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Biallelic loss-of-function mutations in MAD1 result in systemic inflammation, clonal selection of aneuploid cells and high tumor susceptibility

ABSTRACT: Aneuploidy is a frequent feature of tumor cells. Yet, germline mutations leading to chromosomal instability are less frequent and are typically found in patients with mosaic variegated aneuploidy (MVA). We describe here novel germline biallelic loss-of-function mutations in MAD1L1, a gene that encodes the Spindle Assembly Checkpoint (SAC) protein MAD1, in a 36-year-old female with microcephaly and developmental delay. The patient developed a constelation of benign and malignant neoplasias derived from the three embryonic layers, some of them such as pilomatrixoma, bone tumors enchondromas and multinodular goiter rarely described in MVA. Cytogenetic and single-cell DNA analysis of peripheral blood cells detected ~35% of aneuploid cells with a variety of random gains of chromosomes. Functional studies demonstrated deficient SAC responses in the absence of MAD1 in mutant lymphocytes. Transcriptomic studies of peripheral blood cells at the single cell level suggested inhibition of protein synthesis, and increased antigen presentation and cytokine signaling in aneuploid T-cells. These pathways were also deregulated in euploid cells from the patient suggesting an immflamation-like, systemic response to chromosomal instability. In addition, single cell RNA-seq analysis detected clonal expansions affecting chromosomes 12 and 18 in specific B-cell and T-cell populations without evidence of hematopoietic neoplasias. These data point to MAD1L1 as a new gene mutated in MVA, and suggest that clonal expansion of minor aneuploid cell populations can be detected in pro-tumoral stages using single-cell technologies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197267 | GEO | 2022/11/03

REPOSITORIES: GEO

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Project description:Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated and natural aneuploid yeasts triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few, if any, fitness costs in nature. To address these discrepant findings, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples and applied it to natural isolates collected as part of the 1011 genomes project (Peter, J. et al, 2018). For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.

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Biallelic loss-of-function mutations in MAD1 result in systemic inflammation, clonal selection of aneuploid cells and high tumor susceptibility

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