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Mosaic variegated aneuploidy in development, ageing and cancer

Nature Reviews Genetics (2024)Cite this article

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Abstract

Mosaic variegated aneuploidy (MVA) is a rare condition in which abnormal chromosome counts (that is, aneuploidies), affecting different chromosomes in each cell (making it variegated) are found only in a certain number of cells (making it mosaic). MVA is characterized by various developmental defects and, despite its rarity, presents a unique clinical scenario to understand the consequences of chromosomal instability and copy number variation in humans. Research from patients with MVA, genetically engineered mouse models and functional cellular studies have found the genetic causes to be mutations in components of the spindle-assembly checkpoint as well as in related proteins involved in centrosome dynamics during mitosis. MVA is accompanied by tumour susceptibility (depending on the genetic basis) as well as cellular and systemic stress, including chronic immune response and the associated clinical implications.

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Fig. 1: Developmental origin of human aneuploidy syndromes.
Fig. 2: Clinical symptoms of MVA.
Fig. 3: The SAC.

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Acknowledgements

We thank Adrià López Fernández and Judith Balmaña (VHIO) and Ana Losada (CNIO, Madrid) for helpful discussions and comments on the manuscript. C.V.-B. received salary support from Amigos del CNIO, Madrid, and the Ramon y Cajal programme from the Ministerio de Ciencia y Universidades (MICIU)-Agencia Estatal de Investigación (AEI) (RYC2022-035259-I). The M.M. laboratory is supported by research grants from MICIU-AEI/FEDER (PID2021-128726, PDC2022-133408-I00 and RED2022-134792-T), Comunidad de Madrid (Y2020/BIO-6519 and S2022/BMD-7437), Asociación Española Contra el Cáncer (AECC) and the José Baselga Innovative Disruption programme from AstraZeneca. VHIO (CEX2020-001024-S/AEI/10.13039/501100011033) and CNIO (CEX2019-000891-S) are Centers of Excellence Severo Ochoa (MICIU-AEI).

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Authors and Affiliations

  1. Cancer Cell Cycle Group, Systems Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Marcos Malumbres

  2. Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO) Madrid, Madrid, Spain

    Marcos Malumbres & Carolina Villarroya-Beltri

  3. Catalan Institution for Research and Advanced Studies (ICREA) Barcelona, Barcelona, Spain

    Marcos Malumbres

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  1. Marcos Malumbres
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Both authors contributed equally to all aspects of the manuscript.

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Related links

cBioPortal: https://www.cbioportal.org/

COSMIC: https://cancer.sanger.ac.uk/cosmic

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Mitelman Database: https://mitelmandatabase.isb-cgc.org/

OMIM: https://www.omim.org/

Glossary

Autosomal recessive

A mode of inheritance in which the symptoms of the disease only manifest in individuals with syndrome-causing mutations in both alleles of the gene (one inherited from the mother and the other from the father).

Cell-cycle checkpoints

A signalling pathway ensuring that the cell has properly terminated the previous cell-cycle phase before transitioning to the next phase.

Chromosomal instability

(CIN). The acquired elevated chance of unequal distribution of genomic content between two daughter cells and is thus a ‘cellular phenotype’. The level of CIN refers to the frequency and severity of these errors over successive cell-division cycles.

Genome instability

An increased tendency to acquire alterations in the genome, ranging from single nucleotide modifications to structural or numerical alterations of whole chromosomes.

Hypomorphic

A type of mutation that causes only partial loss of function of the protein encoded.

Lordokyphosis

A condition characterized by a combination of lordosis and kyphosis, where the spine exhibits abnormal curvature both inward (lordosis) and outward (kyphosis) simultaneously.

Mitotic checkpoint complex

(MCC). The network of proteins responsible for inhibiting the ubiquitin ligase activity of the anaphase-promoting complex/cyclosome in the spindle-assembly checkpoint. It maintains cells in prometaphase until all chromosomes are properly attached to the mitotic spindle.

Monosomy

A form of aneuploidy in which only one chromosome from a pair of homologous chromosomes is present.

Tetraploidy

The condition of having four, instead of two, complete sets of chromosomes.

Trisomy

A form of aneuploidy in which homologous chromosomes are represented by three copies instead of two.

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Malumbres, M., Villarroya-Beltri, C. Mosaic variegated aneuploidy in development, ageing and cancer. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00762-6

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