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Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer

Kayhanian, Hamzeh (author)
University College London (UCL)
Cross, William (author)
University of Westminster,University College London (UCL)
van der Horst, Suzanne E.M. (author)
University Medical Center Utrecht
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Barmpoutis, Panagiotis (author)
University College London (UCL)
Lakatos, Eszter, 1990 (author)
Chalmers tekniska högskola,Chalmers University of Technology
Caravagna, Giulio (author)
Universita degli Studi di Trieste,University of Trieste
Zapata, Luis (author)
Van Hoeck, Arne (author)
University Medical Center Utrecht
Middelkamp, Sjors (author)
Litchfield, Kevin (author)
University College London (UCL)
Steele, Christopher (author)
University College London (UCL)
Waddingham, William (author)
University College London (UCL)
Patel, Dominic (author)
University College London (UCL)
Milite, Salvatore (author)
Universita degli Studi di Trieste,University of Trieste
Jin, Chen (author)
University College London (UCL)
Baker, Ann Marie (author)
Alexander, D. C. (author)
University College London (UCL)
Khan, Khurum (author)
University College London (UCL)
Hochhauser, Daniel (author)
University College London (UCL)
Novelli, Marco (author)
University College London (UCL)
Werner, Benjamin (author)
van Boxtel, Ruben (author)
University Medical Center Utrecht
Hageman, Joris H. (author)
University Medical Center Utrecht
Buissant des Amorie, Julian R. (author)
University Medical Center Utrecht
Linares, Josep (author)
Ligtenberg, Marjolijn J.L. (author)
Radboud Universiteit,Radboud University
Nagtegaal, Iris D. (author)
Radboud Universiteit,Radboud University
Laclé, Miangela M. (author)
University Medical Center Utrecht
Moons, Leon M.G. (author)
University Medical Center Utrecht
Brosens, Lodewijk A.A. (author)
University Medical Center Utrecht
Pillay, Nischalan (author)
University College London (UCL)
Sottoriva, Andrea (author)
Graham, Trevor A. (author)
Rodriguez-Justo, Manuel (author)
University College London (UCL)
Shiu, Kai Keen (author)
University College London (UCL)
Snippert, Hugo J.G. (author)
University Medical Center Utrecht
Jansen, Marnix (author)
University College London (UCL)
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 (creator_code:org_t)
2024
2024
English.
In: Nature Genetics. - 1546-1718 .- 1061-4036. ; 56:7, s. 1420 -1433
Related links:
https://research.cha... (primary) (free)
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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