Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

Nicholas Light, Mehdi Layeghifard, Ayush Attery, Vallijah Subasri, Matthew Zatzman, Nathaniel D. Anderson, Rupal Hatkar, Sasha Blay, David Chen, Ana Novokmet, Fabio Fuligni, James Tran, Richard Borja, Himanshi Agarwal, Larissa Waldman, Lisa M. Abegglen, Daniel Albertson, Jonathan L. Finlay, Jordan R. Hansford, Sam Behjati, Anita Villani, Moritz Gerstung, Ludmil B. Alexandrov, Gino R. Somers, Joshua D. Schiffman, Varda Rotter, David Malkin () and Adam Shlien ()
Additional contact information
Nicholas Light: The Hospital for Sick Children
Mehdi Layeghifard: The Hospital for Sick Children
Ayush Attery: The Weizmann Institute of Science
Vallijah Subasri: The Hospital for Sick Children
Matthew Zatzman: The Hospital for Sick Children
Nathaniel D. Anderson: The Hospital for Sick Children
Rupal Hatkar: The Hospital for Sick Children
Sasha Blay: The Hospital for Sick Children
David Chen: The Hospital for Sick Children
Ana Novokmet: The Hospital for Sick Children
Fabio Fuligni: The Hospital for Sick Children
James Tran: The Hospital for Sick Children
Richard Borja: The Hospital for Sick Children
Himanshi Agarwal: The Weizmann Institute of Science
Larissa Waldman: The Hospital for Sick Children
Lisa M. Abegglen: University of Utah
Daniel Albertson: University of Utah School of Medicine
Jonathan L. Finlay: The Ohio State University College of Medicine
Jordan R. Hansford: Royal Children’s Hospital
Sam Behjati: Wellcome Sanger Institute
Anita Villani: The Hospital for Sick Children
Moritz Gerstung: European Molecular Biology Laboratory, European Bioinformatics Institute EMBL-EBI
Ludmil B. Alexandrov: University of California
Gino R. Somers: University of Toronto
Joshua D. Schiffman: University of Utah
Varda Rotter: The Weizmann Institute of Science
David Malkin: The Hospital for Sick Children
Adam Shlien: The Hospital for Sick Children

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.

Date: 2023
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DOI: 10.1038/s41467-022-35727-y

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