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 de Borja, Himanshi Agarwal, Larissa Waldman, Lisa M. Abegglen, Daniel J. 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, Adam Shlien
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.