Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer
Journal article, 2024
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.
Author
Hamzeh Kayhanian
University College London (UCL)
William Cross
University of Westminster
University College London (UCL)
Suzanne E.M. van der Horst
University Medical Center Utrecht
Panagiotis Barmpoutis
University College London (UCL)
Eszter Lakatos
Chalmers, Mathematical Sciences, Applied Mathematics and Statistics
Giulio Caravagna
University of Trieste
Luis Zapata
Institute of Cancer Research
Arne Van Hoeck
University Medical Center Utrecht
Sjors Middelkamp
Princess Máxima Center for Pediatric Oncology
Kevin Litchfield
University College London (UCL)
Christopher Steele
University College London (UCL)
William Waddingham
University College London (UCL)
Dominic Patel
University College London (UCL)
Salvatore Milite
University of Trieste
Chen Jin
University College London (UCL)
Ann Marie Baker
Institute of Cancer Research
D. C. Alexander
University College London (UCL)
Khurum Khan
University College London (UCL)
Daniel Hochhauser
University College London (UCL)
Marco Novelli
University College London Hospitals NHS Foundation Trust
University College London (UCL)
Benjamin Werner
Barts Cancer Institute
Ruben van Boxtel
University Medical Center Utrecht
Princess Máxima Center for Pediatric Oncology
Joris H. Hageman
University Medical Center Utrecht
Julian R. Buissant des Amorie
University Medical Center Utrecht
Josep Linares
HSL-AD
Marjolijn J.L. Ligtenberg
Radboud University
Iris D. Nagtegaal
Radboud University
Miangela M. Laclé
University Medical Center Utrecht
Leon M.G. Moons
University Medical Center Utrecht
Lodewijk A.A. Brosens
University Medical Center Utrecht
Nischalan Pillay
University College London (UCL)
Andrea Sottoriva
Institute of Cancer Research
Fondazione Human Technopole
Trevor A. Graham
Institute of Cancer Research
Barts Cancer Institute
Manuel Rodriguez-Justo
University College London (UCL)
University College London Hospitals NHS Foundation Trust
Kai Keen Shiu
University College London (UCL)
Hugo J.G. Snippert
University Medical Center Utrecht
Marnix Jansen
University College London Hospitals NHS Foundation Trust
University College London (UCL)
Nature Genetics
1061-4036 (ISSN)
Vol. 56 7 1420 -1433Subject Categories
Cell and Molecular Biology
Cancer and Oncology
DOI
10.1038/s41588-024-01777-9