Journal Article

DKFZ-2024-02733

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genetic drivers and cellular selection of female mosaic X chromosome loss.

Liu, A. ; Genovese, G. ; Zhao, Y. ; Pirinen, M. ; Zekavat, S. M. ; Kentistou, K. A. ; Yang, Z. ; Yu, K. ; Vlasschaert, C. ; Liu, X. ; Brown, D. W. ; Hudjashov, G. ; Gorman, B. R. ; Dennis, J. ; Zhou, W. ; Momozawa, Y. ; Pyarajan, S. ; Tuzov, V. ; Pajuste, F.-D. ; Aavikko, M. ; Sipilä, T. P. ; Ghazal, A. ; Huang, W.-Y. ; Freedman, N. D. ; Song, L. ; Gardner, E. J. ; FinnGen (Collaboration Author) ; Team, E. B. R. (Collaboration Author) ; Consortium, B. C. A. (Collaboration Author) ; Program, M. V. (Collaboration Author) ; Sankaran, V. G. ; Palotie, A. ; Ollila, H. M. ; Tukiainen, T. ; Chanock, S. J. ; Mägi, R. ; Natarajan, P. ; Daly, M. J. ; Bick, A. ; McCarroll, S. A. ; Terao, C. ; Loh, P.-R. ; Ganna, A. ; Perry, J. R. B. ; Machiela, M. J. ; Metspalu, A. (Contributor) ; Esko, T. (Contributor) ; Nelis, M. (Contributor) ; Milani, L. (Contributor) ; Ahearn, T. U. (Contributor) ; Andrulis, I. L. (Contributor) ; Anton-Culver, H. (Contributor) ; Antoniou, A. C. (Contributor) ; de Gonzalez, A. B. (Contributor) ; Bogdanova, N. V. (Contributor) ; Bojesen, S. E. (Contributor) ; Bolla, M. K. (Contributor) ; Brenner, H. (Contributor)DKFZ* ; Chang-Claude, J. (Contributor)DKFZ* ; Chenevix-Trench, G. (Contributor) ; Colonna, S. V. (Contributor) ; Couch, F. J. (Contributor) ; Cox, A. (Contributor) ; Czene, K. (Contributor) ; Daly, M. B. (Contributor) ; Devilee, P. (Contributor) ; Dörk, T. (Contributor) ; Dunning, A. M. (Contributor) ; Dwek, M. (Contributor) ; Easton, D. F. (Contributor) ; Eccles, D. M. (Contributor) ; Fasching, P. A. (Contributor) ; Fletcher, O. (Contributor) ; Gago-Dominguez, M. (Contributor) ; García-Closas, M. (Contributor) ; Goldberg, M. S. (Contributor) ; González-Neira, A. (Contributor) ; Guénel, P. (Contributor) ; Haiman, C. A. (Contributor) ; Hall, P. (Contributor) ; Hamann, U. (Contributor)DKFZ* ; Hollestelle, A. (Contributor) ; Hoppe, R. (Contributor) ; Hopper, J. L. (Contributor) ; Jakubowska, A. (Contributor) ; Jernström, H. (Contributor) ; John, E. M. (Contributor) ; Kaaks, R. (Contributor)DKFZ* ; Khusnutdinova, E. K. (Contributor) ; Kitahara, C. M. (Contributor) ; Kraft, P. (Contributor) ; Kristensen, V. N. (Contributor) ; Lambrechts, D. (Contributor) ; Lindblom, A. (Contributor) ; Mannermaa, A. (Contributor) ; Menon, U. (Contributor) ; Michailidou, K. (Contributor) ; Murphy, R. A. (Contributor) ; Nevanlinna, H. (Contributor) ; Obi, N. (Contributor) ; Offit, K. (Contributor) ; Peterlongo, P. (Contributor) ; Pharoah, P. D. P. (Contributor) ; Plaseska-Karanfilska, D. (Contributor) ; Rennert, G. (Contributor) ; Romero, A. (Contributor) ; Saloustros, E. (Contributor) ; Schmidt, M. K. (Contributor) ; Schmutzler, R. K. (Contributor) ; Stone, J. (Contributor) ; Tamimi, R. M. (Contributor) ; Teras, L. R. (Contributor) ; Terry, M. B. (Contributor) ; Troester, M. A. (Contributor) ; Vachon, C. M. (Contributor) ; Wang, Q. (Contributor) ; Weinberg, C. R. (Contributor) ; Winqvist, R. (Contributor) ; Wolk, A. (Contributor)

2024
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41586-024-07533-7

Abstract: Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

Keyword(s): Adult (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Alleles (MeSH) ; Aneuploidy (MeSH) ; Autoimmune Diseases: genetics (MeSH) ; Biological Specimen Banks (MeSH) ; Chromosome Segregation: genetics (MeSH) ; Chromosomes, Human, X: genetics (MeSH) ; Chromosomes, Human, Y: genetics (MeSH) ; Clone Cells: metabolism (MeSH) ; Clone Cells: pathology (MeSH) ; Exome: genetics (MeSH) ; F-Box Proteins: genetics (MeSH) ; Genetic Predisposition to Disease: genetics (MeSH) ; Germ-Line Mutation (MeSH) ; Leukemia: genetics (MeSH) ; Leukocytes: metabolism (MeSH) ; Models, Genetic (MeSH) ; Mosaicism (MeSH) ; Multifactorial Inheritance: genetics (MeSH) ; Mutation, Missense: genetics (MeSH) ; F-Box Proteins ; FBXO10 protein, human

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)
2. Präventive Onkologie (C120)
3. DKTK HD zentral (HD01)
4. C020 Epidemiologie von Krebs (C020)
5. Molekulargenetik des Mammakarzinoms (B072)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2024

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