TY - JOUR
T1 - Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis
AU - Light, Nicholas
AU - Layeghifard, Mehdi
AU - Attery, Ayush
AU - Subasri, Vallijah
AU - Zatzman, Matthew
AU - Anderson, Nathaniel D.
AU - Hatkar, Rupal
AU - Blay, Sasha
AU - Chen, David
AU - Novokmet, Ana
AU - Fuligni, Fabio
AU - Tran, James
AU - de Borja, Richard
AU - Agarwal, Himanshi
AU - Waldman, Larissa
AU - Abegglen, Lisa M.
AU - Albertson, Daniel
AU - Finlay, Jonathan L.
AU - Hansford, Jordan R.
AU - Behjati, Sam
AU - Villani, Anita
AU - Gerstung, Moritz
AU - Alexandrov, Ludmil B.
AU - Somers, Gino R.
AU - Schiffman, Joshua D.
AU - Rotter, Varda
AU - Malkin, David
AU - Shlien, Adam
N1 - Funding Information:
This study was funded with support from the Terry Fox Research Institute New Frontiers Program Project (#1081, A.S. & D.M.) and Canadian Institutes for Health Research Foundation Scheme Grant (#143234, D.M.). We thank the Centre for Applied Genomics (TCAG) NGS facility for their sequencing services. The SickKids Cancer Sequencing (KiCS) program is supported by the Garron Family Cancer Centre with funds from the SickKids Foundation. A.S. is partially supported by an Early Researcher Award from the Ontario Ministry of Research and Innovation, the Canada Research Chair in Childhood Cancer Genomics, funding from the V Foundation and the Robert J. Arceci Innovation Award from the St. Baldrick’s Foundation. D.M. is supported in part by the CIBC Children’s Foundation Chair in Child Health Research. N.L. is supported in part from the University of Toronto MD/PhD program, the McLaughlin Center, a Ruggles Family Innovation Award, and a CIHR MD/PhD Studentship. V.R’s group is supported by the Flight Attendant Medical Research Institute (FAMRI). Figure A, A, B and Supplementary Fig. 14 were created with BioRender.com.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/1/5
Y1 - 2023/1/5
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85145645758
U2 - 10.1038/s41467-022-35727-y
DO - 10.1038/s41467-022-35727-y
M3 - Article
C2 - 36604421
SN - 2041-1723
VL - 14
SP - 77
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 77
ER -