phenotypes: CRC, other type(s) of cancer, hypogonadism, and polyposis. Person IDs are provided below each column, whereas their corresponding ages, which represent the most recent reported age of each individual, are shown above every column (when available). B, breast cancer; Cx, cervical cancer; GCT, germ cell tumor; M, melanoma; St, stomach cancer.

Figure 3

Disease onset in biallelic MCM8/MCM9 variant carriers The onset of the four primary observed phenotypes (CRC, other type[s] of cancer, hypogonadism, and polyposis) is displayed for each biallelic MCM8/MCM9 variant carrier with available age details in our case series. Those without age details were excluded from the analysis. Individuals are ordered by ACMG/AMP classification (pathogenic or likely pathogenic, VUS)^, and current age or age at the time of death/lost to follow-up.

Figure 4

Biallelic MCM8/MCM9 variants mapped onto the respective protein domains (A) MCM8 and (B) MCM9 variants from all biallelic variant carriers in our case series are mapped onto the domains of the MCM8 and MCM9 proteins, respectively. Each homozygote variant carrier corresponds to one diamond symbol, whereas for compound heterozygous variant carriers, both variants are separately plotted. The fill and color of the diamond symbols correspond to the phenotype of the individual (CRC, other type[s] of cancer, hypogonadism, polyposis) and the ACMG/AMP classification of the variant (pathogenic or likely pathogenic, VUS),^, respectively. N-C, N-C linker domain; RF, arginine finger; VUS, variant of uncertain significance; WA, Walker A; WB, Walker B; WH, winged-helix; ZF, zinc finger.

Figure 5

Mutational landscape of tumors from MCM8/MCM9 variant carriers from our case series (A) Sample overview of the tumors that were available from our case series for mutational signature analysis, including the corresponding genotype, next-generation sequencing (NGS) approach, the availability of normal control tissue, and the tumor type. Control tissue originated from an individual who tested negative for germline MCM8/MCM9 variants. TMB was defined as the number of somatic mutations per megabase. For WGS samples, only somatic mutations located within coding exonic regions were included in the TMB calculation, unlike in the mutational signature analyses, where all somatic mutations were considered. Of note, TMB values derived from WGS samples were lower than those from WES samples. This difference may reflect factors such as WGS sample contamination leading to the exclusion of true variants by variant callers, differences in sequencing depth and coverage, or underlying biological differences between the samples. (B) Oncoplot visualizing the detected driver mutations for every tumor. (C) The number of mutations in each signature is presented for every tumor. Mutational signature assignment was performed using SigProfilerAssignment (version 0.0.32) based on the COSMIC version 3.3 single-base substitution (SBS) and insertion and deletion (ID) reference signatures. SBS1 and SBS5 were classified as clock-like mutational signatures. SBS3 and ID6 were considered to be caused by defective homologous repair (HR). SBS26, ID1, and ID2 were linked to defective MMR, and SBS30 and SBS36 were associated with defective base excision repair (BER). SBS88 was attributed to colibactin exposure, and SBS92 and ID3 were attributed to tobacco smoking. SBS37, SBS40, SBS94, ID4, ID5, ID9, ID10, ID11, ID14, ID15, and ID16 were considered to be of unknown etiology, while SBS40, SBS45, SBS50, SBS51, SBS54, SBS56, SBS58, and SBS95 were considered possible sequencing artifacts. ID, insertion and deletion; MMR, mismatch repair; TMB, tumor mutational burden; WES, whole-exome sequencing; WGS, whole-genome sequencing.